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Severe Paediatric Disorders v1.181 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v4.28 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.157 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure in early childhood v3.6 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v3.133 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.87 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.129 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v4.20 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.54 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe Paediatric Disorders v1.180 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.63 MSTO1 Sarah Leigh changed review comment from: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.; to: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).
Retinal disorders v4.63 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: 28554942, 37431817; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.451 ACBD6 Jana Jezkova reviewed gene: ACBD6: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37951597; Phenotypes: HP:0001263, HP:0001249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v3.10 ADA2 Sarah Leigh Publications for gene: ADA2 were set to 3471198, 25528372
Undiagnosed metabolic disorders v1.613 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism - targeted testing not possible v4.129 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Infantile enterocolitis & monogenic inflammatory bowel disease v1.42 PTEN Sarah Leigh edited their review of gene: PTEN: Added comment: Based on the review from Zornitza Stark, this gene has been demoted to amber on this panel.; Changed rating: AMBER
Infantile enterocolitis & monogenic inflammatory bowel disease v1.42 PTEN Sarah Leigh Classified gene: PTEN as Amber List (moderate evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.42 PTEN Sarah Leigh Gene: pten has been classified as Amber List (Moderate Evidence).
Infantile enterocolitis & monogenic inflammatory bowel disease v1.41 PTEN Sarah Leigh Publications for gene: PTEN were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.188 HSPA1L Zornitza Stark reviewed gene: HSPA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: inflammatory bowel disease, MONDO:0005265, HSPA1L-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v4.36 VWA1 Eleanor Williams Classified gene: VWA1 as Amber List (moderate evidence)
Congenital myopathy v4.36 VWA1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber, with a recommendation for consideration for a green rating following expert review as to whether the phenotype fits the scope of the congenital myopathy panel.
Congenital myopathy v4.36 VWA1 Eleanor Williams Gene: vwa1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v4.35 VWA1 Eleanor Williams gene: VWA1 was added
gene: VWA1 was added to Congenital myopathy. Sources: Literature
Q1_24_promote_green, Q1_24_expert_review tags were added to gene: VWA1.
Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA1 were set to 33459760
Phenotypes for gene: VWA1 were set to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977
Added comment: In PMID: 33459760 Deschauer et al 2021 report 15 affected individuals from six families of German, Arabic, and Roma descent with biallelic loss of function variants in VWA1 and a neuromuscular phenotype. In 3 of the families the onset of symptoms was in childhood (ages 2-18yr in F3, ages 2-3yr in F4, and at school age in F5). Muscle biopsies of 3 individuals (F1-II.2, F2-II.1, and F5-II.1) revealed myopathic changes. A 10-bp tandem repeat is duplicated in one variant (p.Gly25Argfs*74]) and deleted in another variant (p.Gly21Alafs*12]). The duplication was found in 3 German families, homozygous in one and compound heterozygous in the other two.

PMID: 33559681 Pagnamenta et al 2021 report 17 individuals from 15 families with an autosomal-recessive, hereditary motor neuropathy and rare biallelic variants in VWA1. The p.(G25Rfs*74) 10-bp repeat expansion was observed in 14/15 families and was homozygous in 10/15. The authors state that the mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations.

Given the young age of onset in some patients and myopathy seen in biopsys this gene may be a candidate for green rating on this panel, subject to expert review.
Sources: Literature
Hereditary neuropathy or pain disorder v3.83 VWA1 Eleanor Williams Phenotypes for gene: VWA1 were changed from Neuropathy, hereditary motor, with myopathic features OMIM:619216; neuropathy, hereditary motor, with myopathic features MONDO:0030977 to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977
Cystic kidney disease v4.24 OFD1 Nour Elkhateeb changed review comment from: OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females. PMID: 10910455.; to: OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females. PMID: 10910455.
Cystic kidney disease v4.24 OFD1 Nour Elkhateeb reviewed gene: OFD1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 10910455; Phenotypes: renal cysts; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.188 SIRT1 Achchuthan Shanmugasundram Phenotypes for gene: SIRT1 were changed from Type 1 diabetes; autoimmune disease to autoimmune disease, MONDO:0007179
Primary immunodeficiency or monogenic inflammatory bowel disease v4.187 SIRT1 Achchuthan Shanmugasundram Publications for gene: SIRT1 were set to PMID: 23473037
Primary immunodeficiency or monogenic inflammatory bowel disease v4.186 SIRT1 Achchuthan Shanmugasundram Classified gene: SIRT1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.186 SIRT1 Achchuthan Shanmugasundram Gene: sirt1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.185 SIRT1 Achchuthan Shanmugasundram reviewed gene: SIRT1: Rating: RED; Mode of pathogenicity: None; Publications: 23473037; Phenotypes: autoimmune disease, MONDO:0007179; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.185 SCGN Achchuthan Shanmugasundram Classified gene: SCGN as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.185 SCGN Achchuthan Shanmugasundram Gene: scgn has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.184 SCGN Achchuthan Shanmugasundram Phenotypes for gene: SCGN were changed from ?early-onset ulcerative colitis to ulcerative colitis, MONDO:0005101
Primary immunodeficiency or monogenic inflammatory bowel disease v4.183 SCGN Achchuthan Shanmugasundram Publications for gene: SCGN were set to PMID: 31663849
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 SCGN Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 SCGN Achchuthan Shanmugasundram reviewed gene: SCGN: Rating: AMBER; Mode of pathogenicity: None; Publications: 31663849; Phenotypes: ulcerative colitis, MONDO:0005101; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v4.46 ATXN2_CAG Jemeen Sreedharan reviewed STR: ATXN2_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20740007, 21479228, 21537950, 21562247; Phenotypes: amyotrophic lateral sclerosis, spinocerebellar ataxia 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Classified gene: HSPA1L as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Gene: hspa1l has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.181 HSPA1L Achchuthan Shanmugasundram Phenotypes for gene: HSPA1L were changed from Inflammatory bowel disease to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v4.180 HSPA1L Achchuthan Shanmugasundram Publications for gene: HSPA1L were set to PMID: 28126021
Primary immunodeficiency or monogenic inflammatory bowel disease v4.179 HSPA1L Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HSPA1L.
Tag Q1_24_NHS_review tag was added to gene: HSPA1L.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.179 HSPA1L Achchuthan Shanmugasundram reviewed gene: HSPA1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 28126021; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.179 CARD8 Achchuthan Shanmugasundram Publications for gene: CARD8 were set to 29408806
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Classified gene: CARD8 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases with heterozygous variants and Inflammatory bowel disease (Crohn disease). Hence, this gene should be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Gene: card8 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.177 CARD8 Achchuthan Shanmugasundram Phenotypes for gene: CARD8 were changed from ?Inflammatory bowel disease (Crohn disease) 30 to ?Inflammatory bowel disease (Crohn disease) 30, OMIM:619079
Primary immunodeficiency or monogenic inflammatory bowel disease v4.176 CARD8 Achchuthan Shanmugasundram Publications for gene: CARD8 were set to PMID: 29408806
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 CARD8 Achchuthan Shanmugasundram reviewed gene: CARD8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Inflammatory bowel disease (Crohn disease) 30, OMIM:619079; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 ANKZF1 Achchuthan Shanmugasundram Classified gene: ANKZF1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: AS there is sufficient evidence for the association of monoallelic variants with infantile-onset inflammatory bowel disease, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 ANKZF1 Achchuthan Shanmugasundram Gene: ankzf1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_moi' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram Tag watchlist_moi tag was added to gene: ANKZF1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram Mode of inheritance for gene: ANKZF1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.173 ANKZF1 Achchuthan Shanmugasundram Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589
Primary immunodeficiency or monogenic inflammatory bowel disease v4.172 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.172 ANKZF1 Achchuthan Shanmugasundram Phenotypes for gene: ANKZF1 were changed from Inflammatory bowel disease to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 ANKZF1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: ANKZF1.
Tag Q1_24_NHS_review tag was added to gene: ANKZF1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 ANKZF1 Achchuthan Shanmugasundram reviewed gene: ANKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302725, 36857589; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (three unrelated cases and functional studies) for the association of this gene with disabling pansclerotic morphea of childhood (MIM #620443) and hence this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram Classified gene: STAT4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram Gene: stat4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.170 STAT4 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: STAT4.
Tag Q1_24_NHS_review tag was added to gene: STAT4.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.170 STAT4 Achchuthan Shanmugasundram changed review comment from: Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that the variants caused a gain-of-function effect.; to: Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that STAT4 variants caused a gain-of-function effect.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.170 STAT4 Achchuthan Shanmugasundram Mode of inheritance for gene: STAT4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.169 STAT4 Achchuthan Shanmugasundram Added comment: Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that the variants caused a gain-of-function effect.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.169 STAT4 Achchuthan Shanmugasundram Mode of pathogenicity for gene: STAT4 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v4.168 STAT4 Achchuthan Shanmugasundram Publications for gene: STAT4 were set to 29029192
Primary immunodeficiency or monogenic inflammatory bowel disease v4.167 STAT4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #612253 & #620443), but not in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.167 STAT4 Achchuthan Shanmugasundram Phenotypes for gene: STAT4 were changed from Paracoccidioidomycosis; Impaired IFN-γ Immunity; {Systemic lupus erythematosus, susceptibility to, 11}, 612253 to Disabling pansclerotic morphea of childhood, OMIM:620443; {Systemic lupus erythematosus, susceptibility to, 11}, OMIM:612253
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 STAT4 Achchuthan Shanmugasundram reviewed gene: STAT4: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37256972; Phenotypes: Disabling pansclerotic morphea of childhood, OMIM:620443, {Systemic lupus erythematosus, susceptibility to, 11}, OMIM:612253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pituitary hormone deficiency v3.9 KCNQ1 Achchuthan Shanmugasundram Tag Q1_24_NHS_review tag was added to gene: KCNQ1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Tag Q1_24_NHS_review tag was added to gene: LACC1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LACC1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Classified gene: LACC1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the association of this gene with juvenile arthritis and hence with this panel. So, this gene should be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Gene: lacc1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.165 LACC1 Achchuthan Shanmugasundram Publications for gene: LACC1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.164 LACC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #618795), but not yet in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.164 LACC1 Achchuthan Shanmugasundram Phenotypes for gene: LACC1 were changed from Juvenile arthritis to Juvenile arthritis, OMIM:618795
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 LACC1 Achchuthan Shanmugasundram reviewed gene: LACC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25220867, 27881174, 29717096, 30872671; Phenotypes: Juvenile arthritis, OMIM:618795; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v3.9 KCNQ1 Achchuthan Shanmugasundram Publications for gene: KCNQ1 were set to 29097701
Pituitary hormone deficiency v3.8 KCNQ1 Achchuthan Shanmugasundram Classified gene: KCNQ1 as Amber List (moderate evidence)
Pituitary hormone deficiency v3.8 KCNQ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously identified variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.
Pituitary hormone deficiency v3.8 KCNQ1 Achchuthan Shanmugasundram Gene: kcnq1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram commented on gene: KCNQ1: As reviewed by Suzanne Page, PMID:36077086 reports two unrelated cases with KCNQ1 variants in addition to the cases previously reported in PMID: 29097701 with pituitary hormone deficiency and maternally inherited gingival fibromatosis. The single individual reported in PMID:36077086 with p.Pro369Leu variant had growth hormone deficiency and postnatal growth retardation in addition to coarse facial features and early-onset gingival overgrowth. However, three members of the other family with p.Val185Met variant had only coarse facial features and early-onset gingival overgrowth.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram reviewed gene: KCNQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36077086; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Deleted their review
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously reported variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.; to: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously identified variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the NHSE.; to: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously reported variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the GLHs.; to: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the NHSE.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Classified gene: KCNQ1 as Amber List (moderate evidence)
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the GLHs.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Gene: kcnq1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v3.6 KCNQ1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNQ1.
Tag Q1_24_expert_review tag was added to gene: KCNQ1.
Pituitary hormone deficiency v3.6 KCNQ1 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNQ1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pituitary hormone deficiency v3.5 KCNQ1 Achchuthan Shanmugasundram reviewed gene: KCNQ1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 36077086; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Nephrocalcinosis or nephrolithiasis v4.13 SLC26A1 Sarah Leigh reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Nephrocalcinosis or nephrolithiasis v4.13 SLC26A1 Sarah Leigh Classified gene: SLC26A1 as Red List (low evidence)
Nephrocalcinosis or nephrolithiasis v4.13 SLC26A1 Sarah Leigh Gene: slc26a1 has been classified as Red List (Low Evidence).
Nephrocalcinosis or nephrolithiasis v4.12 SLC26A1 Sarah Leigh Publications for gene: SLC26A1 were set to 27210743; 20160351; 30383413; 27125215; 24250268
Osteopetrosis v1.34 RASGRP2 Sarah Leigh Tag Q1_24_expert_review tag was added to gene: RASGRP2.
Osteopetrosis v1.34 RASGRP2 Sarah Leigh reviewed gene: RASGRP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Osteopetrosis v1.34 RASGRP2 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: RASGRP2.
Osteopetrosis v1.34 RASGRP2 Sarah Leigh Publications for gene: RASGRP2 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 SIRT1 Hannah Knight gene: SIRT1 was added
gene: SIRT1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIRT1 were set to PMID: 23473037
Phenotypes for gene: SIRT1 were set to Type 1 diabetes; autoimmune disease
Review for gene: SIRT1 was set to RED
Added comment: In PMID: 36634696 (2023) as one of the genes associated with monogenic IBD.
Just one previous report of it causing disease?
PMID: 23473037 (2013) - five individuals in one family found to have a missense SIRT1 variant (p.L107P). Four presented with type 1 diabetes, and one with ulcerative colitis
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 SCGN Hannah Knight gene: SCGN was added
gene: SCGN was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SCGN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCGN were set to PMID: 31663849
Phenotypes for gene: SCGN were set to ?early-onset ulcerative colitis
Review for gene: SCGN was set to RED
Added comment: Not linked to a phenotype in OMIM.
PMID: 31663849 (2019) reported three siblings with early onset UC, all with a homozygous missense variant in SCGN (p.Arg77His). Parents were both heterozygous. Some functional work done
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 LACC1 Hannah Knight gene: LACC1 was added
gene: LACC1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: LACC1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LACC1 were set to Juvenile arthritis
Review for gene: LACC1 was set to GREEN
Added comment: PMID: 25220867 (2015) - in 13 patients and unaffected members of 5 consanguineous Saudi Arabian families with systemic juvenile idiopathic arthritis, a homozygous missense variant in LACC1 was identified (p.C284R). This segregated fully with disease, and haplotype analysis was consistent with a common founder for the 5 families. Systemic features were present including organomegaly, fevers and rashes
PMID: 27881174 (2016) - 2 Lebanese sisters with juvenile arthritis found to have a homozygous 1bp deletion in LACC1 (c.827delC). Present in heterozygosity in their unaffected consanguineous parents, but was not found in 2 unaffected sibs or in the ExAC database
PMID: 29717096 (2018) identified three different families with homozygous LACC1 variants (p.M1I, p.R414X, p.Ile330del)
PMID: 30872671 (2019) - three affected siblings with a homozygous variant (p.Cys43TyrfsTer6)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 HSPA1L Hannah Knight gene: HSPA1L was added
gene: HSPA1L was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: HSPA1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPA1L were set to PMID: 28126021
Phenotypes for gene: HSPA1L were set to Inflammatory bowel disease
Review for gene: HSPA1L was set to AMBER
Added comment: PMID: 28126021 (2017) identified a heterozygous de novo variant (c.830C > T; p.Ser277Leu) in HSPA1L in a patient with IBD + some in vitro testing which supported pathogenicity
Then identified five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients from their IBD cohort
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 CARD8 Hannah Knight gene: CARD8 was added
gene: CARD8 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CARD8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CARD8 were set to PMID: 29408806
Phenotypes for gene: CARD8 were set to ?Inflammatory bowel disease (Crohn disease) 30
Review for gene: CARD8 was set to AMBER
Added comment: On OMIM as ?association.
PMID: 29408806 (2018) identified a heterozygous missense CARD8 variant (V44I) in a boy, his mother, and his maternal aunt with Crohn disease. Not found in the proband's unaffected father. Functional analysis suggested a dominant-negative effect.

PMID: 37724393 (2023) identified a CARD8 VUS in a paediatric patient with IBD and arthritis. Can't see full paper however
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 ANKZF1 Hannah Knight gene: ANKZF1 was added
gene: ANKZF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ANKZF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589
Phenotypes for gene: ANKZF1 were set to Inflammatory bowel disease
Review for gene: ANKZF1 was set to AMBER
Added comment: PMID: 28302725 (2017) identified two infantile-onset IBD patients with biallelic ANKZF1 variants + some functional work:
One homozygous for R585Q - although this variant is very common in gnomAD
One compound heterozygous for E152K and V32_Q87del
Also two patients with one heterozygous variants

PMID: 36857589 (2023) also identified a de novo variant (p.Leu415Val) in a young patient with IBD
Sources: Literature
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh commented on gene: MADD: Apnoea is a feature of DEEAH syndrome (OMIM:619004) and Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (OMIM:619005), both of which are caused by biallelic MADD variants (PMID: 32761064).
Possible mitochondrial disorder - nuclear genes v3.87 BTD Mohamed Nassr commented on gene: BTD
Intellectual disability v5.451 MADD Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
Intellectual disability v5.450 DHX37 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variant have not been associated with intellectual disability.; to: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variants have not been associated with intellectual disability.
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh edited their review of gene: EFEMP1: Added comment: Monoallelic EFEMP1 variants have been associated with Doyne honeycomb degeneration of retina (OMIM:126600). PMIDs 31792352; 32006683; 33807164 report four recessive EFEMP1 variants in three cases with a pronounced connective tissue disorder. PMID: 31792352 also describes a Efemp1 knockout mouse model, with a phenotype that matches the human cases.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: EFEMP1.
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Classified gene: EFEMP1 as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Gene: efemp1 has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v3.10 EFEMP1 Sarah Leigh Publications for gene: EFEMP1 were set to 32006683; 31792352
Growth failure in early childhood v3.6 MSTO1 Suzanne Page changed review comment from: The associated claims regarding the presence of MSTO1 mutation c.22 G > A (p.Val8Met) in the investigated patients and the direct link between this mutation and patients' myopathy and ataxia phenotypes are retracted.; to: The mode of inheritance for this disorder should be changed to Biallelic. The only reported case of autosomal dominant inheritance (PMID 37431817) has been redacted. "The associated claims regarding the presence of MSTO1 mutation c.22 G > A (p.Val8Met) in the investigated patients and the direct link between this mutation and patients' myopathy and ataxia phenotypes are retracted."
Growth failure in early childhood v3.6 MSTO1 Suzanne Page reviewed gene: MSTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37431817; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Pituitary hormone deficiency v3.5 KCNQ1 Suzanne Page changed review comment from: Bauer et al 2022 PMID: 36077086 - Identified a single individual with the KCNQ1 variant P369L and three family members with the V185M variant. All had gingival overgrowth. Tommiska et al 2017 (PMID: 29097701) have already identified 3 families affected with pituitary hormone deficiency and maternally inherited gingival fibromatosis. Bauer et al showed that all 3 variants impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component.; to: Bauer et al 2022 PMID: 36077086 - Identified a single individual with the KCNQ1 variant P369L and three family members with the V185M variant. All had gingival overgrowth. Tommiska et al 2017 (PMID: 29097701) have already identified 3 families affected with pituitary hormone deficiency and maternally inherited gingival fibromatosis. Bauer et al showed that all 3 variants impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. They suggest that the impaired Ca2+ sensitivity of the KCNQ1 mutant channels R116L, V185M and P369L is causally related to their gain-of-function when forming heteromers with KCNE2.
Pituitary hormone deficiency v3.5 KCNQ1 Suzanne Page reviewed gene: KCNQ1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 36077086; Phenotypes: Gingival overgrowth, with or without postnatal growth retardation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.163 SLC5A6 Helen Lord edited their review of gene: SLC5A6: Added comment: PMID 35013551 Holling et al, 2022 - reporting 5 individuals from 3 families with motor neuropathies. Hom variant c.1285A>G p.(Ser429Gly) in 3 aff siblings and a simplex patient; and a third family where proband had a mat inherited c.280C>T p.(Arg94*) and a pat inherited c.485A>G p.(Tyr162Cys). in silico tools suggest missense variants affect function. No mention of epilepsy in any of these individuals.

PMID 38036278 Hsieh et al 2023 - Family with compound het SLC5A6 missense variants reported. No mention of epilepsy in affected individuals.

PMID 38012394 Utsuno et al 2024 - 3 sibs from a Japanese family with periventricular brain cysts and motor developmental delay - all compund het for SLC5A6 missense variants - no mention of epilepsy/seizure in any of these sibs.

PMID 37391029 Montomoli et al 2023 - 3 members of the same family - Patient 2 had a generalised tonic-clonic seizre and EEG showed sharp waves in left centro-temporal region. No mention of seizures at follow up at 24 years of age, and no mention prior to this seizure but lots of other clinical features. All affecteds had a hom fs SLC5A6 variant, parents het. Table summarising cases showed epilepsy in 2/13 case - patient 2 in this paper and the Byrne et al paper.

PMID 31754459 Byrne et al - see review 31/01/2021.

No new evidence to support a stronger link with SLC5A6 and an epilepsy phenotype.; Changed publications to: 35013551, 38036278, 38012394, 37391029, 31754459, 27904971
Early onset or syndromic epilepsy v4.163 CACNB4 Helen Lord edited their review of gene: CACNB4: Added comment: PMID 35813387 - Naseer et al, 2022: WES i one family and targeted sequencing of SCN1A and CACNB4 in 25 sporadic epilepsy patients. 3 different unrelated patients found to have the c.78_79insG variant in CACNB4. Do mention that tecently het CACNB4 mutations are not linked with epilepsy [Heyne et al 2019] and that het mutated animal model did not show any tyoe of deformities [Coba et al, 2012].

Also PMID32176688 - see previous occurence where identifed homozygously.; Changed rating: AMBER; Changed publications to: 35813387
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 STAT4 Hannah Knight reviewed gene: STAT4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37256972; Phenotypes: Disabling pansclerotic morphea of childhood; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from None to None
Intellectual disability v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from Other to None
Intellectual disability v5.449 ABCC9 Tracy Lester edited their review of gene: ABCC9: Added comment: This gene is currently green for monoallelic inheritance but the associated review relates to cases with biallelic inheritance. The MOI for this gene should be amended to biallelic only. Monoallelic variants are associated with Cantu syndrome which is not primarily an ID disorder or DCM.; Changed rating: GREEN
Intellectual disability v5.449 DHX37 Sarah Leigh Tag Q1_24_MOI tag was added to gene: DHX37.
Tag Q1_24_NHS_review tag was added to gene: DHX37.
Intellectual disability v5.449 DHX37 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variant have not been associated with intellectual disability.
Intellectual disability v5.449 DHX37 Sarah Leigh Mode of inheritance for gene: DHX37 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v5.448 DHX37 Sarah Leigh edited their review of gene: DHX37: Added comment: Biallelic DHX37 variants have been associated with Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies (OMIM:618731). Five DHX37 variants have been reported in three unrelated cases of OMIM:618731. Zebra fish models, support the role of DHX37 variants in aberrant behaviors (PMID: 24027265); Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.448 ABCC9 Sarah Leigh Added comment: Comment on mode of pathogenicity: Loss of function variants do cause the phenotype of Intellectual disability and myopathy syndrome (OMIM:619719) , which is relevant to this panel.
Intellectual disability v5.448 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from to Other
Intellectual disability v5.447 DHX37 Sarah Leigh Publications for gene: DHX37 were set to 26539891; 31256877
Intellectual disability v5.446 ABCC9 Sarah Leigh Tag watchlist_moi was removed from gene: ABCC9.
Tag Q1_24_MOI tag was added to gene: ABCC9.
Tag Q1_24_NHS_review tag was added to gene: ABCC9.
Intellectual disability v5.446 ABCC9 Sarah Leigh Phenotypes for gene: ABCC9 were changed from Cardiomyopathy, dilated, 10, 608569; Atrial fibrillation, familial, 12, 614050; Hypertrichotic osteochondrodysplasia, 239850; CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA to Intellectual disability and myopathy syndrome, OMIM:619719; intellectual disability and myopathy syndrome, MONDO:0859224
Intellectual disability v5.445 ABCC9 Sarah Leigh changed review comment from: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872).; to: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872). Heterozygous parents of the cases, did not show a consistent phenotype, although intrauterine death was reported in two families (PMID: 38217872). In family 4 the fetus was homozygous for c.1858C>T, p.(Arg620Ter) and in family 8 the parents were both heterozygous for c.2140_2141del, p.(Leu714SerfsTer7), but analysis of the fetus was not possible.
Intellectual disability v5.445 ABCC9 Sarah Leigh reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 38217872; Phenotypes: Intellectual disability and myopathy syndrome, OMIM:619719, intellectual disability and myopathy syndrome, MONDO:0859224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.445 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858; 38217872
Intellectual disability v5.444 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858
Intellectual disability v5.443 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to
Early onset or syndromic epilepsy v4.163 MADD Sarah Leigh edited their review of gene: MADD: Added comment: Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.; Changed rating: GREEN; Changed publications to: 32761064
Intellectual disability v5.442 MADD Sarah Leigh edited their review of gene: MADD: Added comment: Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.; Changed rating: GREEN; Changed publications to: 32761064
Paediatric or syndromic cardiomyopathy v3.43 CASZ1 Ludmila Volozonoka gene: CASZ1 was added
gene: CASZ1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 36293425; 31268246; 28099117; 27693370; 37509718
Phenotypes for gene: CASZ1 were set to Pediatric Dilated Cardiomyopathy; Pediatric LVNC
Review for gene: CASZ1 was set to GREEN
Added comment: Loss of Function variants described in patients with pediatric dilated cardiomyopathy, pediatric LVNC (36293425; 31268246). Our laboratory identified the LOF variant in a pediatric patient with LVNC.

The limited implication in congenital ventricular septal defect (27693370) - authors identified a missense variant.

Review article on CASZ1 (37509718).
Sources: Literature
Left Ventricular Noncompaction Cardiomyopathy v1.4 CASZ1 Ludmila Volozonoka gene: CASZ1 was added
gene: CASZ1 was added to Left Ventricular Noncompaction Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 36293425; 31268246; 28099117; 27693370; 37509718
Phenotypes for gene: CASZ1 were set to Pediatric Cardiomyopathy; Pediatric LVNC
Review for gene: CASZ1 was set to GREEN
Added comment: Loss of Function variants described in patients with pediatric dilated cardiomyopathy, pediatric LVNC (36293425; 31268246), as well as in adults (28099117).
The limited implication in congenital ventricular septal defect (27693370) - authors identified a missense variant.
Review article on CASZ1 (37509718).
Our laboratory identified LOF variant in a pediatric patient with LVNC.
Sources: Literature
Retinal disorders v4.63 UBAP1L Achchuthan Shanmugasundram Classified gene: UBAP1L as Amber List (moderate evidence)
Retinal disorders v4.63 UBAP1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are five unrelated cases with four different UBAP1L variants reported with either Rod-cone dystrophy, cone-rod dystrophy or retinitis pigmentosa. Hence, this gene should be promoted to green rating in the next GMS review.
Retinal disorders v4.63 UBAP1L Achchuthan Shanmugasundram Gene: ubap1l has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.62 UBAP1L Achchuthan Shanmugasundram Phenotypes for gene: UBAP1L were changed from Retinitis pigmentosa to Rod-cone dystrophy, HP:0000510; cone-rod dystrophy, MONDO:0015993; retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.61 UBAP1L Achchuthan Shanmugasundram Publications for gene: UBAP1L were set to 28041643
Retinal disorders v4.60 UBAP1L Achchuthan Shanmugasundram Mode of inheritance for gene: UBAP1L was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.59 UBAP1L Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: UBAP1L.
Tag Q1_24_NHS_review tag was added to gene: UBAP1L.
Retinal disorders v4.59 UBAP1L Achchuthan Shanmugasundram edited their review of gene: UBAP1L: Changed phenotypes to: Rod-cone dystrophy, HP:0000510, cone-rod dystrophy, MONDO:0015993, retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.59 UBAP1L Achchuthan Shanmugasundram reviewed gene: UBAP1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Rod-cone dystrophy, HP:0000510, cone-rod dystrophy, MONDO:0015993; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.59 RAX2 Achchuthan Shanmugasundram Publications for gene: RAX2 were set to
Retinal disorders v4.58 RAX2 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic RAX2 variants with retinitis pigmentosa. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.; to: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic RAX2 variants with retinitis pigmentosa. Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Retinal disorders v4.58 RAX2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic RAX2 variants with retinitis pigmentosa. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Retinal disorders v4.58 RAX2 Achchuthan Shanmugasundram Mode of inheritance for gene: RAX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v4.57 RAX2 Achchuthan Shanmugasundram Phenotypes for gene: RAX2 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Macular Degeneration; Eye Disorders; Cone-Rod Dystrophy, Dominant; Cone-rod dystrophy 11 to Cone-rod dystrophy 11, OMIM:610381; Retinitis pigmentosa 95, OMIM:620102; ?Macular degeneration, age-related, 6, OMIM:613757
Retinal disorders v4.56 RAX2 Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: RAX2.
Retinal disorders v4.56 RAX2 Achchuthan Shanmugasundram reviewed gene: RAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30377383, 30607024; Phenotypes: Cone-rod dystrophy 11, OMIM:610381, Retinitis pigmentosa 95, OMIM:620102, ?Macular degeneration, age-related, 6, OMIM:613757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v5.442 KIRREL3 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: KIRREL3.
Intellectual disability v5.442 KIRREL3 Sarah Leigh Phenotypes for gene: KIRREL3 were changed from Mental retardation, autosomal dominant 4, 612581; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4) to Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947
Intellectual disability v5.441 KIRREL3 Sarah Leigh changed review comment from: At least 15 missense KIRREL3 variants have been reported in 17 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 19012874; 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, lists KIRREL3 variants and demonstrates that the variants maybe either de novo (9/16) or inherited from one of the parents (7/9). (PMID: 37605258). The KIRREL3 variants are either absent from control databases or are present at a very low frequency.; to: At least 12 missense KIRREL3 variants have been reported in 12 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, reviews KIRREL3 variants and demonstrates that the variants maybe either de novo (4/11) or inherited from one of the parents (7/11)(mode of inheritance was unknown for one of the variants). The KIRREL3 variants are either absent from controls or are present at a very low frequency. However, the three variants reported in PMID: 19012874, were shown to be present in publicly databases at a high frequency (see KIRREL3 OMIM entry).
Intellectual disability v5.441 KIRREL3 Sarah Leigh Classified gene: KIRREL3 as Amber List (moderate evidence)
Intellectual disability v5.441 KIRREL3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.441 KIRREL3 Sarah Leigh Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.440 KIRREL3 Sarah Leigh reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29271092; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.440 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092; 37605258
Intellectual disability v5.439 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092:37605258
Intellectual disability v5.438 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 37605258
Intellectual disability v5.437 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 33853164; 37605258
Intellectual disability v5.436 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164
Intellectual disability v5.435 KIRREL3 Sarah Leigh Mode of inheritance for gene: KIRREL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pigmentary skin disorders v3.10 LMNA Sarah Leigh Tag Q1_24_promote_green tag was added to gene: LMNA.
Tag Q1_24_NHS_review tag was added to gene: LMNA.
Pigmentary skin disorders v3.10 LMNA Sarah Leigh edited their review of gene: LMNA: Added comment: LMNA variants have been associated with various conditions, including Hutchinson-Gilford progeria (OMIM:176670) and Mandibuloacral dysplasia (OMIM:248370). Skin mottling has been reported in both of these conditions, and hyper and hypopigmentation is a feature of Mandibuloacral dysplasia (OMIM:248370). Numerous LMNA variants have been reported in these conditions.; Changed rating: GREEN
Pigmentary skin disorders v3.10 LMNA Sarah Leigh Classified gene: LMNA as Amber List (moderate evidence)
Pigmentary skin disorders v3.10 LMNA Sarah Leigh Gene: lmna has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v3.9 LMNA Sarah Leigh Added comment: Comment on mode of inheritance: Hutchinson-Gilford progeria, OMIM:176670 is monoallelic, Mandibuloacral dysplasia, OMIM:248370 is biallelic
Pigmentary skin disorders v3.9 LMNA Sarah Leigh Mode of inheritance for gene: LMNA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pigmentary skin disorders v3.8 LMNA Sarah Leigh Phenotypes for gene: LMNA were changed from Hutchinson-Gilford progeria syndrome (HGPS) (MIM 176670); Mandibuloacral dysplasia with type A lipodystrophy (MADA) to Hutchinson-Gilford progeria, OMIM:176670; Hutchinson-Gilford progeria syndrome, MONDO:0008310; Mandibuloacral dysplasia, OMIM:248370; mandibuloacral dysplasia with type A lipodystrophy MONDO:0009557
Pigmentary skin disorders v3.7 LMNA Sarah Leigh Publications for gene: LMNA were set to PMID: 12714972; https://www.ncbi.nlm.nih.gov/books/NBK1121/#; 12075506; 17848409
Retinal disorders v4.56 UBAP1L Hannah Knight reviewed gene: UBAP1L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38293907, PMID: 28041643; Phenotypes: Rod-cone dystrophy, cone-rod dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 LCP2 Hannah Knight reviewed gene: LCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37211057, PMID: 36474126; Phenotypes: ?Immunodeficiency 81; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v3.24 PHYH Sarah Leigh Phenotypes for gene: PHYH were changed from Refsum disease to Refsum disease, OMIM:266500
Palmoplantar keratodermas v3.23 PHYH Sarah Leigh reviewed gene: PHYH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.23 PHYH Sarah Leigh Tag Q1_24_demote_red tag was added to gene: PHYH.
Tag Q1_24_expert_review tag was added to gene: PHYH.
Palmoplantar keratodermas v3.23 SLC27A4 Sarah Leigh Tag Q1_24_expert_review tag was added to gene: SLC27A4.
Palmoplantar keratodermas v3.23 SLC27A4 Sarah Leigh Phenotypes for gene: SLC27A4 were changed from Ichthyosis prematurity syndrome to Ichthyosis prematurity syndrome, OMIM:608649
Palmoplantar keratodermas v3.22 SLC27A4 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: SLC27A4.
Palmoplantar keratodermas v3.22 SLC27A4 Sarah Leigh reviewed gene: SLC27A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 POPDC3 Sarah Leigh Classified gene: POPDC3 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 POPDC3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 POPDC3 Sarah Leigh Gene: popdc3 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.29 POPDC3 Sarah Leigh Tag watchlist was removed from gene: POPDC3.
Tag Q1_24_promote_green tag was added to gene: POPDC3.
Tag Q1_24_NHS_review tag was added to gene: POPDC3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.29 POPDC3 Sarah Leigh reviewed gene: POPDC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.29 POPDC3 Sarah Leigh Phenotypes for gene: POPDC3 were changed from Muscular dystrophy, limb-girdle, autosomal recessive 26, OMIM:618848 to Muscular dystrophy, limb-girdle, autosomal recessive 26, OMIM:618848; muscular dystrophy, limb-girdle, autosomal recessive 26, MONDO:0030014
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.28 POPDC3 Sarah Leigh Publications for gene: POPDC3 were set to 31610034
Likely inborn error of metabolism - targeted testing not possible v4.129 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 27604308
Undiagnosed metabolic disorders v1.613 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 27604308
Congenital disorders of glycosylation v4.18 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 18455129; 18452889; 26864433; 27148795
Intellectual disability v5.434 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to
Likely inborn error of metabolism - targeted testing not possible v4.128 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from TUSC3-CDG (Disorders of protein N-glycosylation); Mental retardation, autosomal recessive 7 to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Fetal anomalies v3.133 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Undiagnosed metabolic disorders v1.612 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from TUSC3-CDG (Disorders of protein N-glycosylation); Mental retardation, autosomal recessive 7 to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Congenital disorders of glycosylation v4.17 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from Mental retardation, autosomal recessive 7 611093; TUSC3-CDG (Disorders of protein N-glycosylation) to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Intellectual disability v5.433 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from Mental retardation, autosomal recessive 7, 611093; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 (MRT7) to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Intellectual disability v5.432 CC2D1A Arina Puzriakova Publications for gene: CC2D1A were set to
Retinal disorders v4.56 LRRC32 Hannah Knight gene: LRRC32 was added
gene: LRRC32 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to PMID: 30976112; PMID: 35656379
Phenotypes for gene: LRRC32 were set to Cleft palate, proliferative retinopathy, and developmental delay
Review for gene: LRRC32 was set to AMBER
Added comment: PMID: 30976112 - homozygous founder variant (p.R544X) identified in two consanguineous families of Palestinian descent - sister and brother, and an unrelated boy. All with cleft palate, proliferative retinopathy, and developmental delay. Segregated with disease in both families.
PMID: 35656379 - rare homozygous missense in a patient who presented with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy
Sources: Literature
Intellectual disability v5.431 CC2D1A Arina Puzriakova Phenotypes for gene: CC2D1A were changed from Mental retardation, autosomal recessive 3, 608443; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 (MRT3) to Intellectual developmental disorder, autosomal recessive 3, OMIM:608443
Fetal anomalies v3.132 CC2D1A Arina Puzriakova Phenotypes for gene: CC2D1A were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 to Intellectual developmental disorder, autosomal recessive 3, OMIM:608443
White matter disorders and cerebral calcification - narrow panel v3.31 RARS Arina Puzriakova Publications for gene: RARS were set to 24777941; 27564080
Intellectual disability v5.430 RARS Arina Puzriakova Publications for gene: RARS were set to 31814314; 28905880; 24777941; 30500859
Intellectual disability v5.429 LRRC32 Hannah Knight reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.179 RARS Arina Puzriakova Publications for gene: RARS were set to 24777941; 27564080
Early onset or syndromic epilepsy v4.163 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Inherited white matter disorders v1.178 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
White matter disorders and cerebral calcification - narrow panel v3.30 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Intellectual disability v5.429 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Intellectual disability v5.428 ASPM Arina Puzriakova Publications for gene: ASPM were set to
Severe microcephaly v4.59 ASPM Arina Puzriakova Publications for gene: ASPM were set to
Malformations of cortical development v4.23 ASPM Arina Puzriakova Publications for gene: ASPM were set to 12355089
Fetal anomalies v3.131 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from PRIMARY AUTOSOMAL RECESSIVE MICROCEPHALY to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Intellectual disability v5.427 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive, 608716; PRIMARY AUTOSOMAL RECESSIVE MICROCEPHALY to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Severe microcephaly v4.58 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive; MCPH; primary microcephaly; Primary Microcephaly, Recessive; Autosomal recessive primary microcephaly (MCPH) ; Microcephaly 5, primary, autosomal recessive, 608716; Microcephaly 5, Primary, Autosomal Recessive to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Malformations of cortical development v4.22 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive 608716 to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Intellectual disability v5.426 RARS Arina Puzriakova Publications for gene: RARS were set to 31814314; 28905880; 24777941
Malformations of cortical development v4.21 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Early onset or syndromic epilepsy v4.162 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to 21834044; 20890278; 20729831; 28377545
Severe microcephaly v4.57 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Intellectual disability v5.425 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Intellectual disability v5.424 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly, Cortical Malformations, and Mental Retardation; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; MICROCEPHALY CORTICAL MALFORMATIONS AND MENTAL RETARDATION (MCMMR) to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Early onset or syndromic epilepsy v4.161 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Severe microcephaly v4.56 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from MCPH; primary microcephaly; Primary Microcephaly 2 With or Without Cortical Malformations; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; microcephaly cortical malformations and mental retardation (MCMMR), 604317; Microcephaly 2, Primary, Autosomal Recessive, With Or Without Cortical Malformations to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Malformations of cortical development v4.20 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations 604317 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Intellectual disability v5.423 MCPH1 Arina Puzriakova Publications for gene: MCPH1 were set to
Severe microcephaly v4.55 MCPH1 Arina Puzriakova Publications for gene: MCPH1 were set to
Intellectual disability v5.422 MCPH1 Arina Puzriakova Phenotypes for gene: MCPH1 were changed from genetic heterogeneity Microcephaly 1, primary, autosomal recessive, 251200; MICROCEPHALY PRIMARY TYPE 1 (MCPH1) to Microcephaly 1, primary, autosomal recessive, OMIM:251200
Severe microcephaly v4.54 MCPH1 Arina Puzriakova Phenotypes for gene: MCPH1 were changed from MCPH; primary microcephaly; Primary Microcephaly, Recessive; Microcephaly 1, primary, autosomal recessive, 251200; Microcephaly 1, Primary, Autosomal Recessive to Microcephaly 1, primary, autosomal recessive, OMIM:251200
Early onset or syndromic epilepsy v4.160 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - seizures can be a reported feature of HSD10 disease (PMID: 12872843; 22132097; 26950678; 27295195; 34765396)
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.19 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Optic neuropathy v4.18 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Optic neuropathy v4.18 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - optic nerve atrophy with visual loss can be a reported feature of HSD10 disease (PMIDs: 22132097; 26950678; 27295195)
Optic neuropathy v4.18 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.71 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova changed review comment from: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 31654490); to: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 27295195; 31654490)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 31654490)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.69 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
Childhood onset dystonia, chorea or related movement disorder v3.68 HSD17B10 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: HSD17B10.
Childhood onset dystonia, chorea or related movement disorder v3.68 HSD17B10 Arina Puzriakova reviewed gene: HSD17B10: Rating: GREEN; Mode of pathogenicity: None; Publications: 19706438, 22132097, 12696021, 26950678, 27604308, 12872843, 12555940; Phenotypes: HSD10 mitochondrial disease, OMIM:300438; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Optic neuropathy v4.17 HSD17B10 Arina Puzriakova gene: HSD17B10 was added
gene: HSD17B10 was added to Optic neuropathy. Sources: Literature
Q1_24_promote_green tags were added to gene: HSD17B10.
Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Phenotypes for gene: HSD17B10 were set to HSD10 mitochondrial disease, OMIM:300438
Review for gene: HSD17B10 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for intellectual development disorder syndromic X-linked type 10. Multiple unrelated individuals (at least 8 variants) with supportive functional studies reported in the literature, including some affected female carriers presenting with mild to moderate developmental delay or intellectual disability.
Phenotype in severely affected males comprises developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation.
Sources: Literature
Early onset or syndromic epilepsy v4.158 HSD17B10 Arina Puzriakova gene: HSD17B10 was added
gene: HSD17B10 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_24_promote_green tags were added to gene: HSD17B10.
Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Phenotypes for gene: HSD17B10 were set to HSD10 mitochondrial disease, OMIM:300438
Review for gene: HSD17B10 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for intellectual development disorder syndromic X-linked type 10. Multiple unrelated individuals (at least 8 variants) with supportive functional studies reported in the literature, including some affected female carriers presenting with mild to moderate developmental delay or intellectual disability.
Phenotype in severely affected males comprises developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation.
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v4.127 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308
Intellectual disability v5.421 HSD17B10 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'XL, biallelic in females' to 'XL, monoallelic in females' as female patients harbouring heterozygous variants have been described. Some carrier females shown to have mild to moderate developmental delay or intellectual disability (PMIDs: 12112118; 16148061; 22127393; 34765396)
Intellectual disability v5.421 HSD17B10 Arina Puzriakova Mode of inheritance for gene: HSD17B10 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v5.420 HSD17B10 Arina Puzriakova Tag Q1_24_MOI tag was added to gene: HSD17B10.
Childhood onset dystonia, chorea or related movement disorder v3.68 HSD17B10 Arina Puzriakova Mode of inheritance for gene: HSD17B10 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v5.420 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
Possible mitochondrial disorder - nuclear genes v3.87 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
Mitochondrial disorders v4.157 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease 300438 to HSD10 mitochondrial disease, OMIM:300438
Intellectual disability v5.419 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from 17-beta-hydroxysteroid dehydrogenase X deficiency, 300438Mental retardation, X-linked syndromic 10, 300220Mental retardation, X-linked 17/31, microduplication, 300705; 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY (MHBD DEFICIENCY) to HSD10 mitochondrial disease, OMIM:300438
Childhood onset dystonia, chorea or related movement disorder v3.67 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from to HSD10 mitochondrial disease, OMIM:300438
Likely inborn error of metabolism - targeted testing not possible v4.126 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease 300438 to HSD10 mitochondrial disease, OMIM:300438
Possible mitochondrial disorder - nuclear genes v3.86 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease, 300438 to HSD10 mitochondrial disease, OMIM:300438
Undiagnosed metabolic disorders v1.611 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease 300438 to HSD10 mitochondrial disease, OMIM:300438
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Classified gene: COL4A3BP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Gene: col4a3bp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova commented on gene: COL4A3BP: Added new-gene-name tag, new approved HGNC gene symbol for COL4A3BP is CERT1
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova Tag new-gene-name tag was added to gene: COL4A3BP.
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova gene: COL4A3BP was added
gene: COL4A3BP was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_24_promote_green tags were added to gene: COL4A3BP.
Mode of inheritance for gene: COL4A3BP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Phenotypes for gene: COL4A3BP were set to Intellectual developmental disorder, autosomal dominant 34, OMIM:616351
Review for gene: COL4A3BP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and in Gene2Phenotype (definitive disease confidence category for CERT1-related INTELLECTUAL DISABILITY)

At least 35 cases have been reported in literature with heterozygous variants. Seizures were observed in at least 19 individuals.
Sources: Literature
Intellectual disability v5.418 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Intellectual disability v5.417 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Intellectual disability v5.417 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962; 33347465
Intellectual disability v5.416 COL4A3BP Arina Puzriakova Phenotypes for gene: COL4A3BP were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder, autosomal dominant 34, OMIM:616351
Intellectual disability v5.415 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore changed review comment from: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines. ; to: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines.
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore changed review comment from: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign). Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.; to: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines.
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore reviewed gene: PLD1: Rating: RED; Mode of pathogenicity: Other; Publications: PMIDs: 27799408 and 33645542; Phenotypes: Paediatric cardiomyopathy, cardiac valvular defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary neuropathy or pain disorder v3.82 GAN Tracy Lester reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301315; Phenotypes: neuropathy, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.414 GAN Tracy Lester reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301315; Phenotypes: Intellectual disability, developmental delay, neuropathy, hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 AMFR Boaz Palterer gene: AMFR was added
gene: AMFR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: AMFR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AMFR were set to 38277122
Phenotypes for gene: AMFR were set to Severe VZV; Varicella; HLH; Hemophagocytic lymphohistyocytosis
Penetrance for gene: AMFR were set to Incomplete
Review for gene: AMFR was set to RED
Added comment: 1 patient from one kindred with severe disseminated VZV and HLH, incomplete penetrance as mother and siblings are not affected. Extensive functional ex-vivo and in-vitro data.
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v4.125 GSTZ1 Achchuthan Shanmugasundram Classified gene: GSTZ1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.125 GSTZ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:27876694 and reviewed by Saikat Santra, there are three boys and three girls with maleylacetoacetate isomerase deficiency (MAAID), identified by newborn screening with mildly elevated succinylacetone (SA) by mass spectrometry on dried blood spot.

Four of them were identified with homozygous GSTZ1 variants, one with compound heterozygous variants and one with heterozygous variant.

Hence, there is sufficient evidence available for the association of biallelic GSTZ1 variants with MAAID and this gene can be promoted to green rating in the next GMS review.
Likely inborn error of metabolism - targeted testing not possible v4.125 GSTZ1 Achchuthan Shanmugasundram Gene: gstz1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.124 GSTZ1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with maleylacetoacetate isomerase deficiency in OMIM (MIM #617596), but not with any phenotypes in Gene2Phenotype.
Likely inborn error of metabolism - targeted testing not possible v4.124 GSTZ1 Achchuthan Shanmugasundram Phenotypes for gene: GSTZ1 were changed from Biochemical to [Maleylacetoacetate isomerase deficiency], OMIM:617596
Likely inborn error of metabolism - targeted testing not possible v4.123 GSTZ1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: GSTZ1.
Tag Q1_24_NHS_review tag was added to gene: GSTZ1.
Likely inborn error of metabolism - targeted testing not possible v4.123 GSTZ1 Achchuthan Shanmugasundram reviewed gene: GSTZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: [Maleylacetoacetate isomerase deficiency], OMIM:617596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Classified gene: KCNA3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:37964487 and reviewed by Gavin Ryan, epilepsy was present in eight of twelve patients for whom detailed clinical information was available. Hence, this gene can be promoted to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Gene: kcna3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.154 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Intellectual disability; Developmental Delay; Epilepsy to Neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.153 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to PMID: 37964487
Early onset or syndromic epilepsy v4.152 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA3.
Tag Q1_24_NHS_review tag was added to gene: KCNA3.
Early onset or syndromic epilepsy v4.152 KCNA3 Achchuthan Shanmugasundram reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.414 KCNA3 Achchuthan Shanmugasundram Classified gene: KCNA3 as Amber List (moderate evidence)
Intellectual disability v5.414 KCNA3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:37964487 and reviewed by Gavin Ryan, 12 patients had developmental delays, of which nine patients had mild, moderate or severe intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.414 KCNA3 Achchuthan Shanmugasundram Gene: kcna3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.413 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.413 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.413 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Intellectual disability; Developmental Delay; Epilepsy to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.412 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to 37964487
Intellectual disability v5.412 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to PMID: 37964487
Intellectual disability v5.411 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_NHS_review tag was added to gene: KCNA3.
Intellectual disability v5.411 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA3.
Intellectual disability v5.411 KCNA3 Achchuthan Shanmugasundram reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.82 HMBS Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (three unrelated families) for the association of biallelic HMBS variants with peripheral neuropathy. Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Hereditary neuropathy or pain disorder v3.82 HMBS Achchuthan Shanmugasundram Mode of inheritance for gene: HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.81 HMBS Achchuthan Shanmugasundram Phenotypes for gene: HMBS were changed from AIP, Abdominal pain, psychosis, depression, seizures, axonal predominantly motor neuropathy; Porphyria, acute intermittent, 176000 to Porphyria, acute intermittent, OMIM:76000; Porphyria, acute intermittent, nonerythroid variant, OMIM:176000; Leukoencephalopathy, HP:0002352; hereditary peripheral neuropathy, MONDO:0020127
Hereditary neuropathy or pain disorder v3.80 HMBS Achchuthan Shanmugasundram edited their review of gene: HMBS: Changed phenotypes to: Porphyria, acute intermittent, OMIM:76000, Porphyria, acute intermittent, nonerythroid variant, OMIM:176000, Leukoencephalopathy, HP:0002352, hereditary peripheral neuropathy, MONDO:0020127
Hereditary neuropathy or pain disorder v3.80 HMBS Achchuthan Shanmugasundram Publications for gene: HMBS were set to
Hereditary neuropathy or pain disorder v3.79 HMBS Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: HMBS.
Hereditary neuropathy or pain disorder v3.79 HMBS Achchuthan Shanmugasundram reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27558376, 34089223; Phenotypes: Leukoencephalopathy, HP:0002352, hereditary peripheral neuropathy, MONDO:0020127; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with ataxia. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: There are three unrelated families reported with ataxia. Hence, this gene can be promoted to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram Classified gene: HMBS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with ataxia. Hence, this gene can be promoted to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram Gene: hmbs has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.53 HMBS Achchuthan Shanmugasundram Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064 to Leukoencephalopathy, HP:0002352; cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - narrow panel v4.52 HMBS Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HMBS.
Ataxia and cerebellar anomalies - narrow panel v4.52 HMBS Achchuthan Shanmugasundram edited their review of gene: HMBS: Changed phenotypes to: Leukoencephalopathy, HP:0002352, cerebellar ataxia, MONDO:0000437
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Classified gene: HMBS as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with spastic paraparesis. Hence, this gene can be promoted to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Gene: hmbs has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.38 HMBS Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HMBS.
Ataxia and cerebellar anomalies - narrow panel v4.52 HMBS Achchuthan Shanmugasundram gene: HMBS was added
gene: HMBS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: HMBS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMBS were set to 27558376; 34089223
Phenotypes for gene: HMBS were set to Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064
Review for gene: HMBS was set to GREEN
Added comment: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.38 HMBS Achchuthan Shanmugasundram gene: HMBS was added
gene: HMBS was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: HMBS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMBS were set to 27558376; 34089223
Phenotypes for gene: HMBS were set to Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064
Review for gene: HMBS was set to GREEN
Added comment: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v3.29 HMBS Achchuthan Shanmugasundram Classified gene: HMBS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v3.29 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with white matter abnormalities. Hence, this gene can be promoted to green rating in the next GMS review.
White matter disorders and cerebral calcification - narrow panel v3.29 HMBS Achchuthan Shanmugasundram Gene: hmbs has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v3.28 HMBS Achchuthan Shanmugasundram Phenotypes for gene: HMBS were changed from to Leukoencephalopathy, HP:0002352
White matter disorders and cerebral calcification - narrow panel v3.27 HMBS Achchuthan Shanmugasundram Publications for gene: HMBS were set to 27558376, 27271711
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HMBS.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram changed review comment from: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene has been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram changed review comment from: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

; to: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene has been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram changed review comment from: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported three patients from two unrelated families with; to: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27558376, 34089223; Phenotypes: Leukoencephalopathy, HP:0002352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.411 LGI3 Achchuthan Shanmugasundram changed review comment from: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotypes in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram changed review comment from: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.

Distal deformities included knee, hip, and ankle contractures (4/14); contractures/deformities of fingers and feet (6/14); and other uncharacterized deformities (4/14). All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.

Distal deformities included knee, hip, and ankle contractures (4/14); contractures/deformities of fingers and feet (6/14); and other uncharacterized deformities (4/14). All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotypes in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram Classified gene: LGI3 as Amber List (moderate evidence)
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram Gene: lgi3 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v5.21 LGI3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LGI3.
Arthrogryposis v5.21 LGI3 Achchuthan Shanmugasundram gene: LGI3 was added
gene: LGI3 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Review for gene: LGI3 was set to GREEN
Added comment: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.

Distal deformities included knee, hip, and ankle contractures (4/14); contractures/deformities of fingers and feet (6/14); and other uncharacterized deformities (4/14). All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.411 LGI3 Achchuthan Shanmugasundram Classified gene: LGI3 as Amber List (moderate evidence)
Intellectual disability v5.411 LGI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated families and mouse model) for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.411 LGI3 Achchuthan Shanmugasundram Gene: lgi3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.410 LGI3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LGI3.
Intellectual disability v5.410 LGI3 Achchuthan Shanmugasundram gene: LGI3 was added
gene: LGI3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Review for gene: LGI3 was set to GREEN
Added comment: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v4.50 TP53 Sarah Leigh Classified gene: TP53 as Red List (low evidence)
Skeletal dysplasia v4.50 TP53 Sarah Leigh Gene: tp53 has been classified as Red List (Low Evidence).
Skeletal dysplasia v4.49 TP53 Sarah Leigh edited their review of gene: TP53: Added comment: This gene is rated as red, because the variants are somatic, occurring in the tumour.; Changed rating: RED
Skeletal dysplasia v4.49 TP53 Sarah Leigh changed review comment from: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.
This gene is rated as red, because the variants are somatic, occurring in the tumour.; to: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.
Skeletal dysplasia v4.49 TP53 Sarah Leigh changed review comment from: PMID: 33147331 reports inactivating TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in
tumorigenesis, giving rise to the dedifferentiated component in DDCS.; to: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.
This gene is rated as red, because the variants are somatic, occurring in the tumour.
Skeletal dysplasia v4.49 IDH2 Sarah Leigh Deleted their comment
Skeletal dysplasia v4.49 IDH2 Sarah Leigh Classified gene: IDH2 as Red List (low evidence)
Skeletal dysplasia v4.49 IDH2 Sarah Leigh Gene: idh2 has been classified as Red List (Low Evidence).
Skeletal dysplasia v4.48 IDH2 Sarah Leigh changed review comment from: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as amber, because the variants are somatic, occurring in the tumour.; to: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as red, because the variants are somatic, occurring in the tumour.
Early onset or syndromic epilepsy v4.152 KCNA3 Gavin Ryan gene: KCNA3 was added
gene: KCNA3 was added to Early onset or syndromic epilepsy. Sources: Expert Review
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA3 were set to PMID: 37964487
Phenotypes for gene: KCNA3 were set to Intellectual disability; Developmental Delay; Epilepsy
Penetrance for gene: KCNA3 were set to unknown
Review for gene: KCNA3 was set to GREEN
Added comment: Soldovieri et al identified 14 de novo missense variants in KCNA3 gene. The majority of individuals presented with ID, developmental delay, and epilepsy, amongst other features. Functional studies showed loss-of-function effects for some variants and possible gain-of-function for others. One of these variants has also been identified in NHS GMS WGS patient with consistent features.
Sources: Expert Review
Intellectual disability v5.409 KCNA3 Gavin Ryan gene: KCNA3 was added
gene: KCNA3 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA3 were set to PMID: 37964487
Phenotypes for gene: KCNA3 were set to Intellectual disability; Developmental Delay; Epilepsy
Penetrance for gene: KCNA3 were set to unknown
Review for gene: KCNA3 was set to GREEN
Added comment: Soldovieri et al identified 14 de novo missense variants in KCNA3 gene. The majority of individuals presented with ID, developmental delay, and epilepsy, amongst other features. Functional studies showed loss-of-function effects for some variants and possible gain-of-function for others. One of these variants has also been identified in NHS GMS WGS patient with consistent features.
Sources: Expert Review
Intellectual disability v5.409 BAZ2B Dmitrijs Rots gene: BAZ2B was added
gene: BAZ2B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: BAZ2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAZ2B were set to PMID: 31999386
Phenotypes for gene: BAZ2B were set to developmental delay, intellectual disability and autism spectrum disorder
Review for gene: BAZ2B was set to GREEN
Added comment: BAZ2B gene is intolerant to LoF variants in population (pLI=1) and PMID: 31999386 described that de novo LoF variants are statistically enriched among NDD cases & summarize 10 cases. Enough evidence for the green rating.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v3.21 FCGR3B Dmitrijs Rots reviewed gene: FCGR3B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v4.53 ZNF335 Dmitrijs Rots reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.409 ABCC9 Tracy Lester reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ectodermal dysplasia v3.28 LEF1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are four unrelated families reported with monoallelic variants and a single individual reported with biallelic variants. Hence, this gene should be promoted to green rating in the next GMS review and the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.; to: Comment on list classification: There are four unrelated families reported with monoallelic variants and a single individual reported with biallelic variants. Hence, this gene should be promoted to green rating in the next GMS review and the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Ectodermal dysplasia v3.28 LEF1 Achchuthan Shanmugasundram Classified gene: LEF1 as Amber List (moderate evidence)
Ectodermal dysplasia v3.28 LEF1 Achchuthan Shanmugasundram Gene: lef1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v3.27 LEF1 Achchuthan Shanmugasundram Classified gene: LEF1 as Red List (low evidence)
Ectodermal dysplasia v3.27 LEF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with monoallelic variants and a single individual reported with biallelic variants. Hence, this gene should be promoted to green rating in the next GMS review and the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Ectodermal dysplasia v3.27 LEF1 Achchuthan Shanmugasundram Gene: lef1 has been classified as Red List (Low Evidence).
Ectodermal dysplasia v3.26 LEF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Germline variants in this gene have not yet been associated with any phenotypes in OMIM, but monoallelic variants have been associated with LEF1-related ectodermal dysplasia and limb malformation in Gene2Phenotype ('moderate' rating on the DD panel).
Ectodermal dysplasia v3.26 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from ectodermal dysplasia syndrome, MONDO:0019287 to ectodermal dysplasia syndrome, MONDO:0019287
Ectodermal dysplasia v3.25 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from Ectodermal dysplasia, no OMIM# yet to ectodermal dysplasia syndrome, MONDO:0019287
Ectodermal dysplasia v3.24 LEF1 Achchuthan Shanmugasundram Publications for gene: LEF1 were set to 32022899
Ectodermal dysplasia v3.23 LEF1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LEF1.
Ectodermal dysplasia v3.23 LEF1 Achchuthan Shanmugasundram reviewed gene: LEF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35583550; Phenotypes: ectodermal dysplasia syndrome, MONDO:0019287, limb malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Iron metabolism disorders - NOT common HFE mutations v2.4 STAB1 Achchuthan Shanmugasundram Classified gene: STAB1 as Amber List (moderate evidence)
Iron metabolism disorders - NOT common HFE mutations v2.4 STAB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of STAB1 gene to green rating in the next GMS review.
Iron metabolism disorders - NOT common HFE mutations v2.4 STAB1 Achchuthan Shanmugasundram Gene: stab1 has been classified as Amber List (Moderate Evidence).
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram changed review comment from: PMID:37490907 reported the identification of biallelic variants in STAB10 gene in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.; to: PMID:37490907 reported the identification of biallelic variants in STAB10 gene in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram commented on gene: STAB1: PMID:37490907 reported the identification of biallelic variants in STAB10 gene in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: STAB1.
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram reviewed gene: STAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37490907; Phenotypes: Genetic hyperferritinemia without iron overload (disorder), SNOMED:766929007; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v4.6 NOS1AP Achchuthan Shanmugasundram Classified gene: NOS1AP as Amber List (moderate evidence)
Proteinuric renal disease v4.6 NOS1AP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark and reported in PMID:33523862, there are two unrelated individuals with homozygous NOS1AP variants (c.428G>A/ p.Cys143Tyr & c.345-3T-G) and presenting with nephrotic syndrome, type 22 (MIM# 619155).

Introduction of patient variant (c.428G>A) has resulted in aberrant glomeruli formation in kidney organoids. In addition, homozygous exon 3-deleted mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis.

Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Proteinuric renal disease v4.6 NOS1AP Achchuthan Shanmugasundram Gene: nos1ap has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v4.5 NOS1AP Achchuthan Shanmugasundram Phenotypes for gene: NOS1AP were changed from Nephrotic syndrome, type 22, MIM# 619155 to Nephrotic syndrome, type 22, OMIM:619155
Proteinuric renal disease v4.4 NOS1AP Achchuthan Shanmugasundram Publications for gene: NOS1AP were set to
Proteinuric renal disease v4.3 NOS1AP Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: NOS1AP.
Proteinuric renal disease v4.3 NOS1AP Achchuthan Shanmugasundram reviewed gene: NOS1AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33523862; Phenotypes: Nephrotic syndrome, type 22, OMIM:619155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.409 MTSS1L Achchuthan Shanmugasundram edited their review of gene: MTSS1L: Changed phenotypes to: Intellectual developmental disorder with ocular anomalies and distinctive facial features, OMIM:620086
Intellectual disability v5.409 MTSS1L Achchuthan Shanmugasundram changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for MTSS1L is MTSS2.; to: New approved HGNC gene symbol for MTSS1L is MTSS2.
Intellectual disability v5.409 MTSS1L Achchuthan Shanmugasundram commented on gene: MTSS1L
Cytopenias and congenital anaemias v1.116 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Hypereosinophilic syndrome, idiopathic, resistant to imatinib 607685 to Hypereosinophilic syndrome, idiopathic, resistant to imatinib, OMIM:607685
Inherited predisposition to GIST v1.14 PDGFRA Arina Puzriakova Publications for gene: PDGFRA were set to
Adult solid tumours cancer susceptibility v2.29 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Gastrointestinal stromal tumor to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Childhood solid tumours cancer susceptibility v1.26 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Familial GIST; Gastrointestinal stromal tumor, somatic 606764 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Sarcoma cancer susceptibility v1.24 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Familial GIST; Gastrointestinal stromal tumor, somatic 606764 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Childhood solid tumours v4.15 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Familial Gastrointestinal stromal tumour; Gastrointestinal stromal tumor, somatic 606764; Familial GIST; Gastrointestinal stromal tumor, somatic, 606764 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Adult solid tumours for rare disease v1.40 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Gastrointestinal stromal tumor to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510
Hereditary Erythrocytosis v2.6 PKLR Arina Puzriakova Publications for gene: PKLR were set to 22274579
Hereditary Erythrocytosis v2.5 PKLR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'monoallelic' only. Limited evidence but historic reports linked heterozygous variants in the PKLR gene to elevation of red cell ATP levels, accompanied by elevated red cell pyruvate kinase activity and mild erythrocytosis. Patients were asymptomatic and no recent cases have been published therefore Red rating is appropriate (PMIDs: 9090535; 4160306; 14300761; 7426754).

Biallelic variants cause pyruvate kinase deficiency which results in nonspherocytic hemolytic anemia rather than erythrocytosis.
Hereditary Erythrocytosis v2.5 PKLR Arina Puzriakova Mode of inheritance for gene: PKLR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal hydrops v1.63 PKLR Arina Puzriakova Classified gene: PKLR as Green List (high evidence)
Fetal hydrops v1.63 PKLR Arina Puzriakova Added comment: Comment on list classification: Rating Green as non-immune hydrops fetalis reported in multiple cases of Pyruvate kinase deficiency.

Green rating also inline with classification on equivalent GMS panel R21 Fetal anomalies (v3.0).
Fetal hydrops v1.63 PKLR Arina Puzriakova Gene: pklr has been classified as Green List (High Evidence).
Fetal hydrops v1.62 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Pyruvate Kinase deficiency to Pyruvate kinase deficiency, OMIM:266200
Cytopenias and congenital anaemias v1.115 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from PYRUVATE KINASE DEFICIENCY; Enzyme Disorder; Pyruvate kinase deficiency, 266200 to Pyruvate kinase deficiency, OMIM:266200
Rare anaemia v3.7 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Enzyme Disorder; PYRUVATE KINASE DEFICIENCY; Pyruvate kinase deficiency; 266200 PYRUVATE KINASE DEFICIENCY; 266200 Pyruvate kinase deficiency; Pyruvate kinase deficiency, 266200 to Pyruvate kinase deficiency, OMIM:266200
Fetal anomalies v3.130 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Pyruvate kinase deficiency 266200 to Pyruvate kinase deficiency, OMIM:266200
Hereditary Erythrocytosis v2.4 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Familial erythrocytosis to Adenosine triphosphate, elevated, of erythrocytes, OMIM:102900
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: POMP.
Tag Q1_24_expert_review tag was added to gene: POMP.
Palmoplantar keratodermas v3.22 POMP Arina Puzriakova Tag Q1_24_demote_red tag was added to gene: POMP.
Tag Q1_24_expert_review tag was added to gene: POMP.
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Classified gene: POMP as Red List (low evidence)
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support the gene-disease association but based on previous reviews, POMP is currently classified as Red on this panel due the single 1bp deletion identified in all cases to date residing in the 5'UTR of the POMP gene.

The gene rating is conflicting on the R166 Palmoplantar keratodermas, where POMP is rated Green for the same phenotype. This has been tagged for NHSE expert review, and therefore also tagging the association on this panel so that the two panels can be considered together and the overall classification be aligned.
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Gene: pomp has been classified as Red List (Low Evidence).
Palmoplantar keratodermas v3.22 POMP Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

There is sufficient evidence to support a gene-disease association, however the pathogenic variant reported in all cases so far is in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

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Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

PPK is a key feature of KLICK syndrome, and there are sufficient cases to support causation (PMID:20226437 and PMID:27503413). However, the pathogenic variant reported in all cases so far is the same 1bp deletion in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

---
Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.
Ichthyosis and erythrokeratoderma v3.21 POMP Arina Puzriakova Publications for gene: POMP were set to 27503413; 20226437
Palmoplantar keratodermas v3.22 POMP Arina Puzriakova Publications for gene: POMP were set to 27503413; 20226437
Ichthyosis and erythrokeratoderma v3.20 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952
Palmoplantar keratoderma and erythrokeratodermas v1.31 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952
Palmoplantar keratodermas v3.21 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Keratosis linearis with ichthyosis congenita and sclerosing keratoderma to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952
Palmoplantar keratodermas v3.20 POMP Arina Puzriakova Publications for gene: POMP were set to
Palmoplantar keratodermas v3.19 POMP Arina Puzriakova Classified gene: POMP as Green List (high evidence)
Palmoplantar keratodermas v3.19 POMP Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

There is sufficient evidence to support a gene-disease association, however the pathogenic variant reported in all cases so far is in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

---
Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.
Palmoplantar keratodermas v3.19 POMP Arina Puzriakova Gene: pomp has been classified as Green List (High Evidence).
Palmoplantar keratodermas v3.18 POMP Arina Puzriakova Classified gene: POMP as Green List (high evidence)
Palmoplantar keratodermas v3.18 POMP Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

There is sufficient evidence to support a gene-disease association, however the pathogenic variant reported in all cases so far is in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

---
Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.
Palmoplantar keratodermas v3.18 POMP Arina Puzriakova Gene: pomp has been classified as Green List (High Evidence).
Ichthyosis and erythrokeratoderma v3.19 POMP Arina Puzriakova Tag non-coding-known-pathogenic tag was added to gene: POMP.
Palmoplantar keratodermas v3.17 POMP Arina Puzriakova Tag promoter tag was added to gene: POMP.
Tag non-coding-known-pathogenic tag was added to gene: POMP.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Proteasome-associated autoinflammatory syndrome 2, 618048; combined immunodeficiency with autoinflammation to Proteasome-associated autoinflammatory syndrome 2, OMIM:618048; CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Combined immunodeficiency with autoinflammation
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Classified gene: COQ7 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Gene: coq7 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.78 COQ7 Achchuthan Shanmugasundram Phenotypes for gene: COQ7 were changed from autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9) to Neuronopathy, distal hereditary motor, autosomal recessive 9, OMIM:620402
Hereditary neuropathy or pain disorder v3.77 COQ7 Achchuthan Shanmugasundram Publications for gene: COQ7 were set to PMID: 36758993; 37077559
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: COQ7.
Tag Q1_24_NHS_review tag was added to gene: COQ7.
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram changed review comment from: PMID:36454683 reported three siblings of Portuguese decent with distal hereditary motor neuropathy and identified with a homozygous COQ7 variant that disrupted the start codon of the main COQ7 isoform 1 (c.3G-T).

PMID:36758993 reported two unrelated males of Chinese decent, who developed slowly progressive distal muscle weakness and atrophy at 14 to 15 years of age. They were identified with compound heterozygous variants in COQ7 gene (family 1: c.253-2A-T/ p.Leu156Gln & c.467T-A/ p.Leu156Gln; family 2: c.160C-T/ p.Arg54Trp & c.467T-G/ p.Leu156Arg).

PMID:3707755 reported three siblings of Syrian decent who presented with progressive distal limb muscle weakness and atrophy due to a length-dependent peripheral motor neuropathy. They were identified with a homozygous COQ7 variant (c.1A-G).

This gene has been associated with relevant phenotype in OMIM (MIM #620402), but not in Gene2Phenotype.; to: PMID:36454683 reported three siblings of Portuguese decent with distal hereditary motor neuropathy and identified with a homozygous COQ7 variant that disrupted the start codon of the main COQ7 isoform 1 (c.3G-T).

PMID:36758993 reported two unrelated males of Chinese decent, who developed slowly progressive distal muscle weakness and atrophy at 14 to 15 years of age. They were identified with compound heterozygous variants in COQ7 gene (family 1: c.253-2A-T/ p.Leu156Gln & c.467T-A/ p.Leu156Gln; family 2: c.160C-T/ p.Arg54Trp & c.467T-G/ p.Leu156Arg).

PMID:37077559 reported three siblings of Syrian decent who presented with progressive distal limb muscle weakness and atrophy due to a length-dependent peripheral motor neuropathy. They were identified with a homozygous COQ7 variant (c.1A-G).

This gene has been associated with relevant phenotype in OMIM (MIM #620402), but not in Gene2Phenotype.
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram edited their review of gene: COQ7: Changed publications to: 36454683, 36758993, 37077559
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36454683, 36758993, 3707755; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 9, OMIM:620402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v4.48 MGP Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available (two unrelated cased and functional studies) for the association of monoallelic MGP variants with spondyloepiphyseal dysplasia, the MOI should be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Skeletal dysplasia v4.48 MGP Achchuthan Shanmugasundram Mode of inheritance for gene: MGP was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v4.47 MGP Achchuthan Shanmugasundram Phenotypes for gene: MGP were changed from Keutel syndrome 245150; Keutel syndrome 245150 to Keutel syndrome, OMIM:245150; spondyloepiphyseal dysplasia, MONDO:0016761
Skeletal dysplasia v4.46 MGP Achchuthan Shanmugasundram Publications for gene: MGP were set to
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: MGP.
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram changed review comment from: PMID:37923733 reported four individuals from two unrelated families with two different heterozygous MGP variants affecting Cys 19 residue (family 1: p.Cys19Phe; family 2: p.Cys19Tyr) and with previously undescribed spondyloepiphyseal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. In addition, functional evidence from heterozygous ‘knock-in’ mice expressing Cys19Phe MGP recapitulate most of the skeletal anomalies observed in the affected individuals.; to: PMID:37923733 reported four individuals from two unrelated families with two different heterozygous MGP variants affecting Cys 19 residue (family 1: p.Cys19Phe; family 2: p.Cys19Tyr) and with previously undescribed spondyloepiphyseal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. In addition, functional evidence from heterozygous ‘knock-in’ mice expressing Cys19Phe MGP recapitulate most of the skeletal anomalies observed in the affected individuals.

Although phenotype caused by biallelic MGP variants are already reported in both OMIM (MIM #245150) and Gene2Phenotype, phenotype caused by monoallelic variants are not yet reported in either resources.
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram edited their review of gene: MGP: Changed phenotypes to: Keutel syndrome, OMIM:245150, spondyloepiphyseal dysplasia, MONDO:0016761
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram reviewed gene: MGP: Rating: GREEN; Mode of pathogenicity: None; Publications: 37923733; Phenotypes: spondyloepiphyseal dysplasia, MONDO:0016761; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v5.409 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; {Schizophrenia, susceptibility to, OMIM:4}, 600850 to Hyperprolinemia, type I, OMIM:239500; {Schizophrenia, susceptibility to, OMIM:4}, 600850
Early onset or syndromic epilepsy v4.152 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Likely inborn error of metabolism - targeted testing not possible v4.123 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Undiagnosed metabolic disorders v1.610 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Hypogonadotropic hypogonadism v1.41 KISS1R Arina Puzriakova Phenotypes for gene: KISS1R were changed from Hypogonadotropic hypogonadism 8 with or without anosmia, 614837; Precocious puberty, central, 1, (AD), 176400 to Hypogonadotropic hypogonadism 8 with or without anosmia, OMIM:614837; ?Precocious puberty, central, 1, OMIM:176400
Hypogonadotropic hypogonadism (GMS) v3.15 KISS1R Arina Puzriakova Phenotypes for gene: KISS1R were changed from Hypogonadotropic hypogonadism type 8 (OMIM 614837) to Hypogonadotropic hypogonadism 8 with or without anosmia, OMIM:614837
Palmoplantar keratoderma and erythrokeratodermas v1.30 KRT17 Arina Puzriakova Phenotypes for gene: KRT17 were changed from Pachyonychia Congenita, Type 2; Pachyonychia congenita, Jackson-Lawler type, 167210; Steatocystoma multiplex, 184500 to Pachyonychia congenita 2, OMIM:167210; Steatocystoma multiplex, OMIM:184500
Familial hidradenitis suppurativa v1.4 KRT17 Arina Puzriakova Phenotypes for gene: KRT17 were changed from Pachyonychia congenita 2, 167210; pachyonychia congenita with hidradenitis suppurativa to Pachyonychia congenita 2, OMIM:167210; Pachyonychia congenita with hidradenitis suppurativa
Non-syndromic hypotrichosis v1.13 KRT74 Arina Puzriakova Phenotypes for gene: KRT74 were changed from hypotrichosis simplex of the scalp; Hypotrichosis 3, 613981; HYPT3 to Hypotrichosis 3, OMIM:613981; HYPT3
Ectodermal dysplasia v3.23 KRT74 Arina Puzriakova Phenotypes for gene: KRT74 were changed from Pure hair and nail ectodermal dysplasia (PHNED) Ectodermal dysplasia 7, hair/nail type 614929; hypotrichosis simplex of the scalp; Hypotrichosis 3, 613981; HYPT3 to Woolly hair, autosomal dominant, OMIM:194300 (AD); ?Hypotrichosis 3, OMIM:613981 (AD); ?Ectodermal dysplasia 7, hair/nail type, OMIM:614929 (AR)
Ectodermal dysplasia without a known gene mutation v1.27 KRT74 Arina Puzriakova Phenotypes for gene: KRT74 were changed from Pure hair and nail ectodermal dysplasia (PHNED) Ectodermal dysplasia 7, hair/nail type 614929 to Woolly hair, autosomal dominant, OMIM:194300 (AD); ?Hypotrichosis 3, OMIM:613981 (AD); ?Ectodermal dysplasia 7, hair/nail type, OMIM:614929 (AR)
Ectodermal dysplasia without a known gene mutation v1.26 KRT74 Arina Puzriakova Classified gene: KRT74 as Green List (high evidence)
Ectodermal dysplasia without a known gene mutation v1.26 KRT74 Arina Puzriakova Gene: krt74 has been classified as Green List (High Evidence).
Ectodermal dysplasia without a known gene mutation v1.25 KRT74 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic to monoallelic inline with MOI on equivalent GMS panel (R163 Ectodermal dysplasia v3.0).

"This gene is Green on the Non-syndromic hypotrichosis panel (version 1.1, code 189) with a monoallelic mode of inheritance for Hypotrichosis. It has a Red rating with a biallelic mode of inheritance on the Ectodermal dysplasia without a known gene mutation panel (version 1.15, code 136), for Ectodermal dysplasia 7 due to one family report (PMID: 24714551). Therefore for the Green status, a monoallelic mode of inheritance is given here."
Ectodermal dysplasia without a known gene mutation v1.25 KRT74 Arina Puzriakova Mode of inheritance for gene: KRT74 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy v1.476 MME Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"; to: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder v3.24).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"
Ectodermal dysplasia v3.22 KRT74 Arina Puzriakova Tag watchlist_moi tag was added to gene: KRT74.
Hereditary neuropathy v1.476 MME Arina Puzriakova Added comment: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"
Hereditary neuropathy v1.476 MME Arina Puzriakova Mode of inheritance for gene: MME was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v3.129 MYLK Arina Puzriakova Phenotypes for gene: MYLK were changed from Megacystis Microcolon Intestinal Hypoperistalsis Syndrome; MMIH to Megacystis-microcolon-intestinal hypoperistalsis syndrome 1, OMIM:249210
Thoracic aortic aneurysm or dissection v1.127 MYLK Arina Puzriakova Phenotypes for gene: MYLK were changed from Aortic aneurysm, familial thoracic 7, 613780; Aortic aneurysm, familial thoracic 7 (613780) to Aortic aneurysm, familial thoracic 7, OMIM:613780
Thoracic aortic aneurysm or dissection (GMS) v3.8 MYLK Arina Puzriakova Phenotypes for gene: MYLK were changed from Aortic aneurysm, familial thoracic 7 (613780); Aortic aneurysm, familial thoracic 7, 613780 to Aortic aneurysm, familial thoracic 7, OMIM:613780
Amyotrophic lateral sclerosis/motor neuron disease v1.69 OPTN Arina Puzriakova Added comment: Comment on publications: PMID: 26566915 - "Here, we report a Chinese family spanning three generations with ALS8 caused by the same VAPB-P56S mutation detected in these cohorts, but which in its initial manifestation displays different features. We also detected a R545Q variant of optineurin (OPTN) in this family and which was previously considered a pathogenic mutation. However, our analysis showed that OPTN-R545Q is benign and that VAPB-P56S accounts for the phenotype."
PMID: 26503823
PMID: 26303227 "We conclude that: (i) OPTN mutations are associated with ALS
(ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS
(iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient
and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration."
PMID: 26203661
PMID: 25943890
PMID: 25859013 - functional evidence
PMID: 25681989
Amyotrophic lateral sclerosis/motor neuron disease v1.69 OPTN Arina Puzriakova Publications for gene: OPTN were set to PMID: 26566915 - "Here, we report a Chinese family spanning three generations with ALS8 caused by the same VAPB-P56S mutation detected in these cohorts, but which in its initial manifestation displays different features. We also detected a R545Q variant of optineurin (OPTN) in this family and which was previously considered a pathogenic mutation. However, our analysis showed that OPTN-R545Q is benign and that VAPB-P56S accounts for the phenotype."; PMID: 26503823; PMID: 26303227 "We conclude that: (i) OPTN mutations are associated with ALS; (ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS; (iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient; and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration."; PMID: 26203661; PMID: 25943890; PMID: 25859013 - functional evidence; PMID: 25681989
Amyotrophic lateral sclerosis/motor neuron disease v1.68 OPTN Arina Puzriakova Phenotypes for gene: OPTN were changed from Amyotrophic Lateral Sclerosis, Recessive; Glaucoma 1, open angle, E, 137760 to Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia, OMIM:613435
Structural eye disease v3.73 OPTN Arina Puzriakova Phenotypes for gene: OPTN were changed from Glaucoma 1, open angle, E, 137760; {Glaucoma, normal tension, susceptibility to} 606657 to Glaucoma 1, open angle, E, OMIM:137760; {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Adult-onset
Glaucoma (developmental) v1.43 OPTN Arina Puzriakova Phenotypes for gene: OPTN were changed from Glaucoma 1, open angle, E 137760; {Glaucoma, normal tension, susceptibility to} 606657 to Glaucoma 1, open angle, E, OMIM:137760; {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Adult-onset
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified to date in Genomics England's Clinical Variant Archive (CVA) dataset are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variants (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova Publications for gene: PRICKLE1 were set to 18976727; 21276947
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova edited their review of gene: PRICKLE1: Changed publications to: 30564977, 30345727, 21276947, 26727662, 29790814, 31875159, 31035234, 15634728, 15642921, 16376507, 18976727, 20301774
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Tag Q1_24_demote_amber tag was added to gene: PRICKLE1.
Tag Q1_24_expert_review tag was added to gene: PRICKLE1.
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Classified gene: PRICKLE1 as Green List (high evidence)
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variants (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Gene: prickle1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v4.149 PRICKLE1 Arina Puzriakova Tag disputed tag was added to gene: PRICKLE1.
Hereditary ataxia with onset in adulthood v4.28 PRICKLE1 Arina Puzriakova Classified gene: PRICKLE1 as Red List (low evidence)
Hereditary ataxia with onset in adulthood v4.28 PRICKLE1 Arina Puzriakova Gene: prickle1 has been classified as Red List (Low Evidence).
Adult onset neurodegenerative disorder v4.46 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive Myoclonus Epilepsy with Ataxia to Epilepsy, progressive myoclonic 1B, OMIM:612437
Early onset or syndromic epilepsy v4.149 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Intellectual disability v5.408 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Hereditary ataxia with onset in adulthood v4.27 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Hereditary ataxia v1.332 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive Myoclonus Epilepsy with Ataxia to Epilepsy, progressive myoclonic 1B, OMIM:612437
Ataxia and cerebellar anomalies - narrow panel v4.51 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive Myoclonus Epilepsy with Ataxia to Epilepsy, progressive myoclonic 1B, OMIM:612437
Hereditary neuropathy or pain disorder v3.76 PRX Arina Puzriakova Publications for gene: PRX were set to 11157804; 10848494
Hereditary neuropathy v1.475 PRX Arina Puzriakova Publications for gene: PRX were set to 11157804; 10848494
Intellectual disability v5.407 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine-Sottas disease, 145900; Charcot-Marie-Tooth disease, type 4F, 614895 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Hereditary neuropathy or pain disorder v3.75 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine Sottas disease, autosomal recessive, 145900; Charcot Marie Tooth disease, type 4F, 614895 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Hereditary neuropathy v1.474 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine Sottas disease, autosomal recessive, 145900; Charcot Marie Tooth disease, type 4F, 614895; Dejerine Sottas disease, autosomal recessive, 145900 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Fetal anomalies v3.128 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine-Sottas disease, OMIM; 145900 to Dejerine-Sottas disease, OMIM:145900
Fetal anomalies v3.127 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Charcot-Marie-Tooth disease, type 4F 614895; Dejerine-Sottas disease 145900 to Dejerine-Sottas disease, OMIM; 145900
Fetal anomalies v3.126 PRX Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'biallelic' as only recessive cases have been reported in literature.

OMIM states AD/AR inheritance for Dejerine-Sottas disease as this can be caused by both heterozygous and homozygous variants in other genes (e.g. PMP22, EGR2) but seemingly not in PRX.
Fetal anomalies v3.126 PRX Arina Puzriakova Mode of inheritance for gene: PRX was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal muscle channelopathy v3.5 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Skeletal muscle channelopathy v3.5 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Fetal anomalies v3.125 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Skeletal muscle channelopathy v3.4 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Paroxysmal central nervous system disorders v3.10 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
COVID-19 research v1.141 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Distal myopathies v3.17 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Skeletal Muscle Channelopathies v1.46 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Severe Paediatric Disorders v1.180 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Severe Paediatric Disorders v1.180 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Fetal anomalies v3.125 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Fetal anomalies v3.125 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Tag Q1_24_promote_green tag was added to STR: CNBP_CCTG.
Skeletal muscle channelopathy v3.4 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Skeletal muscle channelopathy v3.4 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Distal myopathies v3.17 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Distal myopathies v3.17 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh Deleted their comment
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh Deleted their comment
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh commented on STR: CNBP_CCTG: As STR: CNBP_CCTG has been reviewed and confirmed by the NHS Genomic Medicine Service, it can be rated as Green on this panel.
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Tag Q1_24_promote_green tag was added to STR: CNBP_CCTG.
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh Deleted their comment
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh commented on STR: CNBP_CCTG: As STR: CNBP_CCTG has been reviewed and confirmed by the NHS Genomic Medicine Service, it can be rated as Green on this panel.
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Tag Q1_24_promote_green tag was added to STR: CNBP_CCTG.
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh commented on STR: CNBP_CCTG: As STR: CNBP_CCTG has been reviewed and confirmed by the NHS Genomic Medicine Service, it can be rated as Green on this panel.
Skeletal Muscle Channelopathies v1.46 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Green List (high evidence)
Skeletal Muscle Channelopathies v1.46 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.45 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal Muscle Channelopathies v1.45 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.180 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Green List (high evidence)
Severe Paediatric Disorders v1.180 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Green List (High Evidence).
Severe Paediatric Disorders v1.179 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.179 CNBP_CCTG Sarah Leigh Entity copied from Skeletal Muscle Channelopathies v1.45
Severe Paediatric Disorders v1.179 CNBP_CCTG Sarah Leigh STR: CNBP_CCTG was added
STR: CNBP_CCTG was added to Severe Paediatric Disorders. Sources: Expert list,NHS GMS,Expert Review Red
STR, NGS Not Validated tags were added to STR: CNBP_CCTG.
Mode of inheritance for STR: CNBP_CCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: CNBP_CCTG were set to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Retinal disorders v4.56 MIR204 Achchuthan Shanmugasundram Mode of inheritance for gene: MIR204 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.156 SLC25A24 Achchuthan Shanmugasundram Tag Q3_23_MOI was removed from gene: SLC25A24.
Mitochondrial disorders v4.156 SLC25A24 Achchuthan Shanmugasundram Mode of inheritance for gene: SLC25A24 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.406 MTOR Sarah Leigh Publications for gene: MTOR were set to 26542245; 27830187; 25851998; 28892148; DOI: 10.4137/JGE.S12583; 27159400
Early onset or syndromic epilepsy v4.148 MTOR Sarah Leigh Publications for gene: MTOR were set to
Early onset or syndromic epilepsy v4.147 MTOR Sarah Leigh Phenotypes for gene: MTOR were changed from Focal cortical dysplasia, type II, somatic to Smith-Kingsmore syndrome, OMIM:616638; macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, MONDO:0014716; Focal cortical dysplasia, type II, somatic, OMIM:607341isolated focal cortical dysplasia type II, MONDO:0011818
Likely inborn error of metabolism - targeted testing not possible v4.122 RNASEH2A Saikat Santra reviewed gene: RNASEH2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intracerebral calcification disorders, Inherited White Matter Disorders, Inherited basal ganglia disease; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.122 RNASEH2B Saikat Santra reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intracerebral calcification disorders, Inherited White Matter Disorders, Inherited basal ganglia disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.122 RNASEH2C Saikat Santra reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intracerebral calcification disorders, Inherited White Matter Disorders, Inherited basal ganglia disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.405 DHX37 Tracy Lester reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877, 35982159; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v4.146 CACNB4 Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: CACNB4.
Adult onset leukodystrophy v3.24 RPS6KA3 Achchuthan Shanmugasundram Tag Q3_23_expert_review tag was added to gene: RPS6KA3.
Adult onset leukodystrophy v3.24 RNF216 Achchuthan Shanmugasundram Tag Q3_23_expert_review tag was added to gene: RNF216.
Likely inborn error of metabolism - targeted testing not possible v4.122 SLC6A20 Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: SLC6A20.
Likely inborn error of metabolism - targeted testing not possible v4.122 GSTZ1 Saikat Santra edited their review of gene: GSTZ1: Changed phenotypes to: Biochemical: hypersuccinylacetonaemia
Intellectual disability v5.405 FAM111A Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: FAM111A.
Likely inborn error of metabolism - targeted testing not possible v4.122 GSTZ1 Saikat Santra gene: GSTZ1 was added
gene: GSTZ1 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review,Eligibility statement prior genetic testing
Mode of inheritance for gene: GSTZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSTZ1 were set to 27876694
Phenotypes for gene: GSTZ1 were set to Biochemical
Penetrance for gene: GSTZ1 were set to unknown
Review for gene: GSTZ1 was set to GREEN
Added comment: GSTZ1 is established as the molecular cause for maleylacetoacetate isomerase deficiency which is an established inherited metabolic disorder and associated with succinylacetone excretion so may be detected on newborn screening programmes for hereditary tyrosinaemia type1 (FAH). The committee established for developing the pathways for rolling this out recommended that genetic testing for GSTZ1 be made available via the R98 panel to help evaluate patients with mild hypersuccinylacetonaemia - but patients with elevated succinylacetone on routine metabolic testing would also benefit from this being available.
Sources: Literature, Expert Review, Eligibility statement prior genetic testing
Skeletal dysplasia v4.45 TP53 Sarah Leigh edited their review of gene: TP53: Added comment: PMID: 33147331 reports inactivating TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in
tumorigenesis, giving rise to the dedifferentiated component in DDCS.; Changed rating: AMBER
Skeletal dysplasia v4.45 TP53 Sarah Leigh Added comment: Comment on mode of inheritance: TP53 variants associated with chondrosarcomas are somatic, occurring in the tumour material.
Skeletal dysplasia v4.45 TP53 Sarah Leigh Mode of inheritance for gene: TP53 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Skeletal dysplasia v4.44 TP53 Sarah Leigh Tag somatic tag was added to gene: TP53.
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Added comment: Comment on mode of inheritance: IDH2 variants associated with chondrosarcomas are somatic, occurring in the tumour material.
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Mode of inheritance for gene: IDH2 was changed from Other to Other
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Added comment: Comment on mode of inheritance: IDH2 variants associated with chondrosarcomas are somatic, occurring in the tumour material.
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Mode of inheritance for gene: IDH2 was changed from Unknown to Other
Skeletal dysplasia v4.43 IDH2 Sarah Leigh changed review comment from: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.; to: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as amber, because the variants are somatic, occurring in the tumour.
Skeletal dysplasia v4.43 IDH2 Sarah Leigh edited their review of gene: IDH2: Changed rating: AMBER
Skeletal dysplasia v4.43 IDH2 Sarah Leigh Tag Q1_24_promote_green was removed from gene: IDH2.
Tag Q1_24_NHS_review was removed from gene: IDH2.
Tag somatic tag was added to gene: IDH2.
Skeletal dysplasia v4.43 TP53 Sarah Leigh Publications for gene: TP53 were set to PMID: 33147331
Skeletal dysplasia v4.42 TP53 Sarah Leigh Classified gene: TP53 as Amber List (moderate evidence)
Skeletal dysplasia v4.42 TP53 Sarah Leigh Gene: tp53 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.41 IDH2 Sarah Leigh Classified gene: IDH2 as Amber List (moderate evidence)
Skeletal dysplasia v4.41 IDH2 Sarah Leigh Gene: idh2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.40 IDH2 Sarah Leigh Phenotypes for gene: IDH2 were changed from Maffucci syndrome 614569; Enchondromatosis (Ollier) and Enchondromatosis with hermangiomata (Maffucci) 166000, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (614875); Ollier disease/ Dyschondroplasia 166000; D-2-hydroxyglutaric aciduria 2 613657 to D-2-hydroxyglutaric aciduria 2, OMIM:613657; d-2-hydroxyglutaric aciduria 2, MONDO:0013345
Skeletal dysplasia v4.39 IDH2 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: IDH2.
Tag Q1_24_NHS_review tag was added to gene: IDH2.
Skeletal dysplasia v4.39 IDH2 Sarah Leigh edited their review of gene: IDH2: Added comment: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.; Changed rating: GREEN
Skeletal dysplasia v4.39 IDH2 Sarah Leigh Publications for gene: IDH2 were set to 24049096; 22057234; 22057236
Brugada syndrome and cardiac sodium channel disease v3.8 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Brugada syndrome 5, OMIM:612838 to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Dilated Cardiomyopathy and conduction defects v1.85 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Cardiac conduction defect, nonspecific ; Nonspecific Cardiac Conduction Defect to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Dilated Cardiomyopathy and conduction defects v1.84 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v3.10 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Cardiac conduction defect, nonspecific (612838); Atrial fibrillation, familial, 13 (615377); Brugada syndrome 5 (612838); Epileptic encephalopathy, early infantile, 52 (617350); Epilepsy, generalized, with febrile seizures plus, type 1 (604233) to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Progressive cardiac conduction disease v2.6 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Cardiac conduction defect, nonspecific, OMIM:612838 to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Brugada syndrome and cardiac sodium channel disease v3.7 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Brugada syndrome and cardiac sodium channel disease v3.6 SCN1B Arina Puzriakova Tag disputed tag was added to gene: SCN1B.
Early onset or syndromic epilepsy v4.146 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Epilepsy, generalized, with febrile seizures plus, type 1 604233 AD; Epileptic encephalopathy, early infantile, 52 617350 AR to Developmental and epileptic encephalopathy 52, OMIM:617350 (AR); Generalized epilepsy with febrile seizures plus, type 1, OMIM:604233 (AD)
Early onset or syndromic epilepsy v4.145 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 12011299; 16205844; 9697698
Hereditary neuropathy or pain disorder v3.74 COQ7 Lucy Jackson edited their review of gene: COQ7: Changed publications to: 36758993, 37077559
Hereditary neuropathy or pain disorder v3.74 COQ7 Lucy Jackson gene: COQ7 was added
gene: COQ7 was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to PMID: 36758993; 37077559
Phenotypes for gene: COQ7 were set to autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9)
Review for gene: COQ7 was set to GREEN
Added comment: This gene is associated with autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9)
Sources: NHS GMS
Sarcoma cancer susceptibility v1.23 T Arina Puzriakova Publications for gene: T were set to 19801981; 23064415
Sarcoma cancer susceptibility v1.22 T Arina Puzriakova Phenotypes for gene: T were changed from Familial Chordoma; Chordoma to Chordoma (disease), MONDO:0008978
Sarcoma susceptibility v1.77 T Arina Puzriakova Publications for gene: T were set to 23064415; 19801981; 34837714
Sarcoma susceptibility v1.76 T Arina Puzriakova Publications for gene: T were set to 23064415; 19801981
Cerebral vascular malformations v3.9 COL5A1 Dmitrijs Rots changed review comment from: PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen; to: PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen
Cerebral vascular malformations v3.9 COL5A1 Dmitrijs Rots gene: COL5A1 was added
gene: COL5A1 was added to Cerebral vascular malformations. Sources: Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: COL5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL5A1 were set to PMID: 32938213
Phenotypes for gene: COL5A1 were set to Fibromuscular dysplasia, multifocal
Mode of pathogenicity for gene: COL5A1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: COL5A1 was set to GREEN
Added comment: PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen
Childhood onset dystonia, chorea or related movement disorder v3.66 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Childhood onset dystonia, chorea or related movement disorder v3.66 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Childhood onset hereditary spastic paraplegia v4.37 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Childhood onset hereditary spastic paraplegia v4.37 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Ataxia and cerebellar anomalies - narrow panel v4.50 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Ataxia and cerebellar anomalies - narrow panel v4.50 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Severe microcephaly v4.53 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Severe microcephaly v4.53 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Severe microcephaly. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Intellectual disability v5.405 ACBD6 Arina Puzriakova Classified gene: ACBD6 as Amber List (moderate evidence)
Intellectual disability v5.405 ACBD6 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v5.405 ACBD6 Arina Puzriakova Gene: acbd6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.404 ACBD6 Arina Puzriakova Publications for gene: ACBD6 were set to 21937992; 32108178
Intellectual disability v5.403 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.402 ACBD6 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: ACBD6.
Intellectual disability v5.402 ACBD6 Arina Puzriakova edited their review of gene: ACBD6: Added comment: - PMID: 21937992 (2011) - single individuals with a p.G22fs variant in the ACBD6 gene, presenting with mild ID, microcephaly, facial dysmorphism, spasticity. Limited additional information.

- PMID: 32108178 (2020) - two unrelated individuals with neurodevelopmental disorder (moderate ID is noted but otherwise limited clinical information) and carrying homozygous LoF variants in the ACBD6 gene (1 frameshift, 1 canonical splice). One individual also carried an allelic homozygous variant in the PRDX6 gene (unlikely but unknown disease consequence). Skin-derived patient fibroblasts showed reduced ACBD6 expression and N-myristoylation deficiency.

- PMID: 36457943 (2023) - two Thai siblings presenting with profound ID, morbid obesity, pancytopenia with severe recurrent infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Sequencing showed a novel homozygous single bp duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene. Parents were heterozygous carriers.

- PMID: 37951597 (2023) - 45 previously undiagnosed individuals from 28 families with a neurodevelopmental syndrome including a complex and progressive movement disorder phenotype. Cardinal clinical features include moderate-to-severe GDD/ID (45/45), facial dysmorphism (38/40), HC <2nd percentile (21/31), weight >50th percentile (20/34), mild cerebellar ataxia (35/41), limb spasticity/hypertonia (31/41), gait abnormalities (33/35), dystonia (30/32) and variable epilepsy (13/29).

Homozygous ACBD6 variants were identified by WES in all cases, including 18 predicted LoF, 1 missense and 1 inframe insertion. Knockout studies in zebrafish recapitulate clinical features reported in patients such as movement disorders, seizures, and facial dysmorphology, while inactivation of acbd6 in X. tropicalis predominantly caused embryo death while surviving tadpoles demonstrated microcephaly, reduced movement, eye abnormalities, and brain structure differences.; Changed rating: GREEN; Changed publications to: 21937992, 32108178, 36457943, 37951597; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.402 ACBD6 Arina Puzriakova Added comment: Comment on publications: PMID: 32108178 (2020) paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v5.402 ACBD6 Arina Puzriakova Publications for gene: ACBD6 were set to 21937992; 32108178
Skeletal dysplasia v4.38 FBXW11 Achchuthan Shanmugasundram Tag Q4_21_NHS_review was removed from gene: FBXW11.
Tag Q4_23_NHS_review tag was added to gene: FBXW11.
Structural eye disease v3.72 GDF3 Achchuthan Shanmugasundram Tag Q4_23_demote_amber was removed from gene: GDF3.
Tag Q4_23_expert_review was removed from gene: GDF3.
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: NEPRO.
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Classified gene: NEPRO as Amber List (moderate evidence)
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with three different homozygous variants in NEPRO gene. Three unrelated cases were of Arabic/ partial Arabic descent, while the fourth case from India. The evidence available is sufficient enough to promote the rating to green in the next GMS review.
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Gene: nepro has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.37 NEPRO Achchuthan Shanmugasundram Phenotypes for gene: NEPRO were changed from Anauxetic dysplasia 3, MIM618853 to Anauxetic dysplasia 3, OMIM:618853
Skeletal dysplasia v4.36 NEPRO Achchuthan Shanmugasundram Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram changed review comment from: PMID:26633546 reported a sister and brother among 31 Saudi Arabian families studied with skeletal dysplasia and homozygous missense variant in NEPRO gene (p.Arg49Cys).

PMID:29620724 reported the same homozygous NEPRO variant (p.Arg49Cys) in two brothers of Arab descent with skeletal dysplasia. The disorder is identical to phenotypes reported in PMID:26633546 and haplotype analysis confirmed the founder nature of the variant.

PMID:31250547 reported a 13-year-old Indian girl with a different homozygous missense variant (p.Leu145Phe) and with severe short stature and skeletal dysplasia with sparse scalp hair and skin and joint laxity. Her second-cousin parents were heterozygous for the same variant.

This gene has been associated with relevant phenotypes in OMIM (MIM #618853), but not in Gene2Phenotype.; to: PMID:26633546 reported a sister and brother among 31 Saudi Arabian families studied with skeletal dysplasia and homozygous missense variant in NEPRO gene (p.Arg49Cys).

PMID:29620724 reported the same homozygous NEPRO variant (p.Arg49Cys) in two brothers of Arab descent with skeletal dysplasia. The disorder is identical to phenotypes reported in PMID:26633546 and haplotype analysis confirmed the founder nature of the variant.

PMID:31250547 reported a 13-year-old Indian girl with a different homozygous missense variant (p.Leu145Phe) and with severe short stature and skeletal dysplasia with sparse scalp hair and skin and joint laxity. Her second-cousin parents were heterozygous for the same variant.

PMID:37294112 reported a 7-year-old girl from an Arabic-speaking community in Eastern Africa with Anauxetic dysplasia 3 and another homozygous NEPRO variant (p.Arg94Cys). She was born to consanguineous parents, who reported that their shared ancestor was of Arab descent. This patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly.

This gene has been associated with relevant phenotypes in OMIM (MIM #618853), but not in Gene2Phenotype.
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram edited their review of gene: NEPRO: Changed rating: GREEN; Changed publications to: 26633546, 29620724, 31250547, 37294112
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram reviewed gene: NEPRO: Rating: AMBER; Mode of pathogenicity: None; Publications: 26633546, 29620724, 31250547; Phenotypes: Anauxetic dysplasia 3, OMIM:618853; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal ciliopathies v3.20 GRK2 Achchuthan Shanmugasundram Classified gene: GRK2 as Amber List (moderate evidence)
Skeletal ciliopathies v3.20 GRK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families and some functional data available in support of the disease association. Hence, it should be rated amber with current evidence.
Skeletal ciliopathies v3.20 GRK2 Achchuthan Shanmugasundram Gene: grk2 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v3.19 GRK2 Achchuthan Shanmugasundram Phenotypes for gene: GRK2 were changed from Jeune asphyxiating thoracic dystrophy (ATD) to Jeune syndrome, MONDO:0018770
Skeletal ciliopathies v3.18 GRK2 Achchuthan Shanmugasundram reviewed gene: GRK2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Jeune syndrome, MONDO:0018770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.144 TRIP13 Achchuthan Shanmugasundram Tag founder-effect was removed from gene: TRIP13.
Early onset or syndromic epilepsy v4.144 TRIP13 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: TRIP13.
Acute rhabdomyolysis v1.18 ACAD9 Anderson Steven Deleted their review
Acute rhabdomyolysis v1.18 ACAD9 Anderson Steven commented on gene: ACAD9
Early onset or syndromic epilepsy v4.144 PCLO Dmitrijs Rots reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.401 KIRREL3 Dmitrijs Rots reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37605258; Phenotypes: NDD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sarcoma susceptibility v1.75 TP53 Adrienne Flanagan reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31529158; Phenotypes: Solitary Fibrous Tumour; Mode of inheritance: None
Sarcoma susceptibility v1.75 TERT Adrienne Flanagan gene: TERT was added
gene: TERT was added to Sarcoma susceptibility. Sources: Literature,Other
Mode of inheritance for gene: TERT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TERT were set to PMID: 31529158
Phenotypes for gene: TERT were set to Solitary Fibrous Tumour
Review for gene: TERT was set to GREEN
Added comment: Solitary fibrous tumour (SFT) is a rare mesenchymal tumour with a wide anatomical distribution, including superficial and deep soft tissue, visceral organs and bone and is most common in adults. The tumours classified in the intermediate risk group by WHO grading system are difficult to prognosticate. Recent studies show that C228T TERT promoter (pTERT) mutation is associated with reduced survival in SFT. pTERT mutation is more common in intermediate and high-risk groups, and is associated with poorer outcome. Detection of the pTERT mutation has the potential to improve current prognostication and guide management of patients with intermediate-risk solitary fibrous tumours.
These findings were validated by a study presented at the 2023 joint winter meeting of Pathological Society with the RSM, abstract OF6:

https://www.pathsoc.org/_userfiles/pages/files/abstracts_booklet_winter_meeting_2023.pdf
Sources: Literature, Other
Intellectual disability v5.401 ACBD6 Sarah Leigh Classified gene: ACBD6 as Amber List (moderate evidence)
Intellectual disability v5.401 ACBD6 Sarah Leigh Gene: acbd6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.401 ACBD6 Sarah Leigh Classified gene: ACBD6 as Amber List (moderate evidence)
Intellectual disability v5.401 ACBD6 Sarah Leigh Gene: acbd6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.400 ACBD6 Sarah Leigh edited their review of gene: ACBD6: Added comment: ACBD6 variants have not been associated with a phenotype in OMIM, and as an autosomal recessive condition with Limited strength in Gen2Phen. Three variants have been reported in three unrelated cases with intellectual disability, however, in one of these carriers the ACBD6 variant was allelic with PRDX6 gene c.136del; p.(ValCysfs*23), therefore the contribution of the ACBD6 variant to intellectual disability is uncertain in this case (PMID: 21937992, 32108178).; Changed rating: AMBER
Intellectual disability v5.400 ACBD6 Sarah Leigh Publications for gene: ACBD6 were set to 21937992
Limb disorders v4.14 FBXW11 Sarah Leigh Entity copied from Skeletal dysplasia v4.35
Limb disorders v4.14 FBXW11 Sarah Leigh gene: FBXW11 was added
gene: FBXW11 was added to Limb disorders. Sources: Literature,Expert Review Amber
Q4_21_NHS_review, Q4_23_promote_green tags were added to gene: FBXW11.
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:0030057
Penetrance for gene: FBXW11 were set to unknown
Skeletal dysplasia v4.35 IDH2 Adrienne Flanagan reviewed gene: IDH2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36042521; Phenotypes: Chondrosarcoma Conventional Central; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v4.35 TP53 Adrienne Flanagan gene: TP53 was added
gene: TP53 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TP53 were set to PMID: 33147331
Phenotypes for gene: TP53 were set to Central conventional chondrosrcoma
Review for gene: TP53 was set to GREEN
Added comment: Inactivating mutations in TP53 are common in dedifferentiated chondrosarcoma (DDCS) and, in a subset of cases, the TP53 mutation is restricted to the dedifferentiated nonchondrogenic component (8/11, 73% of the cases tested). Half of the tumours where the conventional chondrogenic component was paired with the high-grade non-chondrogenic component showed TP53 mutation in the chondrogenic area (3/6, 50%). These findings imply that TP53 alterations occur late in tumorigenesis, potentially with a TP53-mutant subclone that progresses to the dedifferentiated component in DDCS. Identification of TP53 mutation in an otherwise low-grade central chondrosarcoma may indicate the tumor is at increased risk of dedifferentiation.
Genetic testing for TP53 along with IDH1, IDH2 and TERT promoter mutations in central conventional chondrosarcoma could be useful in patient stratification.
Sources: Literature
Pigmentary skin disorders v3.6 LMNA Tom Cullup gene: LMNA was added
gene: LMNA was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: LMNA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LMNA were set to PMID: 12714972; https://www.ncbi.nlm.nih.gov/books/NBK1121/#; 12075506; 17848409
Phenotypes for gene: LMNA were set to Hutchinson-Gilford progeria syndrome (HGPS) (MIM 176670); Mandibuloacral dysplasia with type A lipodystrophy (MADA)
Penetrance for gene: LMNA were set to Complete
Mode of pathogenicity for gene: LMNA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMNA was set to GREEN
Added comment: LMNA requested to be added to pigmentary disorders panel by Prof Kinsler, due to pigmentary lesions being an early sign of LMNA-progeria (AD).
Mottled pigmentation also a feature of MADA (AR).
Sources: Expert list
Unexplained young onset end-stage renal disease v3.37 CLCNKB Achchuthan Shanmugasundram Publications for gene: CLCNKB were set to
Unexplained young onset end-stage renal disease v3.36 CLCNKB Achchuthan Shanmugasundram Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 3, MONDO:0011822; Bartter disease type 4B, MONDO:0000909; Bartter syndrome, type 3, OMIM:607364 to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822
Unexplained young onset end-stage renal disease v3.35 CLCNKB Achchuthan Shanmugasundram Tag monogenic-polygenic tag was added to gene: CLCNKB.
Unexplained young onset end-stage renal disease v3.35 CLCNKB Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Sarah Leigh in 'R256 Nephrocalcinosis or nephrolithiasis' and 'R198 Renal tubulopathies' panels, the mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), this phenotype is not relevant to this panel and the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Unexplained young onset end-stage renal disease v3.35 CLCNKB Achchuthan Shanmugasundram Mode of inheritance for gene: CLCNKB was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.34 CLCNKB Achchuthan Shanmugasundram edited their review of gene: CLCNKB: Changed publications to: 120550, 9326936, 15717167; Changed phenotypes to: Bartter syndrome, type 3, OMIM:607364, Bartter disease type 3, MONDO:0011822; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.34 WDR72 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/) and 'R256 Nephrocalcinosis or nephrolithiasis'(https://panelapp.genomicsengland.co.uk/panels/149/gene/WDR72/), this gene should be promoted to green rating in this panel as well.; to: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/) and 'R256 Nephrocalcinosis or nephrolithiasis' (https://panelapp.genomicsengland.co.uk/panels/149/gene/WDR72/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 WDR72 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/), this gene should be promoted to green rating in this panel as well.; to: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/) and 'R256 Nephrocalcinosis or nephrolithiasis'(https://panelapp.genomicsengland.co.uk/panels/149/gene/WDR72/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/RMND1/), this gene should be promoted to green rating in this panel as well.; to: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/RMND1/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram Classified gene: RMND1 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/RMND1/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram Gene: rmnd1 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.33 RMND1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RMND1.
Unexplained young onset end-stage renal disease v3.33 RMND1 Achchuthan Shanmugasundram gene: RMND1 was added
gene: RMND1 was added to Unexplained young onset end-stage renal disease. Sources: Literature
Mode of inheritance for gene: RMND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RMND1 were set to 31568715; 31889854; 32911714
Phenotypes for gene: RMND1 were set to Combined oxidative phosphorylation deficiency 11, OMIM:614922
Review for gene: RMND1 was set to GREEN
Added comment: PMID:31568715 - Four patients identified with pathogenic variants in RMND1 were reported with renal disease characterised by tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4).

PMID:31889854 - A very rare homozygous pathogenic variant in RMND1 (p.Val211Met) was identified in a patient presenting with chronic kidney disease (CKD) and sensorineural hearing loss (SNHL).

PMID:32911714 - Compound heterozygous missense variants in RMND1 (p.Gly195Arg & p.Tyr273Ser) was identified in female siblings presenting with severe-to-profound bilateral SNHL, ovarian dysfunction and CKD that developed in the fourth decade of life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #614922) and Gene2Phenotype. The clinical manifestations such as cystic kidneys, renal tubular acidosis and renal disease have been recorded as part of the OMIM phenotype.
Sources: Literature
Unexplained young onset end-stage renal disease v3.32 WDR72 Achchuthan Shanmugasundram Classified gene: WDR72 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.32 WDR72 Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.32 WDR72 Achchuthan Shanmugasundram Gene: wdr72 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.31 WDR72 Achchuthan Shanmugasundram Phenotypes for gene: WDR72 were changed from Amelogenesis imperfecta, type IIA3, OMIM:613211 to hereditary distal renal tubular acidosis; distal renal tubular acidosis, MONDO:0015827; Amelogenesis imperfecta, type IIA3, OMIM:613211; amelogenesis imperfecta hypomaturation type 2A3, MONDO:0013181
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: WDR72.
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram edited their review of gene: WDR72: Changed phenotypes to: hereditary distal renal tubular acidosis, distal renal tubular acidosis, MONDO:0015827, Amelogenesis imperfecta, type IIA3, OMIM:613211, amelogenesis imperfecta hypomaturation type 2A3, MONDO:0013181
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram edited their review of gene: WDR72: Changed rating: GREEN
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram gene: WDR72 was added
gene: WDR72 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review
Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR72 were set to 30028003; 30779877; 31959358; 33033857
Phenotypes for gene: WDR72 were set to Amelogenesis imperfecta, type IIA3, OMIM:613211
Review for gene: WDR72 was set to RED
Added comment: Reviews from Eleanor Williams in 'R198 Renal tubulopathies' panel:

Additional families reported with distal renal tubular acidosis, along with amelogenesis imperfecta.

PMID: 30779877 (Zhang et al 2019) - 6 families (1 African, 5 Turkish) identified using WES with biallelic WDR72 variants. The affected members showed generalized hypomaturation Amelogenesis imperfecta. 2 families, although unrelated, shared the same variant. 3 out of the 8 tested patients showed decreased serum pH, consistent with a diagnosis of renal tubular acidosis.

PMID: 31959358 - (Jobst-Schwan et al 2020) - 2 families (Indian, Turkish) with different homozygous variants in WDR72 identified by WES. All 3 affected individuals had Distal renal tubular acidosis. 1 individual is reported to have nephrocalcinosis.

PMID: 33033857 - Khandelwal et al 2021 - 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Genome analysis of 3 of the patients identified 3 different homozygous nonsense variants in WDR72. Ultrasound showed bilateral grade I medullary nephrocalcinosis in the 3 patients.
Created: 1 Mar 2023, 9:46 p.m. | Last Modified: 1 Mar 2023, 9:46 p.m.

Panel Version: 3.4

Comment on list classification: Rating this gene as amber as 2 reported families to date.
Created: 12 Feb 2019, 10:38 p.m.

No association with a renal phenotype in OMIM (only with Amelogenesis imperfecta) or Gene2Phenotype.

PMID: 30028003 (Rungroj et al 2018) report 2 families, of Thai and Indian ethnicities, with compound heterozygous and homozygous nonsense WDR72 variations respectively. Both were affected by hereditary distal renal tubular acidosis (dRTA). 3 different variants were found in WDR72; c.1777A>G:p.R593G and c.2522T>A:p.L841Q (predicted as disease causing or damaging, found as compound heterzygotes in family 1) and c.2686C>T:p.R896X. (protein truncating, homozygous in family 2). The truncating variant has been previously reported in a Pakistani family affected by hypomaturation AI, however no other clinical phenotypes in the patients were reported (PMID: 21196691).

Patients in family 1 presented with proximal muscle weakness and/or growth retardation at ages under 7 years. One member of family 1 also had nephrolithiasis and localized enamel hypoplasia. Family 2 has consanguineous parents with one affected child which presented with hypoplastic amelogenesis imperfect in addition to dRTA. She also showed nephrocalcinosis.
Created: 12 Feb 2019, 10:36 p.m. | Last Modified: 1 Mar 2023, 7:39 p.m.

Panel Version: 3.4
Sources: Expert Review
Unexplained young onset end-stage renal disease v3.29 SEC63 Achchuthan Shanmugasundram Classified gene: SEC63 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.29 SEC63 Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'Cystic kidney disease' panel (https://panelapp.genomicsengland.co.uk/panels/283/gene/SEC63/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.29 SEC63 Achchuthan Shanmugasundram Gene: sec63 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.28 SEC63 Achchuthan Shanmugasundram Phenotypes for gene: SEC63 were changed from to Polycystic liver disease 2 with or without kidney cysts, OMIM:617004
Unexplained young onset end-stage renal disease v3.27 SEC63 Achchuthan Shanmugasundram Publications for gene: SEC63 were set to
Unexplained young onset end-stage renal disease v3.26 SEC63 Achchuthan Shanmugasundram Mode of inheritance for gene: SEC63 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.25 SEC63 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SEC63.
Unexplained young onset end-stage renal disease v3.25 SEC63 Achchuthan Shanmugasundram reviewed gene: SEC63: Rating: GREEN; Mode of pathogenicity: None; Publications: 24886261; Phenotypes: Polycystic liver disease 2 with or without kidney cysts, OMIM:617004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.25 PRKCSH Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PRKCSH.
Unexplained young onset end-stage renal disease v3.25 PRKCSH Achchuthan Shanmugasundram Phenotypes for gene: PRKCSH were changed from to Polycystic liver disease 1 with or without kidney cysts, OMIM:174050
Unexplained young onset end-stage renal disease v3.24 PRKCSH Achchuthan Shanmugasundram Publications for gene: PRKCSH were set to
Unexplained young onset end-stage renal disease v3.23 PRKCSH Achchuthan Shanmugasundram Classified gene: PRKCSH as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.23 PRKCSH Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'Cystic kidney disease' panel (https://panelapp.genomicsengland.co.uk/panels/283/gene/PRKCSH/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.23 PRKCSH Achchuthan Shanmugasundram Gene: prkcsh has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.22 PRKCSH Achchuthan Shanmugasundram Mode of inheritance for gene: PRKCSH was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 PRKCSH Achchuthan Shanmugasundram reviewed gene: PRKCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24886261; Phenotypes: Polycystic liver disease 1 with or without kidney cysts, OMIM:174050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 PDSS2 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green in 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/PDSS2/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/PDSS2/).
Unexplained young onset end-stage renal disease v3.21 CD151 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).
Unexplained young onset end-stage renal disease v3.21 FN1 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).
Unexplained young onset end-stage renal disease v3.21 FN1 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green in 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).
Unexplained young onset end-stage renal disease v3.21 CD151 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green on 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).
Unexplained young onset end-stage renal disease v3.21 APRT Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it is already green on 'Nephrocalcinosis or nephrolithiasis' panel (https://panelapp.genomicsengland.co.uk/panels/149/gene/APRT/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R256 Nephrocalcinosis or nephrolithiasis' panel (https://panelapp.genomicsengland.co.uk/panels/149/gene/APRT/).
Unexplained young onset end-stage renal disease v3.21 CASR Achchuthan Shanmugasundram edited their review of gene: CASR: Changed phenotypes to: Familial Hypocalciuric Hypercalcemia, Hypocalciuric hypercalcemia, type I, 145980Hyperparathyroidism, neonatal, 239200Hypocalcemia, autosomal dominant, 601198Hypocalcemia, autosomal dominant, with Bartter syndrome, 601198{Epilepsy idiopathic generalized, susceptibility to,, Hypocalcemia (dominant), Familial Hypocalciuric Hypercalcemia (dominant), hypocalciuric hypercalcaemia
Unexplained young onset end-stage renal disease v3.21 YRDC Achchuthan Shanmugasundram reviewed gene: YRDC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galloway-Mowat syndrome MONDO:0009627; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 WNK4 Achchuthan Shanmugasundram reviewed gene: WNK4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type IIB, 614491; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 TULP3 Achchuthan Shanmugasundram reviewed gene: TULP3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hepatorenocardiac degenerative fibrosis, OMIM:619902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 TTR Achchuthan Shanmugasundram reviewed gene: TTR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, hereditary, transthyretin-related 105210; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.21 TRPM6 Achchuthan Shanmugasundram reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia 1, intestinal, 602014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 TPRKB Achchuthan Shanmugasundram reviewed gene: TPRKB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galloway-Mowat syndrome 5, OMIM:617731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 STRADA Achchuthan Shanmugasundram reviewed gene: STRADA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Polyhydramnios, megalencephaly, and symptomatic epilepsy, 611087; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC5A2 Achchuthan Shanmugasundram reviewed gene: SLC5A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Renal glucosuria, 233100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC4A4 Achchuthan Shanmugasundram reviewed gene: SLC4A4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Renal tubular acidosis, proximal, with ocular abnormalities, 604278, Proximal Renal Tubular Acidosis with Ocular Abnormalities, Proximal Renal Tubular Acidosis with Ocular Abnormalities (recessive).; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC4A1 Achchuthan Shanmugasundram reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Renal tubular acidosis, distal, AD, 179800, distal renal tubular acidosis, Renal tubular acidosis, distal, AR 611590; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC34A3 Achchuthan Shanmugasundram reviewed gene: SLC34A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: hereditary hypophosphatemic rickets with hypercalciuria, MONDO:0009431, Hypophosphatemic rickets with hypercalciuria, OMIM:241530, HHRH; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC34A1 Achchuthan Shanmugasundram reviewed gene: SLC34A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286, Hypophosphatemic Nephrolithiasis/Osteoporosis (recessive), Hypophosphatemic Nephrolithiasis/Osteoporosis, Nephrolithiasis with osteoporosis and hypophosphatemia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC2A2 Achchuthan Shanmugasundram reviewed gene: SLC2A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fanconi-Bickel syndrome, OMIM:227810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC12A3 Achchuthan Shanmugasundram reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Gitelman syndrome, MONDO:0009904, Gitelman syndrome, OMIM: 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC12A1 Achchuthan Shanmugasundram reviewed gene: SLC12A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter syndrome, type 1, OMIM:601678, Bartter disease type 1, MONDO:0100344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SCNN1G Achchuthan Shanmugasundram reviewed gene: SCNN1G: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type I, 264350; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SCNN1B Achchuthan Shanmugasundram reviewed gene: SCNN1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type I, 264350; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SCNN1A Achchuthan Shanmugasundram reviewed gene: SCNN1A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type I, 264350, ?Liddle syndrom 3, 618126, Bronchiectasis with or without elevated sweat chloride 2 613021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SARS2 Achchuthan Shanmugasundram reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, OMIM:613845, Progressive Spastic Paresis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 RRAGD Achchuthan Shanmugasundram reviewed gene: RRAGD: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: salt wasting, hypomagnesaemia, cardiomyopathy, nephrocalcinosis, tubular renal disease-cardiomyopathy syndrome, MONDO:0019130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 PHEX Achchuthan Shanmugasundram reviewed gene: PHEX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypophosphatemic rickets, X-linked dominant 307800; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Unexplained young onset end-stage renal disease v3.21 NR3C2 Achchuthan Shanmugasundram reviewed gene: NR3C2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism type I, autosomal dominant, 177735, Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy, 605115 no inheritance pattern; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 MOCOS Achchuthan Shanmugasundram reviewed gene: MOCOS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Xanthinuria, type II, OMIM:603592; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 MAGED2 Achchuthan Shanmugasundram reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter syndrome, type 5, antenatal, transient, 300971; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Unexplained young onset end-stage renal disease v3.21 LYZ Achchuthan Shanmugasundram reviewed gene: LYZ: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, renal 105200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 LCAT Achchuthan Shanmugasundram reviewed gene: LCAT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Norum disease, MONDO:0009515, LCAT DEFICIENCY, Norum disease, OMIM:245900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KLHL3 Achchuthan Shanmugasundram reviewed gene: KLHL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type IID, 614495; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KCNJ16 Achchuthan Shanmugasundram reviewed gene: KCNJ16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypokalemic tubulopathy and deafness, OMIM:619406; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KCNJ10 Achchuthan Shanmugasundram reviewed gene: KCNJ10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: SESAME/EAST syndrome, 612780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KCNJ1 Achchuthan Shanmugasundram reviewed gene: KCNJ1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: often initial transient hyperkalemia, Antenatal Bartter Syndrome, Type 2 Bartter syndrome, Bartter syndrome, type 2, 241200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 IFT27 Achchuthan Shanmugasundram reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Bardet-Biedl syndrome 19, OMIM:615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 IFT172 Achchuthan Shanmugasundram reviewed gene: IFT172: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Short-rib thoracic dysplasia 10 with or without polydactyly, OMIM:615630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 IFT140 Achchuthan Shanmugasundram reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964, cystic kidney disease, MONDO:0002473, Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 HPRT1 Achchuthan Shanmugasundram reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Lesch-Nyhan syndrome, OMIM:300322, Hyperuricemia, HRPT-related, OMIM:300323; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Unexplained young onset end-stage renal disease v3.21 HNF4A Achchuthan Shanmugasundram reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM:616026; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.21 GSN Achchuthan Shanmugasundram reviewed gene: GSN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, Finnish type, OMIM:105120; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 GON7 Achchuthan Shanmugasundram reviewed gene: GON7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galloway-Mowat syndrome MONDO:0009627; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 GNA11 Achchuthan Shanmugasundram reviewed gene: GNA11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypocalcemia, autosomal dominant 2 615361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 FLCN Achchuthan Shanmugasundram reviewed gene: FLCN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: renal cell carcinoma, Birt-Hogg-Dube syndrome, OMIM:135150, renal oncocytoma, pneumothorax, renal cysts, cutaneous fibrofolliculoma, pulmonary cysts; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 FGA Achchuthan Shanmugasundram reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, familial visceral, OMIM:105200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 FAM20A Achchuthan Shanmugasundram reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 FAH Achchuthan Shanmugasundram reviewed gene: FAH: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Tyrosinemia, type I, OMIM:276700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 DLG5 Achchuthan Shanmugasundram reviewed gene: DLG5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: DLG5-associated developmental disorder (biallelic), DLG5-associated developmental disorder (monoallelic); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 DAAM2 Achchuthan Shanmugasundram reviewed gene: DAAM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: steroid-resistant nephrotic syndrome MONDO:0044765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CYP24A1 Achchuthan Shanmugasundram reviewed gene: CYP24A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Infantile hypercalcaemia, Hypercalcemia, infantile, 143880, Infantile Hypercalcemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CUL3 Achchuthan Shanmugasundram reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type IIE, 214496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 CNNM2 Achchuthan Shanmugasundram reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: renal hypomagnesemia 6, MONDO:0013480, Hypomagnesemia, seizures, and mental retardation, MONDO:0014631, Hypomagnesemia 6, renal, OMIM:613882, Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLDN19 Achchuthan Shanmugasundram reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, hypomagensemia with nephrocalcinosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLDN16 Achchuthan Shanmugasundram reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia 3, renal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLDN10 Achchuthan Shanmugasundram reviewed gene: CLDN10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypokalemic-alkalotic salt-losing tubulopathy, HELIX syndrome, OMIM:617671; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLCNKB Achchuthan Shanmugasundram reviewed gene: CLCNKB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter disease type 4B, MONDO:0000909, Bartter syndrome, type 4b, digenic, OMIM:613090, Bartter syndrome, type 3, OMIM:607364, Bartter disease type 3, MONDO:0011822; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CFHR2 Achchuthan Shanmugasundram reviewed gene: CFHR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: C3 glomerulopathy, Immune complex MPGN, Immune-complex-mediated MPGN, IC-MPGN, C3G; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CASR Achchuthan Shanmugasundram reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Familial Hypocalciuric Hypercalcemia, Hypocalcemia (dominant), hypocalciuric hypercalcaemia, Familial Hypocalciuric Hypercalcemia (dominant), Hypocalciuric hypercalcemia, type I, 145980Hyperparathyroidism, neonatal, 239200Hypocalcemia, autosomal dominant, 601198Hypocalcemia, autosomal dominant, with Bartter syndrome, 601198{Epilepsy idiopathic generalized, susceptibility to,; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CA2 Achchuthan Shanmugasundram reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 AVPR2 Achchuthan Shanmugasundram reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539, Diabetes insipidus, nephrogenic, OMIM:304800; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Unexplained young onset end-stage renal disease v3.21 ATP6V1B1 Achchuthan Shanmugasundram reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: distal renal tubular acidosis, Renal tubular acidosis with deafness 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 ATP6V0A4 Achchuthan Shanmugasundram reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 ATP1A1 Achchuthan Shanmugasundram reviewed gene: ATP1A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia, seizures, and mental retardation 2 618314, Charcot-Marie-Tooth disease, axonal, type 2DD, 618036; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 AQP2 Achchuthan Shanmugasundram reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Diabetes insipidus, nephrogenic, 125800, Nephrogenic diabetes insipidus; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 APOE Achchuthan Shanmugasundram reviewed gene: APOE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Lipoprotein glomerulopathy, OMIM:611771; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 APOC2 Achchuthan Shanmugasundram reviewed gene: APOC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 APOA2 Achchuthan Shanmugasundram reviewed gene: APOA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 APOA1 Achchuthan Shanmugasundram reviewed gene: APOA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, 3 or more types OMIM:105200, familial visceral amyloidosis MONDO:0007099; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 AP2S1 Achchuthan Shanmugasundram reviewed gene: AP2S1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Familial hypocalciuric hypercalcemia type III 600740; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 ALG9 Achchuthan Shanmugasundram reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: cystic liver disease, cystic kidney disease, Gillessen-Kaesbach-Nishimura syndrome, 263210; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 ALG8 Achchuthan Shanmugasundram reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: cystic liver disease, Polycystic liver disease 3 with or without kidney cysts, 617874, cystic kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.21 ALG5 Achchuthan Shanmugasundram reviewed gene: ALG5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Polycystic kidney disease 7, OMIM:620056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.20 FAH Achchuthan Shanmugasundram Phenotypes for gene: FAH were changed from Tyrosinemia, type I,OMIM:276700 to Tyrosinemia, type I, OMIM:276700
Unexplained young onset end-stage renal disease v3.19 FAH Achchuthan Shanmugasundram Phenotypes for gene: FAH were changed from Tyrosinemia, type I to Tyrosinemia, type I,OMIM:276700
Unexplained young onset end-stage renal disease v3.18 WNK4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: WNK4.
Unexplained young onset end-stage renal disease v3.18 YRDC Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: YRDC.
Unexplained young onset end-stage renal disease v3.18 TTR Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TTR.
Unexplained young onset end-stage renal disease v3.18 TULP3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TULP3.
Unexplained young onset end-stage renal disease v3.18 TRPM6 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TRPM6.
Unexplained young onset end-stage renal disease v3.18 TPRKB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TPRKB.
Unexplained young onset end-stage renal disease v3.18 STRADA Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: STRADA.
Unexplained young onset end-stage renal disease v3.18 SLC5A2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC5A2.
Unexplained young onset end-stage renal disease v3.18 SLC4A4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC4A4.
Unexplained young onset end-stage renal disease v3.18 SLC4A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC4A1.
Unexplained young onset end-stage renal disease v3.18 SLC34A3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC34A3.
Unexplained young onset end-stage renal disease v3.18 SLC34A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC34A1.
Unexplained young onset end-stage renal disease v3.18 SLC2A2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC2A2.
Unexplained young onset end-stage renal disease v3.18 SLC12A3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC12A3.
Unexplained young onset end-stage renal disease v3.18 SLC12A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC12A1.
Unexplained young onset end-stage renal disease v3.18 SCNN1G Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SCNN1G.
Unexplained young onset end-stage renal disease v3.18 SCNN1B Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SCNN1B.
Unexplained young onset end-stage renal disease v3.18 SCNN1A Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SCNN1A.
Unexplained young onset end-stage renal disease v3.18 SARS2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SARS2.
Unexplained young onset end-stage renal disease v3.18 RRAGD Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RRAGD.
Unexplained young onset end-stage renal disease v3.18 PHEX Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PHEX.
Unexplained young onset end-stage renal disease v3.18 NR3C2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NR3C2.
Unexplained young onset end-stage renal disease v3.18 MOCOS Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MOCOS.
Unexplained young onset end-stage renal disease v3.18 MAGED2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MAGED2.
Unexplained young onset end-stage renal disease v3.18 LYZ Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: LYZ.
Unexplained young onset end-stage renal disease v3.18 LCAT Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: LCAT.
Unexplained young onset end-stage renal disease v3.18 KLHL3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KLHL3.
Unexplained young onset end-stage renal disease v3.18 KCNJ16 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KCNJ16.
Unexplained young onset end-stage renal disease v3.18 KCNJ10 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KCNJ10.
Unexplained young onset end-stage renal disease v3.18 KCNJ1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KCNJ1.
Unexplained young onset end-stage renal disease v3.18 IFT27 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IFT27.
Unexplained young onset end-stage renal disease v3.18 IFT172 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IFT172.
Unexplained young onset end-stage renal disease v3.18 IFT140 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IFT140.
Unexplained young onset end-stage renal disease v3.18 HPRT1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HPRT1.
Unexplained young onset end-stage renal disease v3.18 HNF4A Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HNF4A.
Unexplained young onset end-stage renal disease v3.18 GSN Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GSN.
Unexplained young onset end-stage renal disease v3.18 GON7 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GON7.
Unexplained young onset end-stage renal disease v3.18 GNA11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GNA11.
Unexplained young onset end-stage renal disease v3.18 FLCN Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FLCN.
Unexplained young onset end-stage renal disease v3.18 FGA Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FGA.
Unexplained young onset end-stage renal disease v3.18 FAM20A Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FAM20A.
Unexplained young onset end-stage renal disease v3.18 FAH Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FAH.
Unexplained young onset end-stage renal disease v3.18 DLG5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: DLG5.
Unexplained young onset end-stage renal disease v3.18 DAAM2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: DAAM2.
Unexplained young onset end-stage renal disease v3.18 CYP24A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CYP24A1.
Unexplained young onset end-stage renal disease v3.18 CUL3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CUL3.
Unexplained young onset end-stage renal disease v3.18 CNNM2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CNNM2.
Unexplained young onset end-stage renal disease v3.18 CLDN19 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN19.
Unexplained young onset end-stage renal disease v3.18 CLDN16 Achchuthan Shanmugasundram Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal 248250; Hypomagnesemia 3, renal to Hypomagnesemia 3, renal, OMIM: 248250
Unexplained young onset end-stage renal disease v3.17 CLDN16 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN16.
Unexplained young onset end-stage renal disease v3.17 CLDN10 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN10.
Unexplained young onset end-stage renal disease v3.17 CLCNKB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLCNKB.
Unexplained young onset end-stage renal disease v3.17 CFHR2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CFHR2.
Unexplained young onset end-stage renal disease v3.17 CA2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CA2.
Unexplained young onset end-stage renal disease v3.17 CASR Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CASR.
Unexplained young onset end-stage renal disease v3.17 AVPR2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: AVPR2.
Unexplained young onset end-stage renal disease v3.17 ATP6V1B1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ATP6V1B1.
Unexplained young onset end-stage renal disease v3.17 ATP6V0A4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ATP6V0A4.
Unexplained young onset end-stage renal disease v3.17 ATP1A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ATP1A1.
Unexplained young onset end-stage renal disease v3.17 APOE Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOE.
Unexplained young onset end-stage renal disease v3.17 APOC2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOC2.
Unexplained young onset end-stage renal disease v3.17 APOA2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOA2.
Unexplained young onset end-stage renal disease v3.17 APOA1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOA1.
Unexplained young onset end-stage renal disease v3.17 AP2S1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: AP2S1.
Unexplained young onset end-stage renal disease v3.17 ALG9 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ALG9.
Unexplained young onset end-stage renal disease v3.17 ALG8 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ALG8.
Unexplained young onset end-stage renal disease v3.17 ALG5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ALG5.
Unexplained young onset end-stage renal disease v3.17 YRDC Achchuthan Shanmugasundram gene: YRDC was added
gene: YRDC was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: YRDC was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: YRDC were set to Galloway-Mowat syndrome MONDO:0009627
Unexplained young onset end-stage renal disease v3.17 WNK4 Achchuthan Shanmugasundram gene: WNK4 was added
gene: WNK4 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: WNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: WNK4 were set to Pseudohypoaldosteronism, type IIB, 614491
Unexplained young onset end-stage renal disease v3.17 TULP3 Achchuthan Shanmugasundram gene: TULP3 was added
gene: TULP3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TULP3 were set to Hepatorenocardiac degenerative fibrosis, OMIM:619902
Unexplained young onset end-stage renal disease v3.17 TTR Achchuthan Shanmugasundram gene: TTR was added
gene: TTR was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TTR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TTR were set to Amyloidosis, hereditary, transthyretin-related 105210
Unexplained young onset end-stage renal disease v3.17 TRPM6 Achchuthan Shanmugasundram gene: TRPM6 was added
gene: TRPM6 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal, 602014
Unexplained young onset end-stage renal disease v3.17 TPRKB Achchuthan Shanmugasundram gene: TPRKB was added
gene: TPRKB was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TPRKB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TPRKB were set to Galloway-Mowat syndrome 5, OMIM:617731
Unexplained young onset end-stage renal disease v3.17 STRADA Achchuthan Shanmugasundram gene: STRADA was added
gene: STRADA was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: STRADA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STRADA were set to Polyhydramnios, megalencephaly, and symptomatic epilepsy, 611087
Unexplained young onset end-stage renal disease v3.17 SLC5A2 Achchuthan Shanmugasundram gene: SLC5A2 was added
gene: SLC5A2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC5A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC5A2 were set to Renal glucosuria, 233100
Unexplained young onset end-stage renal disease v3.17 SLC4A4 Achchuthan Shanmugasundram gene: SLC4A4 was added
gene: SLC4A4 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC4A4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC4A4 were set to Renal tubular acidosis, proximal, with ocular abnormalities, 604278; Proximal Renal Tubular Acidosis with Ocular Abnormalities; Proximal Renal Tubular Acidosis with Ocular Abnormalities (recessive).
Unexplained young onset end-stage renal disease v3.17 SLC4A1 Achchuthan Shanmugasundram gene: SLC4A1 was added
gene: SLC4A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC4A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC4A1 were set to Renal tubular acidosis, distal, AR 611590; distal renal tubular acidosis; Renal tubular acidosis, distal, AD, 179800
Unexplained young onset end-stage renal disease v3.17 SLC34A3 Achchuthan Shanmugasundram gene: SLC34A3 was added
gene: SLC34A3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC34A3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: SLC34A3 were set to hereditary hypophosphatemic rickets with hypercalciuria, MONDO:0009431; HHRH; Hypophosphatemic rickets with hypercalciuria, OMIM:241530
Unexplained young onset end-stage renal disease v3.17 SLC34A1 Achchuthan Shanmugasundram gene: SLC34A1 was added
gene: SLC34A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC34A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC34A1 were set to Nephrolithiasis with osteoporosis and hypophosphatemia; Hypophosphatemic Nephrolithiasis/Osteoporosis (recessive); Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286; Hypophosphatemic Nephrolithiasis/Osteoporosis
Unexplained young onset end-stage renal disease v3.17 SLC2A2 Achchuthan Shanmugasundram gene: SLC2A2 was added
gene: SLC2A2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC2A2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC2A2 were set to Fanconi-Bickel syndrome, OMIM:227810
Unexplained young onset end-stage renal disease v3.17 SLC12A3 Achchuthan Shanmugasundram gene: SLC12A3 was added
gene: SLC12A3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC12A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC12A3 were set to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Unexplained young onset end-stage renal disease v3.17 SLC12A1 Achchuthan Shanmugasundram gene: SLC12A1 was added
gene: SLC12A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC12A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC12A1 were set to Bartter syndrome, type 1, OMIM:601678; Bartter disease type 1, MONDO:0100344
Unexplained young onset end-stage renal disease v3.17 SCNN1G Achchuthan Shanmugasundram gene: SCNN1G was added
gene: SCNN1G was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SCNN1G was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SCNN1G were set to Pseudohypoaldosteronism, type I, 264350
Unexplained young onset end-stage renal disease v3.17 SCNN1B Achchuthan Shanmugasundram gene: SCNN1B was added
gene: SCNN1B was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SCNN1B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SCNN1B were set to Pseudohypoaldosteronism, type I, 264350
Unexplained young onset end-stage renal disease v3.17 SCNN1A Achchuthan Shanmugasundram gene: SCNN1A was added
gene: SCNN1A was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SCNN1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SCNN1A were set to Pseudohypoaldosteronism, type I, 264350; ?Liddle syndrom 3, 618126; Bronchiectasis with or without elevated sweat chloride 2 613021
Unexplained young onset end-stage renal disease v3.17 SARS2 Achchuthan Shanmugasundram gene: SARS2 was added
gene: SARS2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SARS2 were set to Progressive Spastic Paresis; Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, OMIM:613845
Unexplained young onset end-stage renal disease v3.17 RRAGD Achchuthan Shanmugasundram gene: RRAGD was added
gene: RRAGD was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RRAGD were set to salt wasting; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130; cardiomyopathy; hypomagnesaemia; nephrocalcinosis
Mode of pathogenicity for gene: RRAGD was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Unexplained young onset end-stage renal disease v3.17 PHEX Achchuthan Shanmugasundram gene: PHEX was added
gene: PHEX was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: PHEX were set to Hypophosphatemic rickets, X-linked dominant 307800
Unexplained young onset end-stage renal disease v3.17 NR3C2 Achchuthan Shanmugasundram gene: NR3C2 was added
gene: NR3C2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: NR3C2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NR3C2 were set to Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy, 605115 no inheritance pattern; Pseudohypoaldosteronism type I, autosomal dominant, 177735
Unexplained young onset end-stage renal disease v3.17 MOCOS Achchuthan Shanmugasundram gene: MOCOS was added
gene: MOCOS was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: MOCOS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MOCOS were set to Xanthinuria, type II, OMIM:603592
Unexplained young onset end-stage renal disease v3.17 MAGED2 Achchuthan Shanmugasundram gene: MAGED2 was added
gene: MAGED2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: MAGED2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: MAGED2 were set to Bartter syndrome, type 5, antenatal, transient, 300971
Unexplained young onset end-stage renal disease v3.17 LYZ Achchuthan Shanmugasundram gene: LYZ was added
gene: LYZ was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: LYZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LYZ were set to Amyloidosis, renal 105200
Unexplained young onset end-stage renal disease v3.17 LCAT Achchuthan Shanmugasundram gene: LCAT was added
gene: LCAT was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: LCAT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LCAT were set to Norum disease, OMIM:245900; Norum disease, MONDO:0009515; LCAT DEFICIENCY
Unexplained young onset end-stage renal disease v3.17 KLHL3 Achchuthan Shanmugasundram gene: KLHL3 was added
gene: KLHL3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KLHL3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: KLHL3 were set to Pseudohypoaldosteronism, type IID, 614495
Unexplained young onset end-stage renal disease v3.17 KCNJ16 Achchuthan Shanmugasundram gene: KCNJ16 was added
gene: KCNJ16 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ16 were set to Hypokalemic tubulopathy and deafness, OMIM:619406
Unexplained young onset end-stage renal disease v3.17 KCNJ10 Achchuthan Shanmugasundram gene: KCNJ10 was added
gene: KCNJ10 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KCNJ10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ10 were set to SESAME/EAST syndrome, 612780
Unexplained young onset end-stage renal disease v3.17 KCNJ1 Achchuthan Shanmugasundram gene: KCNJ1 was added
gene: KCNJ1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KCNJ1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ1 were set to often initial transient hyperkalemia; Antenatal Bartter Syndrome; Bartter syndrome, type 2, 241200; Type 2 Bartter syndrome
Unexplained young onset end-stage renal disease v3.17 IFT27 Achchuthan Shanmugasundram gene: IFT27 was added
gene: IFT27 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: IFT27 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFT27 were set to ?Bardet-Biedl syndrome 19, OMIM:615996
Unexplained young onset end-stage renal disease v3.17 IFT172 Achchuthan Shanmugasundram gene: IFT172 was added
gene: IFT172 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: IFT172 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFT172 were set to Short-rib thoracic dysplasia 10 with or without polydactyly, OMIM:615630
Unexplained young onset end-stage renal disease v3.17 IFT140 Achchuthan Shanmugasundram gene: IFT140 was added
gene: IFT140 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: IFT140 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: IFT140 were set to Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; cystic kidney disease, MONDO:0002473; short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964
Unexplained young onset end-stage renal disease v3.17 HPRT1 Achchuthan Shanmugasundram gene: HPRT1 was added
gene: HPRT1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: HPRT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: HPRT1 were set to Lesch-Nyhan syndrome, OMIM:300322; Hyperuricemia, HRPT-related, OMIM:300323
Unexplained young onset end-stage renal disease v3.17 HNF4A Achchuthan Shanmugasundram gene: HNF4A was added
gene: HNF4A was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: HNF4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HNF4A were set to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM:616026
Unexplained young onset end-stage renal disease v3.17 GSN Achchuthan Shanmugasundram gene: GSN was added
gene: GSN was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: GSN was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: GSN were set to Amyloidosis, Finnish type, OMIM:105120
Unexplained young onset end-stage renal disease v3.17 GON7 Achchuthan Shanmugasundram gene: GON7 was added
gene: GON7 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: GON7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GON7 were set to Galloway-Mowat syndrome MONDO:0009627
Unexplained young onset end-stage renal disease v3.17 GNA11 Achchuthan Shanmugasundram gene: GNA11 was added
gene: GNA11 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: GNA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GNA11 were set to Hypocalcemia, autosomal dominant 2 615361
Unexplained young onset end-stage renal disease v3.17 FLCN Achchuthan Shanmugasundram gene: FLCN was added
gene: FLCN was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FLCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FLCN were set to Birt-Hogg-Dube syndrome, OMIM:135150; renal cell carcinoma; renal cysts; pneumothorax; renal oncocytoma; pulmonary cysts; cutaneous fibrofolliculoma
Unexplained young onset end-stage renal disease v3.17 FGA Achchuthan Shanmugasundram gene: FGA was added
gene: FGA was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FGA were set to Amyloidosis, familial visceral, OMIM:105200
Unexplained young onset end-stage renal disease v3.17 FAM20A Achchuthan Shanmugasundram gene: FAM20A was added
gene: FAM20A was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FAM20A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAM20A were set to Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690
Unexplained young onset end-stage renal disease v3.17 FAH Achchuthan Shanmugasundram gene: FAH was added
gene: FAH was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAH were set to Tyrosinemia, type I
Unexplained young onset end-stage renal disease v3.17 DLG5 Achchuthan Shanmugasundram gene: DLG5 was added
gene: DLG5 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: DLG5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DLG5 were set to DLG5-associated developmental disorder (monoallelic); DLG5-associated developmental disorder (biallelic)
Unexplained young onset end-stage renal disease v3.17 DAAM2 Achchuthan Shanmugasundram gene: DAAM2 was added
gene: DAAM2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: DAAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DAAM2 were set to steroid-resistant nephrotic syndrome MONDO:0044765
Unexplained young onset end-stage renal disease v3.17 CYP24A1 Achchuthan Shanmugasundram gene: CYP24A1 was added
gene: CYP24A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CYP24A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CYP24A1 were set to Infantile hypercalcaemia; Infantile Hypercalcemia; Hypercalcemia, infantile, 143880
Unexplained young onset end-stage renal disease v3.17 CUL3 Achchuthan Shanmugasundram gene: CUL3 was added
gene: CUL3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CUL3 were set to Pseudohypoaldosteronism, type IIE, 214496
Unexplained young onset end-stage renal disease v3.17 CNNM2 Achchuthan Shanmugasundram gene: CNNM2 was added
gene: CNNM2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CNNM2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: CNNM2 were set to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; renal hypomagnesemia 6, MONDO:0013480; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631; Hypomagnesemia 6, renal, OMIM:613882
Mode of pathogenicity for gene: CNNM2 was set to Other
Unexplained young onset end-stage renal disease v3.17 CLDN19 Achchuthan Shanmugasundram gene: CLDN19 was added
gene: CLDN19 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLDN19 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CLDN19 were set to hypomagensemia with nephrocalcinosis; Hypomagnesemia 5, renal, with ocular involvement
Unexplained young onset end-stage renal disease v3.17 CLDN16 Achchuthan Shanmugasundram Added phenotypes Hypomagnesemia 3, renal 248250 for gene: CLDN16
Unexplained young onset end-stage renal disease v3.17 CLDN16 Achchuthan Shanmugasundram gene: CLDN16 was added
gene: CLDN16 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLDN16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CLDN16 were set to Hypomagnesemia 3, renal
Unexplained young onset end-stage renal disease v3.17 CLDN10 Achchuthan Shanmugasundram gene: CLDN10 was added
gene: CLDN10 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLDN10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CLDN10 were set to HELIX syndrome, OMIM:617671; Hypokalemic-alkalotic salt-losing tubulopathy
Unexplained young onset end-stage renal disease v3.17 CLCNKB Achchuthan Shanmugasundram gene: CLCNKB was added
gene: CLCNKB was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLCNKB was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: CLCNKB were set to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 3, MONDO:0011822; Bartter disease type 4B, MONDO:0000909; Bartter syndrome, type 3, OMIM:607364
Unexplained young onset end-stage renal disease v3.17 CFHR2 Achchuthan Shanmugasundram gene: CFHR2 was added
gene: CFHR2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CFHR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: CFHR2 were set to Immune complex MPGN; IC-MPGN; C3 glomerulopathy; C3G; Immune-complex-mediated MPGN
Unexplained young onset end-stage renal disease v3.17 CASR Achchuthan Shanmugasundram gene: CASR was added
gene: CASR was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CASR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: CASR were set to Hypocalcemia (dominant); Hypocalciuric hypercalcemia, type I, 145980Hyperparathyroidism, neonatal, 239200Hypocalcemia, autosomal dominant, 601198Hypocalcemia, autosomal dominant, with Bartter syndrome, 601198{Epilepsy idiopathic generalized, susceptibility to,; Familial Hypocalciuric Hypercalcemia (dominant); hypocalciuric hypercalcaemia; Familial Hypocalciuric Hypercalcemia
Mode of pathogenicity for gene: CASR was set to Other
Unexplained young onset end-stage renal disease v3.17 CA2 Achchuthan Shanmugasundram gene: CA2 was added
gene: CA2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis
Unexplained young onset end-stage renal disease v3.17 AVPR2 Achchuthan Shanmugasundram gene: AVPR2 was added
gene: AVPR2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: AVPR2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: AVPR2 were set to Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539; Diabetes insipidus, nephrogenic, OMIM:304800
Mode of pathogenicity for gene: AVPR2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Unexplained young onset end-stage renal disease v3.17 ATP6V1B1 Achchuthan Shanmugasundram gene: ATP6V1B1 was added
gene: ATP6V1B1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ATP6V1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP6V1B1 were set to Renal tubular acidosis with deafness 267300; distal renal tubular acidosis
Unexplained young onset end-stage renal disease v3.17 ATP6V0A4 Achchuthan Shanmugasundram gene: ATP6V0A4 was added
gene: ATP6V0A4 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ATP6V0A4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP6V0A4 were set to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Unexplained young onset end-stage renal disease v3.17 ATP1A1 Achchuthan Shanmugasundram gene: ATP1A1 was added
gene: ATP1A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ATP1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATP1A1 were set to Hypomagnesemia, seizures, and mental retardation 2 618314; Charcot-Marie-Tooth disease, axonal, type 2DD, 618036
Unexplained young onset end-stage renal disease v3.17 AQP2 Achchuthan Shanmugasundram gene: AQP2 was added
gene: AQP2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: AQP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: AQP2 were set to Nephrogenic diabetes insipidus; Diabetes insipidus, nephrogenic, 125800
Unexplained young onset end-stage renal disease v3.17 APOE Achchuthan Shanmugasundram gene: APOE was added
gene: APOE was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APOE were set to Lipoprotein glomerulopathy, OMIM:611771
Unexplained young onset end-stage renal disease v3.17 APOC2 Achchuthan Shanmugasundram gene: APOC2 was added
gene: APOC2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.17 APOA2 Achchuthan Shanmugasundram gene: APOA2 was added
gene: APOA2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.17 APOA1 Achchuthan Shanmugasundram gene: APOA1 was added
gene: APOA1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APOA1 were set to Amyloidosis, 3 or more types OMIM:105200; familial visceral amyloidosis MONDO:0007099
Unexplained young onset end-stage renal disease v3.17 AP2S1 Achchuthan Shanmugasundram gene: AP2S1 was added
gene: AP2S1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AP2S1 were set to Familial hypocalciuric hypercalcemia type III 600740
Unexplained young onset end-stage renal disease v3.17 ALG9 Achchuthan Shanmugasundram gene: ALG9 was added
gene: ALG9 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ALG9 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: ALG9 were set to cystic liver disease; cystic kidney disease; Gillessen-Kaesbach-Nishimura syndrome, 263210
Unexplained young onset end-stage renal disease v3.17 ALG8 Achchuthan Shanmugasundram gene: ALG8 was added
gene: ALG8 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ALG8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ALG8 were set to cystic liver disease; cystic kidney disease; Polycystic liver disease 3 with or without kidney cysts, 617874
Unexplained young onset end-stage renal disease v3.17 ALG5 Achchuthan Shanmugasundram gene: ALG5 was added
gene: ALG5 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ALG5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ALG5 were set to Polycystic kidney disease 7, OMIM:620056
Unexplained young onset end-stage renal disease v3.16 FN1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FN1.
Unexplained young onset end-stage renal disease v3.16 PDSS2 Achchuthan Shanmugasundram Classified gene: PDSS2 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.16 PDSS2 Achchuthan Shanmugasundram Gene: pdss2 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.15 PDSS2 Achchuthan Shanmugasundram Phenotypes for gene: PDSS2 were changed from to Coenzyme Q10 deficiency, primary, 3, OMIM:614652; Leigh syndrome, MONDO:0009723
Unexplained young onset end-stage renal disease v3.14 PDSS2 Achchuthan Shanmugasundram Mode of inheritance for gene: PDSS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.13 PDSS2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PDSS2.
Unexplained young onset end-stage renal disease v3.13 PDSS2 Achchuthan Shanmugasundram reviewed gene: PDSS2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coenzyme Q10 deficiency, primary, 3, OMIM:614652, Leigh syndrome, MONDO:0009723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.13 FN1 Achchuthan Shanmugasundram reviewed gene: FN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glomerulopathy with fibronectin deposits 2, OMIM:601894; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.13 CD151 Achchuthan Shanmugasundram Phenotypes for gene: CD151 were changed from Nephropathy with pretibial epidermolysis bullosa and deafness 609057 to Epidermolysis bullosa simplex 7, with nephropathy and deafness, OMIM:609057
Unexplained young onset end-stage renal disease v3.12 CD151 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CD151.
Unexplained young onset end-stage renal disease v3.12 CD151 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green on 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/); to: This gene should be promoted to green rating in this panel as it has already been rated green on 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).
Unexplained young onset end-stage renal disease v3.12 CD151 Achchuthan Shanmugasundram reviewed gene: CD151: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa simplex 7, with nephropathy and deafness, OMIM:609057; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.12 APRT Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APRT.
Unexplained young onset end-stage renal disease v3.12 APRT Achchuthan Shanmugasundram Phenotypes for gene: APRT were changed from interstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis; Adenine phosphoribosyltransferase deficiency 614723 to Adenine phosphoribosyltransferase deficiency, OMIM:614723
Unexplained young onset end-stage renal disease v3.11 APRT Achchuthan Shanmugasundram reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenine phosphoribosyltransferase deficiency, OMIM:614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Classified gene: CRAT as Amber List (moderate evidence)
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case each with NBIA and Leigh syndrome. Hence, this gene can be promoted to amber with current evidence.
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Gene: crat has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.154 CRAT Achchuthan Shanmugasundram Classified gene: CRAT as Amber List (moderate evidence)
Mitochondrial disorders v4.154 CRAT Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with NBIA and Leigh syndrome. Hence, this gene can be promoted to amber with current evidence.
Mitochondrial disorders v4.154 CRAT Achchuthan Shanmugasundram Gene: crat has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.153 CRAT Achchuthan Shanmugasundram edited their review of gene: CRAT: Changed phenotypes to: ?Neurodegeneration with brain iron accumulation 8, OMIM:617917, Leigh syndrome, MONDO:0009723
Mitochondrial disorders v4.153 CRAT Achchuthan Shanmugasundram Phenotypes for gene: CRAT were changed from ?Neurodegeneration with brain iron accumulation 8, OMIM:617917; Leigh syndrome, OMIM:MONDO:0009723 to ?Neurodegeneration with brain iron accumulation 8, OMIM:617917; Leigh syndrome, MONDO:0009723
Mitochondrial disorders v4.152 CRAT Achchuthan Shanmugasundram Phenotypes for gene: CRAT were changed from ?Neurodegeneration with brain iron accumulation 8 617917 to ?Neurodegeneration with brain iron accumulation 8, OMIM:617917; Leigh syndrome, OMIM:MONDO:0009723
Mitochondrial disorders v4.151 CRAT Achchuthan Shanmugasundram Publications for gene: CRAT were set to 29395073; 29903433; 31448845
Mitochondrial disorders v4.151 CRAT Achchuthan Shanmugasundram Publications for gene: CRAT were set to 29903433; 29395073
Mitochondrial disorders v4.150 CRAT Achchuthan Shanmugasundram Mode of inheritance for gene: CRAT was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.149 CRAT Achchuthan Shanmugasundram reviewed gene: CRAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Neurodegeneration with brain iron accumulation 8, OMIM:617917, Leigh syndrome, OMIM:MONDO:0009723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Classified gene: OXA1L as Amber List (moderate evidence)
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is a single family and functional evidence available in support of the association of OXA1L to this panel. Hence, this gene should be promoted to amber.
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Gene: oxa1l has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.148 OXA1L Achchuthan Shanmugasundram Classified gene: OXA1L as Amber List (moderate evidence)
Mitochondrial disorders v4.148 OXA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is a single family and functional evidence available in support of the association of OXA1L to this panel. Hence, this gene should be promoted to amber.
Mitochondrial disorders v4.148 OXA1L Achchuthan Shanmugasundram Gene: oxa1l has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.147 OXA1L Achchuthan Shanmugasundram Publications for gene: OXA1L were set to
Mitochondrial disorders v4.146 OXA1L Achchuthan Shanmugasundram reviewed gene: OXA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 FGL2 Achchuthan Shanmugasundram Classified gene: FGL2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 FGL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer and reported in PMID:36243222, there is a child with early-onset systemic inflammation, autoantibodies, and vasculitis and homozygous truncating FGL2 variant and functional evidence are available in support of the disease association. Hence, this gene should be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 FGL2 Achchuthan Shanmugasundram Gene: fgl2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.161 FGL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.161 FGL2 Achchuthan Shanmugasundram Phenotypes for gene: FGL2 were changed from autoinflammatory syndrome, MONDO:0019751 to autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v4.160 FGL2 Achchuthan Shanmugasundram Phenotypes for gene: FGL2 were changed from immunedysregulation; autoimmunity; arthritis; Treg dysfunction; leukocytoclastic vasculitis to autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v4.159 FGL2 Achchuthan Shanmugasundram reviewed gene: FGL2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36243222; Phenotypes: autoinflammatory syndrome, MONDO:0019751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.159 CBLB Achchuthan Shanmugasundram Phenotypes for gene: CBLB were changed from immunedysregulation; autoimmunity; hypothyroidism; diabetes mellitus type I; vitiligo; urticaria; HLH; ITP; autoimmune hemolytic anemia to Autoimmune disease, multisystem, infantile-onset, 3, OMIM:620430
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Classified gene: CBLB as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer and reported in PMID:36006710, there are three unrelated cases and functional evidence are available for the association of biallelic CBLB variants with infantile-onset autoimmune disease (MIM #620430). Hence, this gene should be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Gene: cblb has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.157 CBLB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CBLB.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.157 CBLB Achchuthan Shanmugasundram reviewed gene: CBLB: Rating: GREEN; Mode of pathogenicity: None; Publications: 36006710; Phenotypes: Autoimmune disease, multisystem, infantile-onset, 3, OMIM:620430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.399 RPL10 Achchuthan Shanmugasundram Phenotypes for gene: RPL10 were changed from Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998 to Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998
Intellectual disability v5.399 RPL10 Achchuthan Shanmugasundram Phenotypes for gene: RPL10 were changed from Mental retardation, X-linked, syndromic, 35, 300998 to Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998
Intellectual disability v5.398 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability v5.398 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability v5.398 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability v5.397 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability v5.397 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788
Intellectual disability v5.396 RPL10 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Sarah Leigh and Dmitrijs Rots, all the cases reported previously in literature and recently in PMID:35876338 were males with hemizygous RPL10 variants. The females were carriers and showed fully skewed X inactivation of the mutation-bearing X chromosomes.

In addition, this gene has been associated with relevant phenotypes in both OMIM (MIM #300998) and Gene2Phenotype (with 'definitive' rating on the DD panel). The MOI has been recorded as 'X-linked recessive' in OMIM.

The MOI should therefore be updated from 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' to 'X-LINKED: hemizygous mutation in males, biallelic mutations in females' in the next GMS review.
Intellectual disability v5.396 RPL10 Achchuthan Shanmugasundram Mode of inheritance for gene: RPL10 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v5.395 RPL10 Achchuthan Shanmugasundram Tag Q4_23_MOI tag was added to gene: RPL10.
Intellectual disability v5.395 RPL10 Achchuthan Shanmugasundram reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v5.395 RELN Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal"to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.; to: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.
Intellectual disability v5.395 RELN Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal"to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.
Intellectual disability v5.395 RELN Achchuthan Shanmugasundram Mode of inheritance for gene: RELN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.394 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.394 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.393 RELN Achchuthan Shanmugasundram Tag Q4_23_MOI tag was added to gene: RELN.
Intellectual disability v5.393 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.393 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.393 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), 257320; LISSENCEPHALY 2 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.392 RELN Achchuthan Shanmugasundram Publications for gene: RELN were set to
Intellectual disability v5.391 RELN Achchuthan Shanmugasundram reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 35769015; Phenotypes: Lissencephaly 2 (Norman-Roberts type), OMIM:257320, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh changed review comment from: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.; to: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen or Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh changed review comment from: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022). This is because the ALS Gene Curation Expert Panel will only score protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.; to: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: DNAJC7.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh edited their review of gene: DNAJC7: Added comment: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022). This is because the ALS Gene Curation Expert Panel will only score protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.; Changed rating: GREEN
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Classified gene: DNAJC7 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.391 CLDN11 Achchuthan Shanmugasundram Deleted their comment
Childhood onset hereditary spastic paraplegia v4.36 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.391 CLDN11 Achchuthan Shanmugasundram Classified gene: CLDN11 as Amber List (moderate evidence)
Intellectual disability v5.391 CLDN11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated patients) for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.391 CLDN11 Achchuthan Shanmugasundram Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.390 CLDN11 Achchuthan Shanmugasundram Classified gene: CLDN11 as Amber List (moderate evidence)
Intellectual disability v5.390 CLDN11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated patients) for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.390 CLDN11 Achchuthan Shanmugasundram Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.389 CLDN11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN11.
Intellectual disability v5.389 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Review for gene: CLDN11 was set to GREEN
Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. These patients exhibit global developmental delay, particularly motor and speech delay. Intellectual disability was maximally mild in two of three individuals and the intelligence is in a low-normal range in third individual, although IQ testing was not performed in them.

Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes global developmental delay and impaired intellectual development (mild) as clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Adult onset neurodegenerative disorder v4.44 DNAJC7 Sarah Leigh Publications for gene: DNAJC7 were set to https://doi.org/10.1212/NXG.0000000000000503
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes nystagmus as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes nystagmus as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Adult onset neurodegenerative disorder v4.43 DNAJC7 Sarah Leigh Classified gene: DNAJC7 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v4.43 DNAJC7 Sarah Leigh Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.36 RHOB Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID: 32989326 reports RHOB p.Ser73Phe as being gain of function.
Childhood onset hereditary spastic paraplegia v4.36 RHOB Sarah Leigh Mode of pathogenicity for gene: RHOB was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Childhood onset hereditary spastic paraplegia v4.35 RHOB Sarah Leigh reviewed gene: RHOB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset hereditary spastic paraplegia v4.35 RHOB Sarah Leigh Classified gene: RHOB as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.35 RHOB Sarah Leigh Gene: rhob has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: KIAA0586.
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Classified gene: KIAA0586 as Amber List (moderate evidence)
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Gene: kiaa0586 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v3.17 KIAA0586 Sarah Leigh reviewed gene: KIAA0586: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes nystagmus as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram Entity copied from Childhood onset hereditary spastic paraplegia v4.34
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Albinism or congenital nystagmus. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: CLDN11.
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram Classified gene: CLDN11 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated patients) for the promotion of this gene to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.33 CLDN11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN11.
Childhood onset hereditary spastic paraplegia v4.33 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Review for gene: CLDN11 was set to GREEN
Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood solid tumours v4.14 CDKN2A Arina Puzriakova Classified gene: CDKN2A as Amber List (moderate evidence)
Childhood solid tumours v4.14 CDKN2A Arina Puzriakova Added comment: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumours, including cutaneous melanoma, pancreatic cancer and tumours of the nervous system such as astrocytomas.

Onset is typically in adulthood but following specialist review, it was agreed that it is appropriate to include the CDKN2A gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.14 CDKN2A Arina Puzriakova Gene: cdkn2a has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v3.26 CLDN11 Achchuthan Shanmugasundram Phenotypes for gene: CLDN11 were changed from Hypomyelinating leukodystrophy to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Childhood solid tumours v4.13 CDKN2A Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: CDKN2A.
Tag Q4_23_NHS_review tag was added to gene: CDKN2A.
Childhood solid tumours v4.13 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from cutaneous melanoma; pancreatic cancer; astrocytomas to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Melanoma pertinent cancer susceptibility v1.2 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from Malignant Melanoma to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Adult solid tumours for rare disease v1.39 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from Familial Malignant Melanoma and Tumors of the Nervous system, Familial Uveal Melanoma to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Skeletal ciliopathies v3.17 KIAA0586 Sarah Leigh Publications for gene: KIAA0586 were set to 26166481
Skeletal ciliopathies v3.16 KIAA0586 Sarah Leigh Phenotypes for gene: KIAA0586 were changed from Short-rib thoracic dysplasia 14 with polydactyly, MIM# 616546 to Short-rib thoracic dysplasia 14 with polydactyly, OMIM:616546; short-rib thoracic dysplasia 14 with polydactyly, MONDO:0014688
Skeletal ciliopathies v3.15 KIAA0586 Sarah Leigh Classified gene: KIAA0586 as Amber List (moderate evidence)
Skeletal ciliopathies v3.15 KIAA0586 Sarah Leigh Gene: kiaa0586 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.146 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Childhood solid tumours v4.12 BAP1 Arina Puzriakova changed review comment from: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).; to: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review, it was agreed that it is appropriate to include the BAP1 gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.12 BAP1 Arina Puzriakova changed review comment from: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel, as reviewed by Terri McVeigh (The Royal Marsden NHS).; to: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.12 BAP1 Arina Puzriakova Classified gene: BAP1 as Amber List (moderate evidence)
Childhood solid tumours v4.12 BAP1 Arina Puzriakova Added comment: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.12 BAP1 Arina Puzriakova Gene: bap1 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v4.11 BAP1 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: BAP1.
Tag Q4_23_NHS_review tag was added to gene: BAP1.
Pigmentary skin disorders v3.6 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from TPDS; Melanoma susceptility; TUMOR PREDISPOSITION SYNDROME to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Inherited renal cancer v1.27 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Tumor predisposition syndrome, OMIM:614327; BAP1-related tumor predisposition syndrome, MONDO:0013692; Renal cell carcinoma (disease), MONDO:0005086; Clear cell renal carcinoma, MONDO:0005005 to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Familial melanoma v2.4 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Adult solid tumours for rare disease v1.38 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Melanocytic Tumor syndrome, Familial Uveal Melanoma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Melanoma pertinent cancer susceptibility v1.1 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Malignant Melanoma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Childhood solid tumours v4.11 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from uveal melanoma; mesothelioma; cholangiocarcioma; cutaneous melanoma; renal cell carcinoma; meningioma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Adult solid tumours cancer susceptibility v2.28 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Melanocytic Tumor syndrome, Familial Uveal Melanoma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.146 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Mitochondrial disorders v4.146 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.146 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.145 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Likely inborn error of metabolism - targeted testing not possible v4.121 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Mitochondrial disorder with complex IV deficiency v3.13 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Possible mitochondrial disorder - nuclear genes v3.84 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Tag Q4_23_NHS_review tag was added to gene: COX5A.
Likely inborn error of metabolism - targeted testing not possible v4.121 COX5A Sarah Leigh Mode of inheritance for gene: COX5A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.145 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Likely inborn error of metabolism - targeted testing not possible v4.120 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorder with complex IV deficiency v3.13 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from Pulmonary arterial hypertension, lactic acidemia, and failure to thrive to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorders v4.144 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525
Possible mitochondrial disorder - nuclear genes v3.84 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525; 35246835
Likely inborn error of metabolism - targeted testing not possible v4.119 COX5A Sarah Leigh Publications for gene: COX5A were set to
Mitochondrial disorder with complex IV deficiency v3.12 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Classified gene: ALK as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:32989326 reported a large cohort study of cerebral palsy, where two patients were identified with monoallelic ALK variants and presented with spastic diplegia with mild tremor or spastic-dystonic diplegia. Hence, this gene can be rated amber with current evidence.
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Gene: alk has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.31 ALK Achchuthan Shanmugasundram reviewed gene: ALK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: spastic diplegia, MONDO:0001167; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.83 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from Pulmonary arterial hypertension, lactic acidemia, and failure to thrive to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Possible mitochondrial disorder - nuclear genes v3.82 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.385 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability v5.385 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 24075189
Intellectual disability v5.384 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092 to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.384 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092 to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.383 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from MICROPHTHALMIA AND DIAPHRAGMATIC HERNIA to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.382 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Intellectual disability v5.382 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.382 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.381 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.380 COX11 Sarah Leigh commented on gene: COX11: The three unrelated case of Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275) so far reported, all had significant cognitive impairment and 2/3 of the cases had hypotonia (PMID: 36030551;38068960).
Intellectual disability v5.380 YARS Achchuthan Shanmugasundram changed review comment from: As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber. However, 'watchlist' tag has been added to review this gene in future with any new evidence.; to: As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber.
Intellectual disability v5.380 YARS Achchuthan Shanmugasundram reviewed gene: YARS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh edited their review of gene: COX11: Added comment: Epileptic seizures have been seen in 2/3 unrelated cases of Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275) carrying two different COX11 variants (PMID: 36030551;38068960).; Changed rating: AMBER
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh Tag Q4_23_promote_green was removed from gene: COX11.
Possible mitochondrial disorder - nuclear genes v3.81 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.81 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.81 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.80 COX11 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX11.
Tag Q4_23_NHS_review tag was added to gene: COX11.
Mitochondrial disorders v4.143 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Mitochondrial disorders v4.143 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.143 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v3.11 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v3.11 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorder with complex IV deficiency v3.11 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v3.10 COX11 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX11.
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh Entity copied from Mitochondrial disorders v4.142
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh gene: COX11 was added
gene: COX11 was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber
Q4_23_promote_green tags were added to gene: COX11.
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Intellectual disability v5.380 COX11 Sarah Leigh Entity copied from Mitochondrial disorders v4.142
Intellectual disability v5.380 COX11 Sarah Leigh gene: COX11 was added
gene: COX11 was added to Intellectual disability - microarray and sequencing. Sources: NHS GMS,Expert Review Amber
Q4_23_promote_green tags were added to gene: COX11.
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorders v4.142 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Mitochondrial disorders v4.142 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.141 COX11 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX11.
Possible mitochondrial disorder - nuclear genes v3.80 COX11 Sarah Leigh reviewed gene: COX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v4.141 COX11 Sarah Leigh edited their review of gene: COX11: Added comment: COX11 variants have been associated with Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275), but not with a phenotype in Gen2Phen. At least four COX11 variants have been reported in three unrelated cases of OMIM:620275 (PMIDs: 36030551;38068960), together with supportive functional studies in patient's fibroblasts and Saccharomyces cerevisiae.; Changed rating: GREEN
Mitochondrial disorder with complex IV deficiency v3.10 COX11 Sarah Leigh reviewed gene: COX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v3.80 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.141 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v3.10 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.140 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520 to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Possible mitochondrial disorder - nuclear genes v3.79 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520 to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorders v4.139 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551; 38068960
Mitochondrial disorder with complex IV deficiency v3.9 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551; 38068960
Possible mitochondrial disorder - nuclear genes v3.78 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551; 38068960
Rhabdomyolysis and metabolic muscle disorders v3.48 HADHB Achchuthan Shanmugasundram Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency 609015 to Mitochondrial trifunctional protein deficiency 2, OMIM:620300
Rhabdomyolysis and metabolic muscle disorders v3.47 HADHB Achchuthan Shanmugasundram Publications for gene: HADHB were set to 25929793
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Classified gene: MECP2 as Amber List (moderate evidence)
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of MECP2 with severe microcephaly, this gene can be promoted to green rating in the next GMS review.
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Gene: mecp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.51 MECP2 Achchuthan Shanmugasundram Phenotypes for gene: MECP2 were changed from Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673 to Rett syndrome, OMIM:312750; Encephalopathy, neonatal severe, OMIM:300673; Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055; Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260
Severe microcephaly v4.50 MECP2 Achchuthan Shanmugasundram Publications for gene: MECP2 were set to
Severe microcephaly v4.49 MECP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MECP2.
Severe microcephaly v4.49 MECP2 Achchuthan Shanmugasundram reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32393352, 34351885; Phenotypes: Rett syndrome, OMIM:312750, Encephalopathy, neonatal severe, OMIM:300673, Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055, Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mitochondrial disorders v4.138 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551
Possible mitochondrial disorder - nuclear genes v3.77 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551
Mitochondrial disorder with complex IV deficiency v3.8 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551
Mitochondrial disorders v4.137 COX11 Sarah Leigh Publications for gene: COX11 were set to
Mitochondrial disorder with complex IV deficiency v3.7 COX11 Sarah Leigh Publications for gene: COX11 were set to
Possible mitochondrial disorder - nuclear genes v3.76 COX11 Sarah Leigh Publications for gene: COX11 were set to
Possible mitochondrial disorder - nuclear genes v3.75 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.136 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v3.6 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.135 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorder with complex IV deficiency v3.5 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Possible mitochondrial disorder - nuclear genes v3.74 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Breast cancer pertinent cancer susceptibility v2.8 ATRIP Arina Puzriakova Publications for gene: ATRIP were set to 36977412
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova changed review comment from: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.; to: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

This association is also now listed in Gene2Phenotype with a 'moderate' disease confidence category for breast cancer susceptibility.

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova Tag watchlist was removed from gene: ATRIP.
Tag Q4_23_promote_green tag was added to gene: ATRIP.
Tag Q4_23_expert_review tag was added to gene: ATRIP.
Likely inborn error of metabolism - targeted testing not possible v4.118 VPS33A Sarah Leigh Classified gene: VPS33A as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.118 VPS33A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.118 VPS33A Sarah Leigh Gene: vps33a has been classified as Amber List (Moderate Evidence).
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova commented on gene: ATRIP: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.
Likely inborn error of metabolism - targeted testing not possible v4.117 VPS33A Sarah Leigh gene: VPS33A was added
gene: VPS33A was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: VPS33A.
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 28013294; 27547915; 31070736
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome OMIM:617303; mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders MONDO:0015012
Review for gene: VPS33A was set to GREEN
Added comment: This gene has been copied from Lysosomal storage disorder panel:
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian population. Supportive functional studies were also presented (PMID 31070736).
Sarah Leigh (Genomics England Curator), 17 Mar 2021
Single variant (R498W) reported in the Turkish and Yakut population. Functional studies support association of this gene to lysosomal dysfunction. Sources: Expert list
Zornitza Stark (Australian Genomics), 22 Jul 2020
Sources: Other
Lysosomal storage disorder v3.3 VPS33A Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian poputation. Supportive functional studies were also presented (PMID 31070736). ; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian population. Supportive functional studies were also presented (PMID 31070736).
Likely inborn error of metabolism - targeted testing not possible v4.116 VPS16 Sarah Leigh Classified gene: VPS16 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.116 VPS16 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.116 VPS16 Sarah Leigh Gene: vps16 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.115 VPS16 Sarah Leigh Added comment: Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion for this allelic requirement. Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases. VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic)
Arina Puzriakova (Genomics England Curator), 14 Jun 2021
Likely inborn error of metabolism - targeted testing not possible v4.115 VPS16 Sarah Leigh Mode of inheritance for gene: VPS16 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.114 VPS16 Sarah Leigh gene: VPS16 was added
gene: VPS16 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: VPS16.
Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS16 were set to 33938619; 34013567
Phenotypes for gene: VPS16 were set to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia Associated with Lysosomal Abnormalities (monoallelic); Dystonia 30, OMIM:619291
Review for gene: VPS16 was set to GREEN
Added comment: Copied from Lysosomal storage disorder panel: Four individuals from three families were identified (PMIDs: 33938619; 34013567) exhibiting a mucopolysaccharidosis (MPS)-like lysosomal storage phenotype with short stature, coarse facies, DD or regression, peripheral neuropathy, skeletal dysplasia, neutropenia, and high-normal glycosaminoglycan excretion. All harboured homozygous variants in VPS16 which segregated with disease, including a missense variant in a sib pair (c.540G>T; p.Trp180Cys) and a recurrent intronic variant (c.2272‐18C>A) in two supposedly unrelated patients (although both of Middle Eastern descent). Fibroblasts of the two patients with the intronic variant showed accumulation of lysosomal compartments and autophagosomes with significantly decreased VPS16 mRNA and protein levels, as well as HOPS/CORVET complexes. Cellular phenotypes were rescued upon re-expression of wild-type VPS16. ----- Heterozygous variants, as well as a homozygous missense variant (c.156C>A) found in a consanguineous Chinese family (PMID:27174565), have been found to cause dystonia with variable onset (OMIM:619291). It has been suggested that the discrepancies in patient phenotypes are due to different mechanisms of pathogenicity, where variants causing dystonia do not affect the levels of endolysosomal tethering (HOPS/CORVET) complexes. More research is needed to clarify the mechanisms underlying VPS16-related dystonia as only limited functional data is currently available - Steel et al. 2020 (PMID:32808683) did perform electron microscopic studies of lymphocytes and fibroblasts derived from 2 unrelated patients, which showed vacuolar abnormalities suggestive of impaired lysosomal function. Sources: Literature
Arina Puzriakova (Genomics England Curator), 14 Jun 2021
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.113 CLCN7 Sarah Leigh Entity copied from Lysosomal storage disorder v3.3
Likely inborn error of metabolism - targeted testing not possible v4.113 CLCN7 Sarah Leigh gene: CLCN7 was added
gene: CLCN7 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Likely inborn error of metabolism - targeted testing not possible v4.112 KCTD7 Sarah Leigh gene: KCTD7 was added
gene: KCTD7 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Mode of inheritance for gene: KCTD7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCTD7 were set to Epilepsy, progressive myoclonic 3, with or without intracellular inclusions OMIM:611726; progressive myoclonic epilepsy type 3 MONDO:0012721
Review for gene: KCTD7 was set to RED
Added comment: Although this gene is rated as Green on the Neuronal ceroid lipofuscinosis panel, it is not considered to be a metabolic gene and so is rated Red on this panel.
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh Tag Q4_22_promote_green was removed from gene: GRN.
Tag Q4_23_promote_green tag was added to gene: GRN.
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh reviewed gene: GRN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Neuronal ceroid lipofuscinosis v2.6 GRN Sarah Leigh Tag Q4_23_promote_green was removed from gene: GRN.
Tag Q4_22_promote_green tag was added to gene: GRN.
Neuronal ceroid lipofuscinosis v2.6 GRN Sarah Leigh Tag Q4_22_promote_green was removed from gene: GRN.
Tag Q4_23_promote_green tag was added to gene: GRN.
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh Entity copied from Neuronal ceroid lipofuscinosis v2.6
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh gene: GRN was added
gene: GRN was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert Review Amber,NHS GMS,London North GLH
Q4_22_promote_green tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 22608501; 27021778; 28000352; 28404863; 30922528; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 OMIM:614706; neuronal ceroid lipofuscinosis 11 MONDO:0013866
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh edited their review of gene: CTSF: Added comment: Emma Ashton (Great Ormond Street Hospital) ([email protected]); Variants in this GENE are reported as part of current diagnostic practice.; Changed rating: GREEN; Set current diagnostic: yes
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh Classified gene: CTSF as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh Gene: ctsf has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.109 CTSF Sarah Leigh gene: CTSF was added
gene: CTSF was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert list
Q4_23_promote_green tags were added to gene: CTSF.
Mode of inheritance for gene: CTSF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTSF were set to 23297359; 25274848
Phenotypes for gene: CTSF were set to Ceroid lipofuscinosis, neuronal, 13, Kufs type OMIM:615362; neuronal ceroid lipofuscinosis 13 MONDO:0014147
Neuronal ceroid lipofuscinosis v2.6 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.379 CLCN6 Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID 33217309 reports gain of function associated with CLCN6 variants.
Intellectual disability v5.379 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 was changed from None to None
Likely inborn error of metabolism - targeted testing not possible v4.108 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: PMID 33217309 reports gain of function associated with CLCN6 variants.; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Neuronal ceroid lipofuscinosis v2.5 CLCN6 Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID 33217309 reports gain of function associated with CLCN6 variants.
Neuronal ceroid lipofuscinosis v2.5 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 was changed from to None
Intellectual disability v5.378 CLCN6 Sarah Leigh Classified gene: CLCN6 as Amber List (moderate evidence)
Intellectual disability v5.378 CLCN6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.378 CLCN6 Sarah Leigh Gene: clcn6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.377 CLCN6 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: CLCN6.
Intellectual disability v5.377 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: Review copied from Neuronal ceroid lipofuscinosis panel: PMID 33217309: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. Previously, monoallelic variants reported in 3 families with BPEI, but functional data/segregation not compelling. Mouse knockout model has features of NCL (Zornitza Stark (Australian Genomics), 9 Dec 2020).; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Likely inborn error of metabolism - targeted testing not possible v4.108 CLCN6 Sarah Leigh commented on gene: CLCN6: Although this gene is rated as Green on the Neuronal ceroid lipofuscinosis panel, it is not considered to be a metabolic gene and so is rated Red on this panel.
Intellectual disability v5.377 CLCN6 Sarah Leigh gene: CLCN6 was added
gene: CLCN6 was added to Intellectual disability - microarray and sequencing. Sources: Other
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116; 21107136; 33217309; 16950870
Phenotypes for gene: CLCN6 were set to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities OMIM:619173
Review for gene: CLCN6 was set to RED
Added comment: Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.108 CLCN6 Sarah Leigh gene: CLCN6 was added
gene: CLCN6 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116; 21107136; 33217309; 16950870
Phenotypes for gene: CLCN6 were set to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities OMIM:619173
Review for gene: CLCN6 was set to RED
Added comment: Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.107 LMF1 Sarah Leigh Classified gene: LMF1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.107 LMF1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.107 LMF1 Sarah Leigh Gene: lmf1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.106 LMF1 Sarah Leigh changed review comment from: PMID 17994020 and 19820022, both report homozygous terminating variants in severe hypertriglyceridemia, together with functional studies that showed significant reduction of LPL activity. PMID 30885219: heterozygous LMF1 c.1024C > T (p.Arg342*; rs776584760) in a patient with Hypertriglyceridemia and acute pancreatitis (HTG-AP). PMID: 30420299 reports at least 2 likely pathogenic (terminating variants) heterozygous LMF1 variants from 13 variants in severe hypertriglyceridemia patients. PMID: 29910226 reports a compound heterozygous variants (c.257C>T, p.P86L & c.1184C>T,p.T395I) which segrates with hypertriglyceridemia in the family. However PMID: 22239554 reports that a number of missense variants don't have an effect.; to: PMID 17994020 and 19820022, both report homozygous terminating variants in severe hypertriglyceridemia, together with functional studies that showed significant reduction of LPL activity. PMID 30885219: heterozygous LMF1 c.1024C > T (p.Arg342*; rs776584760) in a patient with Hypertriglyceridemia and acute pancreatitis (HTG-AP). PMID: 30420299 reports at least 2 likely pathogenic (terminating variants) heterozygous LMF1 variants from 13 variants in severe hypertriglyceridemia patients. PMID: 29910226 reports a compound heterozygous variants (c.257C>T, p.P86L & c.1184C>T,p.T395I) which segregates with hypertriglyceridemia in the family. However PMID: 22239554 reports that a number of missense variants don't have an effect.
Likely inborn error of metabolism - targeted testing not possible v4.106 LMF1 Sarah Leigh commented on gene: LMF1: PMID 17994020 and 19820022, both report homozygous terminating variants in severe hypertriglyceridemia, together with functional studies that showed significant reduction of LPL activity. PMID 30885219: heterozygous LMF1 c.1024C > T (p.Arg342*; rs776584760) in a patient with Hypertriglyceridemia and acute pancreatitis (HTG-AP). PMID: 30420299 reports at least 2 likely pathogenic (terminating variants) heterozygous LMF1 variants from 13 variants in severe hypertriglyceridemia patients. PMID: 29910226 reports a compound heterozygous variants (c.257C>T, p.P86L & c.1184C>T,p.T395I) which segrates with hypertriglyceridemia in the family. However PMID: 22239554 reports that a number of missense variants don't have an effect.
Likely inborn error of metabolism - targeted testing not possible v4.106 LMF1 Sarah Leigh gene: LMF1 was added
gene: LMF1 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert list
Q4_23_promote_green tags were added to gene: LMF1.
Mode of inheritance for gene: LMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMF1 were set to 17994020; 19820022; 30885219; 30420299; 29910226; 22239554
Phenotypes for gene: LMF1 were set to Lipase deficiency, combined OMIM:246650; lipase deficiency, combined MONDO:0009527
Review for gene: LMF1 was set to GREEN
gene: LMF1 was marked as current diagnostic
Added comment: LMF1 Familial chylomicronaemia syndrome (FCS) panel.
Maggie Williams (North Bristol NHS Trust) [email protected]: Variants in this GENE are reported as part of current diagnostic practice
Sources: Expert list
Likely inborn error of metabolism - targeted testing not possible v4.105 GPIHBP1 Sarah Leigh Classified gene: GPIHBP1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.105 GPIHBP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.105 GPIHBP1 Sarah Leigh Gene: gpihbp1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.104 GPIHBP1 Sarah Leigh gene: GPIHBP1 was added
gene: GPIHBP1 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert list
Q4_23_promote_green tags were added to gene: GPIHBP1.
Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D OMIM:615947; hyperlipoproteinemia, type 1D MONDO:0014412
Review for gene: GPIHBP1 was set to GREEN
Added comment: GPIHBP1 copied from Familial chylomicronaemia syndrome (FCS) panel.
Maggie Williams (North Bristol NHS Trust)([email protected]): Variants in this GENE are reported as part of current diagnostic practice
Sources: Expert list
Likely inborn error of metabolism - targeted testing not possible v4.103 OSTC Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.103 OSTC Sarah Leigh gene: OSTC was added
gene: OSTC was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Red
Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSTC were set to 32267060
Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation
Likely inborn error of metabolism - targeted testing not possible v4.102 EDEM3 Sarah Leigh Classified gene: EDEM3 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.102 EDEM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.102 EDEM3 Sarah Leigh Gene: edem3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.101 EDEM3 Sarah Leigh gene: EDEM3 was added
gene: EDEM3 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: EDEM3.
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to Congenital disorder of glycosylation, type 2V, OMIM:619493
Review for gene: EDEM3 was set to GREEN
Added comment: Reviews copied from entry on Congenital disorders of glycosylation panel.
There is sufficient evidence to promote this gene to Green at the next GMS panel update. EDEM3 is associated with a relevant phenotype in OMIM (MIM# 619493) and G2P with a 'strong' confidence level assertion. 12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms. (Arina Puzriakova (Genomics England Curator), 18 Jul 2022).
PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional studies show loss of EDEM3 enzymatic activity. Sources: Literature (Zornitza Stark (Australian Genomics), 7 Aug 2021).
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.100 CAMLG Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.100 CAMLG Sarah Leigh gene: CAMLG was added
gene: CAMLG was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation, type IIz, OMIM:620201
Likely inborn error of metabolism - targeted testing not possible v4.99 ALG10 Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.99 ALG10 Sarah Leigh gene: ALG10 was added
gene: ALG10 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Red
Mode of inheritance for gene: ALG10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG10 were set to 33798445
Phenotypes for gene: ALG10 were set to Progressive myoclonus epilepsy; CDG
Possible mitochondrial disorder - nuclear genes v3.73 HADHB Achchuthan Shanmugasundram Classified gene: HADHB as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.73 HADHB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Possible mitochondrial disorder - nuclear genes v3.73 HADHB Achchuthan Shanmugasundram Gene: hadhb has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.72 HADHB Achchuthan Shanmugasundram Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency, 609015 to Mitochondrial trifunctional protein deficiency 2, OMIM:620300
Possible mitochondrial disorder - nuclear genes v3.71 HADHB Achchuthan Shanmugasundram Publications for gene: HADHB were set to
Possible mitochondrial disorder - nuclear genes v3.70 HADHB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HADHB.
Possible mitochondrial disorder - nuclear genes v3.70 HADHB Achchuthan Shanmugasundram reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35403730; Phenotypes: Mitochondrial trifunctional protein deficiency 2, OMIM:620300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HADHB.
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Classified gene: HADHB as Amber List (moderate evidence)
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Gene: hadhb has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.133 HADHB Achchuthan Shanmugasundram Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency, 609015 to Mitochondrial trifunctional protein deficiency 2, OMIM:620300
Mitochondrial disorders v4.132 HADHB Achchuthan Shanmugasundram Publications for gene: HADHB were set to
Mitochondrial disorders v4.131 HADHB Achchuthan Shanmugasundram reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35403730; Phenotypes: Mitochondrial trifunctional protein deficiency 2, OMIM:620300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.98 MAN2B2 Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.98 MAN2B2 Sarah Leigh gene: MAN2B2 was added
gene: MAN2B2 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to 31775018; 35637269
Phenotypes for gene: MAN2B2 were set to congenital disorder of glycosylation, MONDO:0015286
Likely inborn error of metabolism - targeted testing not possible v4.97 COG3 Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.97 COG3 Sarah Leigh gene: COG3 was added
gene: COG3 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Corneal abnormalities v1.13 PDGFRB Eleanor Williams gene: PDGFRB was added
gene: PDGFRB was added to Corneal abnormalities. Sources: Literature
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PDGFRB were set to 33450762
Review for gene: PDGFRB was set to RED
Added comment: PMID: 33450762 - Bedrup et al 2021 - report a case of a dominant activating substitution in PDGFRB, NM_002609.3(PDGFRB):c.1996A > T, p.(Asn666Tyr), in a family with Ocular pterygium-digital keloid dysplasia (OPDKD) in which ingrowth of vascularized connective tissue on the cornea leads to severely reduced vision. The variant is affecting the same codon as reported for Penttinen syndrome (which causes widespread destruction of connective tissue causing severe disfigurement). However, unlike the Penttinen syndrome substitution, it was found that the OPDKD substitution is highly activated only at 32°C which is in cocordance with the fact that OPDKD are restricted to body parts (cornea and digits) with lower and more variable temperature than the core temperature.
Sources: Literature
Corneal dystrophy v3.10 PDGFRB Eleanor Williams gene: PDGFRB was added
gene: PDGFRB was added to Corneal dystrophy. Sources: Literature
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PDGFRB were set to 33450762
Review for gene: PDGFRB was set to RED
Added comment: PMID: 33450762 - Bedrup et al 2021 - report a case of a dominant activating substitution in PDGFRB, NM_002609.3(PDGFRB):c.1996A > T, p.(Asn666Tyr), in a family with Ocular pterygium-digital keloid dysplasia (OPDKD) in which ingrowth of vascularized connective tissue on the cornea leads to severely reduced vision. The variant is affecting the same codon as reported for Penttinen syndrome (which causes widespread destruction of connective tissue causing severe disfigurement). However, unlike the Penttinen syndrome substitution, it was found that the OPDKD substitution is highly activated only at 32°C which is in cocordance with the fact that OPDKD are restricted to body parts (cornea and digits) with lower and more variable temperature than the core temperature.
Sources: Literature
Hereditary neuropathy or pain disorder v3.74 PDK3 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenfollowing NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Fetal anomalies v3.124 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Intellectual disability v5.376 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Possible mitochondrial disorder - nuclear genes v3.70 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Likely inborn error of metabolism - targeted testing not possible v4.96 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM :617873 to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM :617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Mitochondrial disorders v4.131 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Classified gene: TRIT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Gene: trit1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.142 TRIT1 Eleanor Williams gene: TRIT1 was added
gene: TRIT1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q4_23_promote_green tags were added to gene: TRIT1.
Mode of inheritance for gene: TRIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIT1 were set to 28185376; 24901367
Phenotypes for gene: TRIT1 were set to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Added comment: Associated with Combined oxidative phosphorylation deficiency 35, OMIM: 617873 (AR)

4 cases reported with biallelic variants in this gene and a syndromic phenotype that includes epilepsy.

PMID: 28185376 - Kernohan et al 2017 - report 4 individuals from 3 unrelated families with recessive mutations in TRIT1 identified by WES and confirmed by Sanger sequencing. Parents were heterozygous for the variants. All patients presented with syndrome features which included microcephaly, profound developmental delay, hypotonia, epilepsy, and brain anomalies.

PMID: 24901367 - Yarham et al 2014 - used WES to identify a homozygous p.Arg323Gln mutation in the TRIT1 gene in 2 affected children that segregates within a consanguineous UK-Pakistani family. The children encephalopathy and myoclonic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v4.141 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Early onset or syndromic epilepsy v4.141 ASL Eleanor Williams Publications for gene: ASL were set to 36994644; 21744316; 28251416
Early onset or syndromic epilepsy v4.140 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815 to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; seizure, HP:0001250
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation of green rating subject to GMS review. 13 cases reported with ASA with epilepsy as a feature and variants in the ASL gene.
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.138 ASL Eleanor Williams commented on gene: ASL
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. 7/10 patients are reported to show spasticity although it is not reporterd whether they all shared the same founder variant in ASL.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53  years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively).

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.
PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient.

More recent retrospectives show that tremors and/or dystonia is reported in some individuals with Argininosuccinic aciduria. 6 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53  years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively).

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Ataxia and cerebellar anomalies - narrow panel v4.49 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.
PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Early onset or syndromic epilepsy v4.138 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Seizure; Neurodevelopmental delay; Intellectual disability; Autism; Abnormality of movement; Ataxia; Hepatomegaly; Elevated hepatic transaminase; Renal tubular dysfunction; Abnormal hair morphology to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Intellectual disability v5.375 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria 207900 to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber, with a recommendation of green rating subject to GMS review. 6 patients with tremor and/or dystonia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023 and PMID: 28251416 - Baruteau et al 2017).
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.64 ASL Eleanor Williams Mode of inheritance for gene: ASL was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.63 ASL Eleanor Williams Phenotypes for gene: ASL were changed from to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; tremor, HP:0001337; Dystonia, HP:0001332
Childhood onset dystonia, chorea or related movement disorder v3.62 ASL Eleanor Williams Publications for gene: ASL were set to
Childhood onset dystonia, chorea or related movement disorder v3.61 ASL Eleanor Williams reviewed gene: ASL: Rating: ; Mode of pathogenicity: None; Publications: 12384776, 17326097, 29326055, 38044746, 28251416; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.49 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram changed review comment from: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, these were the first patients reported with axonal polyneuropathy.; to: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, axonal polyneuropathy reported in these two brothers were not reported in any previous cases.
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive, OMIM:618770; axonal neuropathy, MONDO:0004183
Hereditary neuropathy or pain disorder v3.73 PCYT2 Achchuthan Shanmugasundram Publications for gene: PCYT2 were set to PMID: 35243002
Hereditary neuropathy or pain disorder v3.72 PCYT2 Achchuthan Shanmugasundram Classified gene: PCYT2 as Red List (low evidence)
Hereditary neuropathy or pain disorder v3.72 PCYT2 Achchuthan Shanmugasundram Gene: pcyt2 has been classified as Red List (Low Evidence).
Hereditary neuropathy or pain disorder v3.71 PCYT2 Achchuthan Shanmugasundram reviewed gene: PCYT2: Rating: RED; Mode of pathogenicity: None; Publications: 35243002; Phenotypes: Spastic paraplegia 82, autosomal recessive, OMIM:618770, axonal neuropathy, MONDO:0004183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Classified gene: EMILIN1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families in support of the association of monoallelic EMILIN1 variants with peripheral neuropathy and hence this gene should be rated amber with current evidence.
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Gene: emilin1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.70 EMILIN1 Achchuthan Shanmugasundram Phenotypes for gene: EMILIN1 were changed from Peripheral neuropathy; aortic aneurysm to Neuronopathy, distal hereditary motor, autosomal dominant 10, OMIM:620080
Hereditary neuropathy or pain disorder v3.69 EMILIN1 Achchuthan Shanmugasundram reviewed gene: EMILIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 10, OMIM:620080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants. Microcephaly was severe (-4 to -6 SD) in all three patients measured and hence this gene should be rated amber with current evidence.
Intellectual disability v5.374 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Intellectual disability v5.374 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Intellectual disability v5.374 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram Classified gene: COG3 as Amber List (moderate evidence)
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram Gene: cog3 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v4.15 COG3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620546), but not yet in Gene2Phenotype.
Congenital disorders of glycosylation v4.15 COG3 Achchuthan Shanmugasundram Phenotypes for gene: COG3 were changed from Congenital disorder of glycosylation, type IIbb, OMIM:620546 to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Congenital disorders of glycosylation v4.14 COG3 Achchuthan Shanmugasundram Phenotypes for gene: COG3 were changed from Congenital disorder of glycosylation, type IIbb, MIM# 620546 to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Congenital disorders of glycosylation v4.13 COG3 Achchuthan Shanmugasundram reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: None; Publications: 37711075; Phenotypes: Congenital disorder of glycosylation, type IIbb, OMIM:620546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.157 FOXI3 Achchuthan Shanmugasundram Mode of inheritance for gene: FOXI3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram edited their review of gene: FOXI3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Classified gene: FOXI3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are two unrelated families reported with monoallelic FOXI3 variant. However, the variant was inherited from apparently unaffected father in patient 2, which shows reduced penetrance. In addition, evidence from mouse model shows that FOXI3 is involved in thymus development. Hence, this gene should be rated amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Gene: foxi3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 FOXI3 Achchuthan Shanmugasundram reviewed gene: FOXI3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.; to: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members. This gene should therefore be rated amber with the current evidence.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Classified gene: SGSM3 as Amber List (moderate evidence)
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Gene: sgsm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Classified gene: SGSM3 as No list
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability v5.373 SGSM3 Achchuthan Shanmugasundram Gene: sgsm3 has been removed from the panel.
Intellectual disability v5.372 SGSM3 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: SGSM3.
Intellectual disability v5.372 SGSM3 Achchuthan Shanmugasundram Phenotypes for gene: SGSM3 were changed from Neurodevelopmental disorder (MONDO:0700092), SGSM3-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.371 SGSM3 Achchuthan Shanmugasundram reviewed gene: SGSM3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.95 NUS1 Achchuthan Shanmugasundram Classified gene: NUS1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.95 NUS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic NUS1 variants with intellectual disability and epilepsy, this gene can be promoted to green rating in the next GMS review.
Likely inborn error of metabolism - targeted testing not possible v4.95 NUS1 Achchuthan Shanmugasundram Gene: nus1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.94 NUS1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Dmitrijs Rots, there are more than three unrelated cases and functional evidence available in support of the association of monoallelic NUS1 variants with intellectual disability and epilepsy. This autosomal dominant disorder has been recorded in both OMIM (MIM #617831) and Gene2Phenotype (with 'strong' rating in the DD panel).

However, there is only one family and supporting functional evidence available for the association of biallelic variants with congenital disorder of glycosylation. This phenotype has already been recorded in OMIM (MIM #617082), but not in Gene2Phenotype.

Hence, the MOI should be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Likely inborn error of metabolism - targeted testing not possible v4.94 NUS1 Achchuthan Shanmugasundram Mode of inheritance for gene: NUS1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism - targeted testing not possible v4.93 NUS1 Achchuthan Shanmugasundram Publications for gene: NUS1 were set to 25066056; 31656175; 32334381; 32485575; 33731878
Likely inborn error of metabolism - targeted testing not possible v4.93 NUS1 Achchuthan Shanmugasundram Publications for gene: NUS1 were set to 25066056
Likely inborn error of metabolism - targeted testing not possible v4.92 NUS1 Achchuthan Shanmugasundram Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa OMIM:617082; congenital disorder of glycosylation, type IAA MONDO:0014904 to Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; ?Congenital disorder of glycosylation, type 1aa, OMIM:617082
Likely inborn error of metabolism - targeted testing not possible v4.91 NUS1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NUS1.
Likely inborn error of metabolism - targeted testing not possible v4.91 NUS1 Achchuthan Shanmugasundram reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831, ?Congenital disorder of glycosylation, type 1aa, OMIM:617082; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v4.49 DLG4 Achchuthan Shanmugasundram Classified gene: DLG4 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.49 DLG4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are nine unrelated cases reported with monoallelic DLG4 variants and ataxia. Hence, this gene can be promoted to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.49 DLG4 Achchuthan Shanmugasundram Gene: dlg4 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.48 DLG4 Achchuthan Shanmugasundram Phenotypes for gene: DLG4 were changed from Intellectual developmental disorder, autosomal dominant 62 to Intellectual developmental disorder, autosomal dominant 62, OMIM:618793
Ataxia and cerebellar anomalies - narrow panel v4.47 DLG4 Achchuthan Shanmugasundram Publications for gene: DLG4 were set to PMID: 33597769
Ataxia and cerebellar anomalies - narrow panel v4.46 DLG4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: DLG4.
Ataxia and cerebellar anomalies - narrow panel v4.46 DLG4 Achchuthan Shanmugasundram reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 62, OMIM:618793; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Classified gene: MCTS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (five unrelated cases) for the association of hemizygous MCTS1 variants with MSMD. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Gene: mcts1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.154 MCTS1 Achchuthan Shanmugasundram Phenotypes for gene: MCTS1 were changed from MSMD; non tubercular mycobacteria infection; BCGtis; BCG infection to Inherited susceptibility to mycobacterial diseases, MONDO:0019146
Primary immunodeficiency or monogenic inflammatory bowel disease v4.153 MCTS1 Achchuthan Shanmugasundram Publications for gene: MCTS1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MCTS1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MCTS1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MCTS1 Achchuthan Shanmugasundram reviewed gene: MCTS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37875108; Phenotypes: Inherited susceptibility to mycobacterial diseases, MONDO:0019146; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Classified gene: MECOM as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are more than three unrelated cases with either B cell deficiency and/ or hypogammaglobulinemia. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Gene: mecom has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 MECOM Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MECOM.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 MECOM Achchuthan Shanmugasundram reviewed gene: MECOM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, OMIM:616738; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thalassaemia and other haemoglobinopathies v1.7 HBG2 Arina Puzriakova Classified gene: HBG2 as Amber List (moderate evidence)
Thalassaemia and other haemoglobinopathies v1.7 HBG2 Arina Puzriakova Gene: hbg2 has been classified as Amber List (Moderate Evidence).
Haemoglobinopathy trait or carrier testing v1.7 HBG2 Arina Puzriakova Classified gene: HBG2 as Amber List (moderate evidence)
Haemoglobinopathy trait or carrier testing v1.7 HBG2 Arina Puzriakova Gene: hbg2 has been classified as Amber List (Moderate Evidence).
Thalassaemia and other haemoglobinopathies v1.6 HBG2 Arina Puzriakova gene: HBG2 was added
gene: HBG2 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG2.
Mode of inheritance for gene: HBG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: HBG2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

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Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel for HBG1 gene (also relevant to HBG2):

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Haemoglobinopathy trait or carrier testing v1.6 HBG2 Arina Puzriakova gene: HBG2 was added
gene: HBG2 was added to Haemoglobinopathy trait or carrier testing. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG2.
Mode of inheritance for gene: HBG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: HBG2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

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Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel for HBG1 gene (also relevant to HBG2):

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Rare anaemia v3.6 HBG2 Arina Puzriakova Phenotypes for gene: HBG2 were changed from Globin Disorder; 141749 Globin Disorder; Fetal hemoglobin quantitative trait locus 1,141749; Fetal hemoglobin quantitative trait locus 1; 141749 Hereditary persistance of fetal haemoglobin; Cyanosis, transient neonatal, 613977 to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; Globin Disorder
Cytopenias and congenital anaemias v1.114 HBG2 Arina Puzriakova Phenotypes for gene: HBG2 were changed from Globin Disorder; Cyanosis, transient neonatal, 613977; Fetal hemoglobin quantitative trait locus 1,141749 to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; Globin Disorder
Thalassaemia and other haemoglobinopathies v1.5 HBG1 Arina Puzriakova Classified gene: HBG1 as Amber List (moderate evidence)
Thalassaemia and other haemoglobinopathies v1.5 HBG1 Arina Puzriakova Gene: hbg1 has been classified as Amber List (Moderate Evidence).
Haemoglobinopathy trait or carrier testing v1.5 HBG1 Arina Puzriakova Classified gene: HBG1 as Amber List (moderate evidence)
Haemoglobinopathy trait or carrier testing v1.5 HBG1 Arina Puzriakova Gene: hbg1 has been classified as Amber List (Moderate Evidence).
Thalassaemia and other haemoglobinopathies v1.4 HBG1 Arina Puzriakova gene: HBG1 was added
gene: HBG1 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG1.
Mode of inheritance for gene: HBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: HBG1 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

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Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Haemoglobinopathy trait or carrier testing v1.4 HBG1 Arina Puzriakova gene: HBG1 was added
gene: HBG1 was added to Haemoglobinopathy trait or carrier testing. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG1.
Mode of inheritance for gene: HBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: HBG1 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

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Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Cytopenias and congenital anaemias v1.113 HBG1 Arina Puzriakova Phenotypes for gene: HBG1 were changed from Globin Disorder; Fetal hemoglobin quantitative trait locus 1, 141749 to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Hereditary persistance of fetal haemoglobin; Globin Disorder
Rare anaemia v3.5 HBG1 Arina Puzriakova Phenotypes for gene: HBG1 were changed from Fetal hemoglobin quantitative trait locus 1; 141749 Hereditary persistance of fetal haemoglobin; 141749 Globin Disorder; Fetal hemoglobin quantitative trait locus 1, 141749; Globin Disorder to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Hereditary persistance of fetal haemoglobin; Globin Disorder
Thalassaemia and other haemoglobinopathies v1.3 HBA2 Arina Puzriakova Classified gene: HBA2 as Amber List (moderate evidence)
Thalassaemia and other haemoglobinopathies v1.3 HBA2 Arina Puzriakova Gene: hba2 has been classified as Amber List (Moderate Evidence).
Haemoglobinopathy trait or carrier testing v1.3 HBA2 Arina Puzriakova Classified gene: HBA2 as Amber List (moderate evidence)
Haemoglobinopathy trait or carrier testing v1.3 HBA2 Arina Puzriakova Gene: hba2 has been classified as Amber List (Moderate Evidence).
Thalassaemia and other haemoglobinopathies v1.2 HBA2 Arina Puzriakova gene: HBA2 was added
gene: HBA2 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBA2.
Mode of inheritance for gene: HBA2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Review for gene: HBA2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

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Copied review below regarding MOI from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"There are two alpha globin genes (HBA1 and HBA2), which are encoded in tandem on chromosome 16. Different Mutations in HBA1/HBA2 are associated with different α-thalassemias and different mode of inheritance: 1) α-thalassemia silent carrier: deletion/mutation that leads to loss of 1 α-globin gene (either HBA1 or HBA2) 2) α-thalassemia trait: deletion/mutations that leads to the loss of 2 α-globin genes either in cis (--/αα) or in trans (-α/-α); 3) Hemoglobin H disease is caused by contiguous gene deletion of HBA1 and HBA2 genes on one chromosome, and a defect (deletional / inactivating small indel /single nucleotide variant), in either HBA1 or HBA2 on the other chromosome; 4) 'homozygous alpha-thalassemia' (fatal hydrops fetalis): usually caused by deletions on both chromosomes, leading no/little production of alpha globin and death in utero. The phenotypes relevant to this panel are the α-thalassemia trait and the Hemoglobin H disease. Mostly caused by deletions but rare cases of small indels or point mutations leading to decreased production of the alpha globin chains have been described (16798638, 15481890, 15182057 for example)"
Sources: NHS GMS
Haemoglobinopathy trait or carrier testing v1.2 HBA2 Arina Puzriakova gene: HBA2 was added
gene: HBA2 was added to Haemoglobinopathy trait or carrier testing. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBA2.
Mode of inheritance for gene: HBA2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Review for gene: HBA2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

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Copied review below regarding MOI from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"There are two alpha globin genes (HBA1 and HBA2), which are encoded in tandem on chromosome 16. Different Mutations in HBA1/HBA2 are associated with different α-thalassemias and different mode of inheritance: 1) α-thalassemia silent carrier: deletion/mutation that leads to loss of 1 α-globin gene (either HBA1 or HBA2) 2) α-thalassemia trait: deletion/mutations that leads to the loss of 2 α-globin genes either in cis (--/αα) or in trans (-α/-α); 3) Hemoglobin H disease is caused by contiguous gene deletion of HBA1 and HBA2 genes on one chromosome, and a defect (deletional / inactivating small indel /single nucleotide variant), in either HBA1 or HBA2 on the other chromosome; 4) 'homozygous alpha-thalassemia' (fatal hydrops fetalis): usually caused by deletions on both chromosomes, leading no/little production of alpha globin and death in utero. The phenotypes relevant to this panel are the α-thalassemia trait and the Hemoglobin H disease. Mostly caused by deletions but rare cases of small indels or point mutations leading to decreased production of the alpha globin chains have been described (16798638, 15481890, 15182057 for example)"
Sources: NHS GMS
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 AICDA Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 AICDA Arina Puzriakova Mode of inheritance for gene: AICDA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.150 AICDA Arina Puzriakova Publications for gene: AICDA were set to 12958596; 21700883; 27701145
Primary immunodeficiency or monogenic inflammatory bowel disease v4.149 AICDA Arina Puzriakova Tag recurrent-variant tag was added to gene: AICDA.
Tag Q4_23_MOI tag was added to gene: AICDA.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.149 AICDA Arina Puzriakova reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35748970, 15893695, 35271747; Phenotypes: Immunodeficiency with hyper-IgM, type 2, OMIM:605258; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Comment on list classification: Promoting this gene to amber as there are 2 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023). Consulting with the Genomics England clinical team whether it would be appropriate to rate green.; to: Comment on list classification: Promoting this gene to amber with a recommendation for green rating as there are 5 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023 and PMID: 28251416 - Baruteau et al 2017).
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Mitochondrial disorders v4.130 ATP5E Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ATP5E.
Likely inborn error of metabolism - targeted testing not possible v4.91 ATP5E Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ATP5E.
Mitochondrial disorder with complex V deficiency v2.14 ATP5E Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ATP5E.
Undiagnosed metabolic disorders v1.609 ATP5E Sarah Leigh Classified gene: ATP5E as Green List (high evidence)
Undiagnosed metabolic disorders v1.609 ATP5E Sarah Leigh Gene: atp5e has been classified as Green List (High Evidence).
Mitochondrial disorder with complex V deficiency v2.14 ATP5E Sarah Leigh Publications for gene: ATP5E were set to
Mitochondrial disorders v4.130 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710
Mitochondrial disorders v4.129 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Mitochondrial disorders v4.128 ATP5E Sarah Leigh Classified gene: ATP5E as Amber List (moderate evidence)
Mitochondrial disorders v4.128 ATP5E Sarah Leigh Gene: atp5e has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.91 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Mitochondrial disorder with complex V deficiency v2.13 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Undiagnosed metabolic disorders v1.608 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Undiagnosed metabolic disorders v1.607 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Mitochondrial disorder with complex V deficiency v2.12 ATP5E Sarah Leigh reviewed gene: ATP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 34954817, 20566710; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.90 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Mitochondrial disorders v4.127 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Possible mitochondrial disorder - nuclear genes v3.69 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Sarah Leigh changed review comment from: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name:ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; to: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Sarah Leigh Tag Q4_23_expert_review was removed from gene: ATP5E.
Tag Q4_23_NHS_review tag was added to gene: ATP5E.
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not mentioned as a phenotypic feature.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Sarah Leigh reviewed gene: ATP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as there are 2 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023). Consulting with the Genomics England clinical team whether it would be appropriate to rate green.
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.90 ASL Eleanor Williams Publications for gene: ASL were set to 27604308
Early onset or syndromic epilepsy v4.136 SHQ1 Sarah Leigh Entity copied from Childhood onset dystonia, chorea or related movement disorder v3.61
Early onset or syndromic epilepsy v4.136 SHQ1 Sarah Leigh gene: SHQ1 was added
gene: SHQ1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: SHQ1.
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611; 36189577
Phenotypes for gene: SHQ1 were set to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Intellectual disability v5.371 SHQ1 Sarah Leigh Entity copied from Childhood onset dystonia, chorea or related movement disorder v3.61
Intellectual disability v5.371 SHQ1 Sarah Leigh gene: SHQ1 was added
gene: SHQ1 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: SHQ1.
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611; 36189577
Phenotypes for gene: SHQ1 were set to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Childhood onset dystonia, chorea or related movement disorder v3.61 SHQ1 Sarah Leigh Classified gene: SHQ1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.61 SHQ1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v3.61 SHQ1 Sarah Leigh Gene: shq1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: SHQ1.
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh commented on gene: SHQ1: SHQ1 variants are associated with Neurodevelopmental disorder with dystonia and seizures, OMIM:619922 and Dystonia 35, childhood-onset, OMIM:619921, but not with a phenotype in Gen2Phen. At least 10 SHQ1 variants have been reported (PMIDs: 29178645 34542157; 36810590; 36847845) in eight unrelated cases. The phenotypic features were dystonia (7/7 cases examined), hypotonia (6/7 cases examined), intellectual disability (7/8 cases examined), and seizures (in 4/6 cases and 2 further unrelated cases where remaining affected siblings did not have seizures (1/2 and 3/4)(PMID: 36847845).
Ataxia and cerebellar anomalies - narrow panel v4.45 ASL Eleanor Williams Publications for gene: ASL were set to 38044746; 36994644; 28251416
Ataxia and cerebellar anomalies - narrow panel v4.44 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Ataxia to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; Ataxia, HP:0001251
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh reviewed gene: SHQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.89 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria; Argininosuccinic aciduria (Urea cycle disorders and inherited hyperammonaemias) to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611
Childhood onset dystonia, chorea or related movement disorder v3.59 SHQ1 Sarah Leigh Publications for gene: SHQ1 were set to 34542157; 29178645
Childhood onset dystonia, chorea or related movement disorder v3.58 SHQ1 Sarah Leigh Phenotypes for gene: SHQ1 were changed from Dystonia; Neurodegeneration to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Childhood onset dystonia, chorea or related movement disorder v3.57 SHQ1 Sarah Leigh Classified gene: SHQ1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.57 SHQ1 Sarah Leigh Gene: shq1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.141 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Hyper IgM syndrome with lymphoid hyperplasia; Primary Immune Deficiencies; Immunodeficiency with hyper-IgM, type 2, 605258; Bacterial infections, enlarged lymph nodes and germinal centers; Predominantly Antibody Deficiencies; Immunodeficiency with hyper-IgM, type 2; CSR defects and Hyper IgM (HIGM) syndromes to Immunodeficiency with hyper-IgM, type 2, OMIM:605258; Hyper IgM syndrome with lymphoid hyperplasia; Primary Immune Deficiencies; Bacterial infections, enlarged lymph nodes and germinal centers; Predominantly Antibody Deficiencies; Immunodeficiency with hyper-IgM, type 2; CSR defects and Hyper IgM (HIGM) syndromes
Gastrointestinal epithelial barrier disorders v1.74 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Early Onset Inflammatory Bowel Disease; Immunodeficiency with hyper-IgM, type 2 605258 to Immunodeficiency with hyper-IgM, type 2, OMIM:605258
Infantile enterocolitis & monogenic inflammatory bowel disease v1.40 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Immunodeficiency with hyper-IgM, type 2 605258 to Immunodeficiency with hyper-IgM, type 2, OMIM:605258
Primary immunodeficiency or monogenic inflammatory bowel disease v4.149 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Immunodeficiency with hyper-IgM, type 2; Hyper IgM syndrome with lymphoid hyperplasia; Immunodeficiency with hyper-IgM, type 2, 605258; Primary Immune Deficiencies; CSR defects and Hyper IgM (HIGM) syndromes; Bacterial infections, enlarged lymph nodes and germinal centers; Predominantly Antibody Deficiencies to Immunodeficiency with hyper-IgM, type 2, OMIM:605258
Intellectual disability v5.370 FBXW11 Sarah Leigh Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914 to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:003005
Skeletal dysplasia v4.35 FBXW11 Sarah Leigh Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914 to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:0030057
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh Tag Q4_21_NHS_review tag was added to gene: FBXW11.
Tag Q4_23_promote_green tag was added to gene: FBXW11.
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh Classified gene: FBXW11 as Amber List (moderate evidence)
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh Gene: fbxw11 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.33 FBXW11 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.369
Skeletal dysplasia v4.33 FBXW11 Sarah Leigh gene: FBXW11 was added
gene: FBXW11 was added to Skeletal dysplasia. Sources: Literature,Expert Review Green
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914
Penetrance for gene: FBXW11 were set to unknown
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Classified gene: RETREG1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of RETREG1 gene with spastic paraplegia and hence this gene can be promoted to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Gene: retreg1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.30 RETREG1 Achchuthan Shanmugasundram Phenotypes for gene: RETREG1 were changed from to Neuropathy, hereditary sensory and autonomic, type IIB, OMIM:613115
Childhood onset hereditary spastic paraplegia v4.29 RETREG1 Achchuthan Shanmugasundram Publications for gene: RETREG1 were set to 24327336
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RETREG1.
Tag Q4_23_NHS_review tag was added to gene: RETREG1.
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram changed review comment from: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter); to: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter).

Gavin Ryan also mentioned in his review that LoF homozygous variant in this gene was identified via Diagnostic Discovery in 100K and GMS WGS patient with features of Progressive spasticity, facial hypotonia, dysarthria, and fatiguable weakness.
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram commented on gene: RETREG1: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter)
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram reviewed gene: RETREG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24327336, 30643655; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, OMIM:613115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v3.9 NOTCH3 Arina Puzriakova Classified gene: NOTCH3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v3.9 NOTCH3 Arina Puzriakova Gene: notch3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v3.8 NOTCH3 Arina Puzriakova gene: NOTCH3 was added
gene: NOTCH3 was added to Paediatric disorders - additional genes. Sources: NHS GMS
Q4_23_promote_green, Q4_23_expert_review tags were added to gene: NOTCH3.
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 25394726
Phenotypes for gene: NOTCH3 were set to Lateral meningocele syndrome, OMIM:130720
Mode of pathogenicity for gene: NOTCH3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: NOTCH3 was set to GREEN
Added comment: Monoallelic variants in the NOTCH3 gene are associated with multiple phenotypes including CADASIL (MIM# 125310), Lateral Meningocele syndrome (MIM# 130720), and Myofibromatosis (MIM# 615293).

Currently, CADASIL and myofibromatosis phenotypes are covered by several PanelApp panels; however, Lateral Meningocele syndrome is not - there is enough evidence to support inclusion of this gene-disease association on a diagnostic-grade panel.

At least 5 unrelated de novo cases have been reported in literature (PMID: 25394726). All variants are truncating and cluster in the last exon of NOTCH3. Truncated proteins are predicted to cause increased notch signalling.
An additional case was identified in Genomics England's Clinical Variant Archive (CVA) dataset via the Diagnostic Discovery initiative. The participant was recruited with Lateral Meningocele syndrome (inclusive of hypertelorism, high palate, dural ectasia, high pitched voice) and a diagnostically reported variant in the last exon of this gene was returned, lending further support to adding this gene to the panel.

R27 appears to be the most phenotypically relevant panel for detecting Lateral Meningocele syndrome; however, the possibility of incidental findings of CADASIL needs to be considered. Both phenotypes are caused by GoF variants but those associated with CADASIL are located in exons 2-24 whereas variants in Lateral Meningocele found in exon 33 (last exon).

Given the risk of incidental findings without a mechanism to delineate the types of variants that are prioritised via each panel, the best route for inclusion of Lateral Meningocele syndrome in PanelApp will be flagged for further NHSE expert discussion at the next GMS panel update release.
Sources: NHS GMS
Retinal disorders v4.55 TTC21B Achchuthan Shanmugasundram Classified gene: TTC21B as Amber List (moderate evidence)
Retinal disorders v4.55 TTC21B Achchuthan Shanmugasundram Gene: ttc21b has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.54 TTC21B Achchuthan Shanmugasundram Phenotypes for gene: TTC21B were changed from Eye Disorders to Retinal dystrophy, HP:0000556
Retinal disorders v4.53 TTC21B Achchuthan Shanmugasundram Publications for gene: TTC21B were set to 21068128; 33599192
Retinal disorders v4.52 TTC21B Achchuthan Shanmugasundram Publications for gene: TTC21B were set to
Retinal disorders v4.51 TTC21B Achchuthan Shanmugasundram Mode of inheritance for gene: TTC21B was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.50 TTC21B Achchuthan Shanmugasundram reviewed gene: TTC21B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinal dystrophy, HP:0000556; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.369 TRPC5 Sarah Leigh changed review comment from: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).; to: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 variants have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).
Childhood solid tumours v4.10 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from Infantile myofibromatosis to ?Myofibromatosis, infantile 2, OMIM:615293
Inherited white matter disorders v1.177 NOTCH3 Arina Puzriakova Mode of inheritance for gene: NOTCH3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.369 TRPC5 Sarah Leigh Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability v5.369 TRPC5 Sarah Leigh Added comment: Comment on list classification: This gene is rated amber, despite six published variants being reported in unrelated cases with a neurodevelopmental disorder, this is because it is unclear in the publications, how many of these cases actually have intellectual disability.
Intellectual disability v5.369 TRPC5 Sarah Leigh Gene: trpc5 has been classified as Amber List (Moderate Evidence).
CADASIL v1.4 NOTCH3 Arina Puzriakova Mode of pathogenicity for gene: NOTCH3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v4.148 STAT6 Achchuthan Shanmugasundram Publications for gene: STAT6 were set to 36884218
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available (12 unrelated families and functional data) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram Classified gene: STAT6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram Gene: stat6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: STAT6.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram edited their review of gene: STAT6: Added comment: As reviewed by Dmitrijs Rots, PMID:36884218 reported 16 cases from 10 families with heterozygous STAT6 variants and severe early-onset allergic disease consisting of clinical features including severe, treatment-resistant atopic dermatitis (15/16) and food allergies (15/16) were the most common clinical manifestations, followed by asthma (11/16) and eosinophilic gastrointestinal disease (10/16) and severe episodes of anaphylaxis (9/16).

PMID:36216080 reported heterozygous STAT6 variant with early-onset multiorgan allergies in a family with
3 affected members and PMID:36758835 reported another child with severe atopic dermatitis, eosinophilia and elevated IgE. All these publications also provided extensive functional data which confirms the mechanism as gain-of-function.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620532), but not yet in Gene2Phenotype.; Changed publications to: 36216080, 36758835, 36884218
White matter disorders and cerebral calcification - narrow panel v3.25 NOTCH3 Arina Puzriakova Mode of inheritance for gene: NOTCH3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.368 TRPC5 Sarah Leigh commented on gene: TRPC5: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram Phenotypes for gene: STAT6 were changed from allergic disease, MONDO:0005271 to Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, OMIM:620532
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram edited their review of gene: STAT6: Changed phenotypes to: Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, OMIM:620532
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review. In addition, functional evidence shows that the mechanism is gain-of-function.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram Classified gene: STAT6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram Gene: stat6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.144 STAT6 Achchuthan Shanmugasundram Phenotypes for gene: STAT6 were changed from Primary Atopic Disorder; Atopy; Vascular anomalies; Atopic dermamatitis; Allergy; Atopy; Hyper-IgE; elevated IgE; Eosinophilic esophagitis; Food allergies to allergic disease, MONDO:0005271
Primary immunodeficiency or monogenic inflammatory bowel disease v4.143 STAT6 Achchuthan Shanmugasundram Publications for gene: STAT6 were set to
Intellectual disability v5.368 TRPC5 Sarah Leigh Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability v5.368 TRPC5 Sarah Leigh Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.142 STAT6 Achchuthan Shanmugasundram Mode of inheritance for gene: STAT6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 STAT6 Achchuthan Shanmugasundram reviewed gene: STAT6: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 36884218; Phenotypes: allergic disease, MONDO:0005271; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 KCNA5 Achchuthan Shanmugasundram Classified gene: KCNA5 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 KCNA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: PMID:34536415 reported a 17-year old female patient with early-onset pulmonary and cutaneous vasculitis and biallelic KCNA5 variant (c. 1545C>A) and supporting functional evidence.

Biallelic KCNA5 variants have not yet been associated with any phenotypes either in OMIM or Gene2Phenotype.

This gene should be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 KCNA5 Achchuthan Shanmugasundram Gene: kcna5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.140 KCNA5 Achchuthan Shanmugasundram Phenotypes for gene: KCNA5 were changed from autoimmunity; autoinflammation to early-onset pulmonary and cutaneous vasculitis, MONDO:0800137
Primary immunodeficiency or monogenic inflammatory bowel disease v4.139 KCNA5 Achchuthan Shanmugasundram Publications for gene: KCNA5 were set to PMID: 35748970; PMID: 34536415
Primary immunodeficiency or monogenic inflammatory bowel disease v4.138 KCNA5 Achchuthan Shanmugasundram reviewed gene: KCNA5: Rating: AMBER; Mode of pathogenicity: None; Publications: 34536415; Phenotypes: early-onset pulmonary and cutaneous vasculitis, MONDO:0800137; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.138 IL23R Achchuthan Shanmugasundram Classified gene: IL23R as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.138 IL23R Achchuthan Shanmugasundram Gene: il23r has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.137 IL23R Achchuthan Shanmugasundram Classified gene: IL23R as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.137 IL23R Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.137 IL23R Achchuthan Shanmugasundram Gene: il23r has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.136 IL23R Achchuthan Shanmugasundram Phenotypes for gene: IL23R were changed from Susceptibility to mycobacteria and Salmonella to inherited susceptibility to mycobacterial diseases, MONDO:0019146; chronic mucocutaneous candidiasis, MONDO:0015279
Primary immunodeficiency or monogenic inflammatory bowel disease v4.135 IL23R Achchuthan Shanmugasundram Publications for gene: IL23R were set to 30578351; 31953710
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 IL23R Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IL23R.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 IL23R Achchuthan Shanmugasundram reviewed gene: IL23R: Rating: GREEN; Mode of pathogenicity: None; Publications: 36763636; Phenotypes: inherited susceptibility to mycobacterial diseases, MONDO:0019146, chronic mucocutaneous candidiasis, MONDO:0015279; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
CADASIL v1.3 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Inherited white matter disorders v1.176 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Adult onset leukodystrophy v3.24 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, 125310 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Familial cerebral small vessel disease v1.17 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from Migraine; Encephalopathy; Stroke; Cognitive impairment; Dementia; Seizures; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
White matter disorders and cerebral calcification - narrow panel v3.24 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Cerebral vascular malformations v3.9 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from Cerebral Arteriopathy, Autosomal Dominant, With Subcortical Infarcts And Leukoencephalopathy; Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL); Moyamoya disease; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, 125310 ; Cerebral Arteriopathy, Autosomal Dominant, With Subcortical Infarcts And Leukoencephalopathy (CADASIL) to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 RANBP2 Achchuthan Shanmugasundram Classified gene: RANBP2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 RANBP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are >3 unrelated cases reported with monoallelic variants in this gene, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 RANBP2 Achchuthan Shanmugasundram Gene: ranbp2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.133 RANBP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RANBP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.133 RANBP2 Achchuthan Shanmugasundram reviewed gene: RANBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.367 AGPAT3 Achchuthan Shanmugasundram Classified gene: AGPAT3 as Amber List (moderate evidence)
Intellectual disability v5.367 AGPAT3 Achchuthan Shanmugasundram Gene: agpat3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.366 AGPAT3 Achchuthan Shanmugasundram Classified gene: AGPAT3 as Amber List (moderate evidence)
Intellectual disability v5.366 AGPAT3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, only one family was reported so far with AGPAT3 biallelic variants and intellectual disability. In addition, functional evidence is also available, Hence, this gene should be rated amber.
Intellectual disability v5.366 AGPAT3 Achchuthan Shanmugasundram Gene: agpat3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.365 AGPAT3 Achchuthan Shanmugasundram Phenotypes for gene: AGPAT3 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.365 AGPAT3 Achchuthan Shanmugasundram Phenotypes for gene: AGPAT3 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.365 AGPAT3 Achchuthan Shanmugasundram Phenotypes for gene: AGPAT3 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.364 AGPAT3 Achchuthan Shanmugasundram Phenotypes for gene: AGPAT3 were changed from Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.363 AGPAT3 Achchuthan Shanmugasundram edited their review of gene: AGPAT3: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v5.363 AGPAT3 Achchuthan Shanmugasundram reviewed gene: AGPAT3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.50 VWA8 Arina Puzriakova Tag watchlist tag was added to gene: VWA8.
Retinal disorders v4.50 VWA8 Arina Puzriakova Classified gene: VWA8 as Amber List (moderate evidence)
Retinal disorders v4.50 VWA8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. A single family (PMID: 37012052) with 11 individuals all presenting initial symptoms of visual defects which later progressed to macular changes, including macular degeneration and dystrophy. Two variants (c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter)) on the same allele of the VWA8 gene were found to segregate with disease. Expression studies showed reduced protein expression. Zebrafish knockdown model displayed a similar phenotype to that of humans.

Although there is only one family reported to date, multi-generational segregation with disease and concordant phenotype in a knockdown zebrafish model supports pathogenicity and therefore rating Amber with a 'watchlist' tag.
Retinal disorders v4.50 VWA8 Arina Puzriakova Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.49 VWA8 Arina Puzriakova Phenotypes for gene: VWA8 were changed from ?Retinitis pigmentosa 97 to ?Retinitis pigmentosa 97, OMIM:620422
Cytopenia - NOT Fanconi anaemia v3.21 DUT Arina Puzriakova Tag Q4_23_NHS_review was removed from gene: DUT.
Monogenic diabetes v2.54 DUT Arina Puzriakova Tag Q4_23_NHS_review was removed from gene: DUT.
Monogenic diabetes v2.54 DUT Arina Puzriakova Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v4.133
Monogenic diabetes v2.54 DUT Arina Puzriakova gene: DUT was added
gene: DUT was added to Monogenic diabetes. Sources: Expert Review Amber,Literature
Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: DUT.
Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DUT were set to 28073829; 35611808; 35931051
Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome, OMIM:620044
Cytopenia - NOT Fanconi anaemia v3.21 DUT Arina Puzriakova Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v4.133
Cytopenia - NOT Fanconi anaemia v3.21 DUT Arina Puzriakova gene: DUT was added
gene: DUT was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert Review Amber,Literature
Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: DUT.
Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DUT were set to 28073829; 35611808; 35931051
Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome, OMIM:620044
Primary immunodeficiency or monogenic inflammatory bowel disease v4.133 DUT Arina Puzriakova Publications for gene: DUT were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.132 DUT Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: DUT.
Tag Q4_23_NHS_review tag was added to gene: DUT.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.132 DUT Arina Puzriakova Classified gene: DUT as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.132 DUT Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. Homozygous variants identified in at least 10 individuals from 6 unrelated families (French, Egyptian, two Libyan, Sudanese and Scottish) with bone marrow failure and diabetes. DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway.

Overall there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.132 DUT Arina Puzriakova Gene: dut has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.131 DUT Arina Puzriakova Phenotypes for gene: DUT were changed from Bone marrow failure and diabetes mellitus syndrome to Bone marrow failure and diabetes mellitus syndrome, OMIM:620044
Intellectual disability v5.363 SLC12A6 Arina Puzriakova Phenotypes for gene: SLC12A6 were changed from Agenesis of the corpus callosum with peripheral neuropathy, 218000 -3; AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY (ACCPN) to Agenesis of the corpus callosum with peripheral neuropathy, OMIM:218000
Hereditary neuropathy v1.473 SLC12A6 Arina Puzriakova Phenotypes for gene: SLC12A6 were changed from Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum; Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum to Charcot-Marie-Tooth disease, axonal, type 2II, OMIM:620068; Agenesis of the corpus callosum with peripheral neuropathy, OMIM:218000
Fetal anomalies v3.123 SLC12A6 Arina Puzriakova Phenotypes for gene: SLC12A6 were changed from AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY to Charcot-Marie-Tooth disease, axonal, type 2II, OMIM:620068; Agenesis of the corpus callosum with peripheral neuropathy, OMIM:218000
Hereditary neuropathy or pain disorder v3.69 SLC12A6 Arina Puzriakova Phenotypes for gene: SLC12A6 were changed from Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum to Charcot-Marie-Tooth disease, axonal, type 2II, OMIM:620068; Agenesis of the corpus callosum with peripheral neuropathy, OMIM:218000
Hereditary neuropathy or pain disorder v3.68 SLC12A6 Arina Puzriakova commented on gene: SLC12A6
Hereditary neuropathy or pain disorder v3.68 SLC12A6 Arina Puzriakova Publications for gene: SLC12A6 were set to 12368912; 31439721; 27485015; 16606917; 17893295; 21628467
Hereditary neuropathy or pain disorder v3.67 SLC12A6 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: SLC12A6.
Tag Q4_23_NHS_review tag was added to gene: SLC12A6.
Intellectual disability v5.362 C20orf24 Arina Puzriakova commented on gene: C20orf24: Added new-gene-name tag, new approved HGNC gene symbol for C20orf24 is RAB5IF
Intellectual disability v5.362 C20orf24 Arina Puzriakova Classified gene: C20orf24 as Red List (low evidence)
Intellectual disability v5.362 C20orf24 Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. Biallelic LoF variant identified in a patient with craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome. Authors suggested possible low penetrance due to two relatives with heterozygous variant and cleft lip and/or palate (PMID: 35614220).

Rating Red as only a single family reported to date. In OMIM the relationship between the phenotype and gene is provisional.
Intellectual disability v5.362 C20orf24 Arina Puzriakova Gene: c20orf24 has been classified as Red List (Low Evidence).
Intellectual disability v5.361 C20orf24 Arina Puzriakova Phenotypes for gene: C20orf24 were changed from ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2 to ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2, OMIM:616994
Intellectual disability v5.360 C20orf24 Arina Puzriakova Tag new-gene-name tag was added to gene: C20orf24.
Intellectual disability v5.360 MTF1 Sarah Leigh changed review comment from: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3 & S10).; to: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3, S9 & S10).
Intellectual disability v5.360 TRPC5 Sarah Leigh Added comment: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3, S9 & S10).
Intellectual disability v5.360 TRPC5 Sarah Leigh Publications for gene: TRPC5 were set to 36323681
Intellectual disability v5.359 MTF1 Sarah Leigh Added comment: Comment on publications: PMID: 23033978 reports MTF1: NM_005955.2 c.333del p.(Thr112Hisfs*26) as a de novo variant in a patient with severe ID, who also carries a maternally inherited TRPC5 NM_012471.2 c.1999C>A p.(Pro667Thr) variant (tables S3 & S10).
Intellectual disability v5.359 MTF1 Sarah Leigh Publications for gene: MTF1 were set to 26350204; 28901405; 18341605; 23033978
Intellectual disability v5.358 MTF1 Sarah Leigh Publications for gene: MTF1 were set to 26350204; 28901405; 18341605
Intellectual disability v5.357 TRPC5 Sarah Leigh Entity copied from DDG2P v3.79
Intellectual disability v5.357 TRPC5 Sarah Leigh gene: TRPC5 was added
gene: TRPC5 was added to Intellectual disability - microarray and sequencing. Sources: DD-Gene2Phenotype,Expert Review Red
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to 36323681
Phenotypes for gene: TRPC5 were set to TRPC5-related neurodevelopmental disorder
Intellectual disability v5.356 CDK16 Sarah Leigh Classified gene: CDK16 as Amber List (moderate evidence)
Intellectual disability v5.356 CDK16 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.356 CDK16 Sarah Leigh Gene: cdk16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.355 CDK16 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: CDK16.
Tag Q4_23_NHS_review tag was added to gene: CDK16.
Intellectual disability v5.355 CDK16 Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability, MONDO:0001071 is the phenotype listed for CDK16 in Gene2Phen (2nd January 2024)
Intellectual disability v5.355 CDK16 Sarah Leigh Phenotypes for gene: CDK16 were changed from to Intellectual disability, MONDO:0001071
Intellectual disability v5.354 CDK16 Sarah Leigh edited their review of gene: CDK16: Added comment: To date, CDK16 variants have not been associated with a phenotype in OMIM, but have a limited association with intellectual disability (ID) in Gen2Phen. Four CDK16 variants have been associated with a spectrum of phenotypic features, including ID (n= 3), autism spectrum disorder (n= 3), seizures (n= 2) and spacity (n= 2)(PMID:36323681, 31981491, 25644381).; Changed rating: GREEN
Intellectual disability v5.354 CDK16 Sarah Leigh Publications for gene: CDK16 were set to 26350204; 25644381
Likely inborn error of metabolism - targeted testing not possible v4.88 LDHD Sarah Leigh edited their review of gene: LDHD: Added comment: LDHD variants have been associated with D-lactic aciduria with susceptibility to gout (OMIM:245450), but not with a phenotype in Gen2Phen. At least seven LDHD variants have been reported in seven unrelated cases (PMID: 30931947;31638601;34258137;37021930).; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.88 LDHD Sarah Leigh Phenotypes for gene: LDHD were changed from D-lactic aciduria with susceptibility to gout, OMIM:245450 to D-lactic aciduria with susceptibility to gout, OMIM:245450; lactic aciduria due to D-lactic acid, MONDO:0009505
Likely inborn error of metabolism - targeted testing not possible v4.87 LDHD Sarah Leigh Classified gene: LDHD as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.87 LDHD Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.87 LDHD Sarah Leigh Gene: ldhd has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.86 LDHD Sarah Leigh Publications for gene: LDHD were set to 30931947; 31638601
Likely inborn error of metabolism - targeted testing not possible v4.85 LDHD Sarah Leigh Phenotypes for gene: LDHD were changed from D-lactic aciduria with susceptibility to gout to D-lactic aciduria with susceptibility to gout, OMIM:245450
Likely inborn error of metabolism - targeted testing not possible v4.84 LDHD Sarah Leigh Classified gene: LDHD as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.84 LDHD Sarah Leigh Gene: ldhd has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.84 LDHD Sarah Leigh Classified gene: LDHD as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.84 LDHD Sarah Leigh Gene: ldhd has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.353 ACACA Sarah Leigh Tag Q4_23_NHS_review was removed from gene: ACACA.
Intellectual disability v5.353 ACACA Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.83
Intellectual disability v5.353 ACACA Sarah Leigh gene: ACACA was added
gene: ACACA was added to Intellectual disability - microarray and sequencing. Sources: Expert Review Amber,Literature
Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: ACACA.
Mode of inheritance for gene: ACACA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACACA were set to 6114432; 34552920; 36709796
Phenotypes for gene: ACACA were set to Acetyl-CoA carboxylase deficiency, OMIM: 613933
Likely inborn error of metabolism - targeted testing not possible v4.83 ACACA Sarah Leigh Publications for gene: ACACA were updated from 6114432; 16103361; 34552920; 36709796 to 6114432; 34552920; 36709796
Likely inborn error of metabolism - targeted testing not possible v4.82 ACACA Sarah Leigh Publications for gene: ACACA were set to 6114432; 34552920; 36709796
Likely inborn error of metabolism - targeted testing not possible v4.81 ACACA Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ACACA.
Tag Q4_23_NHS_review tag was added to gene: ACACA.
Likely inborn error of metabolism - targeted testing not possible v4.81 ACACA Sarah Leigh reviewed gene: ACACA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v4.130 LYN Achchuthan Shanmugasundram Classified gene: LYN as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.130 LYN Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.130 LYN Achchuthan Shanmugasundram Gene: lyn has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.129 LYN Achchuthan Shanmugasundram Phenotypes for gene: LYN were changed from Autoinflammatory; Neutrophilic vasculitis; Liver fibrosis; Chronic urticaria; Atopic dermatitis; Fever to Autoinflammatory disease, systemic, with vasculitis, OMIM:620376
Primary immunodeficiency or monogenic inflammatory bowel disease v4.128 LYN Achchuthan Shanmugasundram Publications for gene: LYN were set to 36122175
Primary immunodeficiency or monogenic inflammatory bowel disease v4.127 LYN Achchuthan Shanmugasundram Mode of pathogenicity for gene: LYN was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v4.126 LYN Achchuthan Shanmugasundram Mode of inheritance for gene: LYN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 LYN Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: LYN.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 LYN Achchuthan Shanmugasundram changed review comment from: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence, which suggested gain of function mechanism for variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.; to: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence, which suggested gain of function mechanism for LYN variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 LYN Achchuthan Shanmugasundram changed review comment from: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence which suggested gain of function mechanism for variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.; to: As reviewed by Boaz Palterer, there are four unrelated patients reported with systemic autoinflammatory disorder (SAID) and identified with de novo LYN variants. Of these one patient was reported in PMID:36122175 and three unrelated boys were reported in PMID:36932076. The patient data was also supported by functional evidence, which suggested gain of function mechanism for variants.

This gene was associated with relevant phenotypes in OMIM (MIM #620376), but not yet in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 LYN Achchuthan Shanmugasundram reviewed gene: LYN: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 36122175, 36932076; Phenotypes: Autoinflammatory disease, systemic, with vasculitis, OMIM:620376; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism - targeted testing not possible v4.81 ACACA Sarah Leigh Publications for gene: ACACA were set to 34552920; 36709796
Likely inborn error of metabolism - targeted testing not possible v4.80 ACACA Sarah Leigh Publications for gene: ACACA were set to 34552920; 36709796
Likely inborn error of metabolism - targeted testing not possible v4.80 ACACA Sarah Leigh Publications for gene: ACACA were set to 34552920
Likely inborn error of metabolism - targeted testing not possible v4.79 ACACA Sarah Leigh Phenotypes for gene: ACACA were changed from Acetyl-CoA carboxylase deficiency to Acetyl-CoA carboxylase deficiency, OMIM: 613933
Likely inborn error of metabolism - targeted testing not possible v4.78 ACACA Sarah Leigh Classified gene: ACACA as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.78 ACACA Sarah Leigh Gene: acaca has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v4.24 NEK8 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NEK8.
Cystic kidney disease v4.24 NEK8 Achchuthan Shanmugasundram Classified gene: NEK8 as Amber List (moderate evidence)
Cystic kidney disease v4.24 NEK8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available in support of the association of monoallelic NEK8 variants with polycystic kidney disease. Hence, this gene can be promoted to green rating in the next GMS review.
Cystic kidney disease v4.24 NEK8 Achchuthan Shanmugasundram Gene: nek8 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v4.23 NEK8 Achchuthan Shanmugasundram Mode of inheritance for gene: NEK8 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cystic kidney disease v4.22 NEK8 Achchuthan Shanmugasundram edited their review of gene: NEK8: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Cystic kidney disease v4.22 NEK8 Achchuthan Shanmugasundram changed review comment from: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8.

PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure.

Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources.; to: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8. Carriers of AR-NEK8 disease do not show renal manifestations, as variants are LOF and these variants are suspected of dominant negative effect.

PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure.

Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources.
Cystic kidney disease v4.22 NEK8 Achchuthan Shanmugasundram Mode of pathogenicity for gene: NEK8 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Cystic kidney disease v4.21 NEK8 Achchuthan Shanmugasundram Publications for gene: NEK8 were set to
Cystic kidney disease v4.20 NEK8 Achchuthan Shanmugasundram Phenotypes for gene: NEK8 were changed from Ciliopathy genes associated with cystic kidney disease to polycystic kidney disease, MONDO:0020642; ?Nephronophthisis 9, OMIM:613824
Cystic kidney disease v4.19 NEK8 Achchuthan Shanmugasundram changed review comment from: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8.; to: PMID:37598857 reported the identification of monoallelic NEK8 variants in 12 different families reported with autosomal dominant polycystic kidney disease (ADPKD). Of these, de novo missense variant p.Arg45Trp was found in 10 families and missense variants p.Ile150Met and p.Lys157Gln were found in one family each. Patient fibroblasts show normal ciliogenesis and normal localisation and expression of NEK8.

PMID:18199800 reported one patient with biallelic NEK8 variant (p.His425Tyr) and with nephronophthisis. Nephronophthisis is an autosomal recessive kidney disease that leads to kidney cyst formation and progressive renal failure.

Although nephronophthisis 9 (MIM #613824) caused by biallelic variants is reported in both OMIM and Gene2Phenotype, cystic kidney disease caused by monoallelic variants are not yet reported in these resources.
Cystic kidney disease v4.19 NEK8 Achchuthan Shanmugasundram edited their review of gene: NEK8: Changed publications to: 18199800, 37598857; Changed phenotypes to: polycystic kidney disease, MONDO:0020642, ?Nephronophthisis 9, OMIM:613824
Cystic kidney disease v4.19 NEK8 Achchuthan Shanmugasundram reviewed gene: NEK8: Rating: GREEN; Mode of pathogenicity: None; Publications: 37598857; Phenotypes: polycystic kidney disease, MONDO:0020642; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v4.43 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not mentioned as a phenotypic feature.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals. 2 confirmed cases with ataxia and ASL variants are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not mentioned as a phenotypic feature.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Retinal disorders v4.48 TTC21B Nour Elkhateeb reviewed gene: TTC21B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21068128, 33599192; Phenotypes: Retinal dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.43 ASL Eleanor Williams commented on gene: ASL
Skeletal dysplasia v4.32 UBA2 Eleanor Williams Tag Q4_23_promote_green tag was added to gene: UBA2.
Tag Q4_23_NHS_review tag was added to gene: UBA2.
Skeletal dysplasia v4.32 UBA2 Eleanor Williams commented on gene: UBA2: As reviewer notes there are now additional cases reported with variants in UBA2 and skeletal defects including:

PMID: 34040189 - Schnur et al 2021 - report 16 individuals from 7 families who have variable phenotypes including Aplasia cutis congenita and skeletal defects. Ectrodyctly is present in some individuals from 4/7 families and other skeletal phenotypes such as hip abnormalities, plagiocephaly, Wormian bones, syndactyly, kyphoscoliosis, Variants were heterozygous rare variants not found in GnomAD and consist of frameshift, nonsense and missense variants.
Intellectual disability v5.352 DLG2 Achchuthan Shanmugasundram Tag epigenetics was removed from gene: DLG2.
Intellectual disability v5.352 DIP2B Achchuthan Shanmugasundram Tag epigenetics was removed from gene: DIP2B.
Familial prostate cancer v1.3 BRCA2 Achchuthan Shanmugasundram Tag stratified-medicine was removed from gene: BRCA2.
Familial prostate cancer v1.3 BRCA1 Achchuthan Shanmugasundram Tag stratified-medicine was removed from gene: BRCA1.
Early onset or syndromic epilepsy v4.135 ALPL Achchuthan Shanmugasundram Tag drug-indication was removed from gene: ALPL.
Parkinson Disease and Complex Parkinsonism v1.120 HTT_CAG Achchuthan Shanmugasundram Tag anticipation was removed from STR: HTT_CAG.
Intellectual disability v5.352 GABRQ Achchuthan Shanmugasundram Phenotypes for gene: GABRQ were changed from ASD; schizophrenia; migraine to autism spectrum disorder, MONDO:0005258; schizophrenia, MONDO:0005090; migraine disorder, MONDO:0005277
Intellectual disability v5.351 GABRQ Achchuthan Shanmugasundram Tag Schizophrenia was removed from gene: GABRQ.
Adult onset leukodystrophy v3.23 RNASET2 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: RNASET2.
Tag Q4_21_rating was removed from gene: RNASET2.
Adult onset leukodystrophy v3.23 POLR1C Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: POLR1C.
Tag Q4_21_rating was removed from gene: POLR1C.
Hydrocephalus v4.3 MYMK Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: MYMK.
Tag Q4_21_rating was removed from gene: MYMK.
Tag Q4_21_phenotype was removed from gene: MYMK.
Adult onset leukodystrophy v3.23 MARS Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: MARS.
Tag Q4_21_rating was removed from gene: MARS.
Tag Q4_21_phenotype was removed from gene: MARS.
Hydrocephalus v4.3 HYLS1 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: HYLS1.
Tag Q4_21_rating was removed from gene: HYLS1.
Congenital hyperinsulinism v3.4 GPC3 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: GPC3.
Tag Q4_21_rating was removed from gene: GPC3.
Tag Q4_21_phenotype was removed from gene: GPC3.
Adult onset dystonia, chorea or related movement disorder v3.18 GBA Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: GBA.
Tag Q4_21_rating was removed from gene: GBA.
Severe microcephaly v4.48 DPP6 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: DPP6.
Tag Q4_21_rating was removed from gene: DPP6.
Adult onset leukodystrophy v3.23 COL4A2 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: COL4A2.
Tag Q4_21_rating was removed from gene: COL4A2.
Tag Q4_21_phenotype was removed from gene: COL4A2.
Congenital hyperinsulinism v3.4 AKT2 Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: AKT2.
Tag Q4_21_rating was removed from gene: AKT2.
Tag Q4_21_phenotype was removed from gene: AKT2.
Adult onset leukodystrophy v3.23 AARS Achchuthan Shanmugasundram Tag Q4_21_expert_review was removed from gene: AARS.
Tag Q4_21_rating was removed from gene: AARS.
Cerebral vascular malformations v3.8 SETD5 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: SETD5.
Tag Q3_22_expert_review was removed from gene: SETD5.
Neonatal diabetes v4.4 ONECUT1 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: ONECUT1.
Tag Q3_22_NHS_review was removed from gene: ONECUT1.
Tag Q3_22_expert_review was removed from gene: ONECUT1.
Cerebral vascular malformations v3.8 CNOT3 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: CNOT3.
Tag Q3_22_expert_review was removed from gene: CNOT3.
Neonatal diabetes v4.4 CNOT1 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: CNOT1.
Tag Q3_22_NHS_review was removed from gene: CNOT1.
Tag Q3_22_expert_review was removed from gene: CNOT1.
Cerebral vascular malformations v3.8 CHD4 Achchuthan Shanmugasundram Tag Q3_22_rating was removed from gene: CHD4.
Tag Q3_22_expert_review was removed from gene: CHD4.
Fetal anomalies v3.122 MED12 Achchuthan Shanmugasundram Tag Q3_21_MOI was removed from gene: MED12.
Tag Q3_21_expert_review was removed from gene: MED12.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 DCLRE1B Achchuthan Shanmugasundram Tag Q3_21_rating was removed from gene: DCLRE1B.
Tag Q3_21_expert_review was removed from gene: DCLRE1B.
Childhood onset dystonia, chorea or related movement disorder v3.56 AFG3L2 Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: AFG3L2.
Tag Q2_21_phenotype was removed from gene: AFG3L2.
Fetal anomalies v3.122 KIDINS220 Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: KIDINS220.
Tag Q2_21_expert_review was removed from gene: KIDINS220.
Tag Q2_21_MOI was removed from gene: KIDINS220.
Fetal anomalies v3.122 LIFR Achchuthan Shanmugasundram Tag Q2_22_MOI was removed from gene: LIFR.
Tag Q2_22_expert_review was removed from gene: LIFR.
Intellectual disability v5.351 FAR1 Achchuthan Shanmugasundram Tag Q2_21_expert_review was removed from gene: FAR1.
Tag Q2_21_MOI was removed from gene: FAR1.
Hydrocephalus v4.3 ERF Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: ERF.
Tag Q2_21_expert_review was removed from gene: ERF.
Holoprosencephaly - NOT chromosomal v4.4 DISP1 Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: DISP1.
Tag Q2_21_expert_review was removed from gene: DISP1.
Monogenic hearing loss v4.25 COL9A3 Achchuthan Shanmugasundram Tag Q2_21_rating was removed from gene: COL9A3.
Tag Q2_21_phenotype was removed from gene: COL9A3.
Tag Q2_21_expert_review was removed from gene: COL9A3.
Hereditary neuropathy or pain disorder v3.67 SLC12A6 Achchuthan Shanmugasundram Tag Q1_22_rating was removed from gene: SLC12A6.
Monogenic hearing loss v4.25 FOXI1 Achchuthan Shanmugasundram Tag Q1_22_expert_review was removed from gene: FOXI1.
Tag Q1_22_MOI was removed from gene: FOXI1.
Congenital myopathy v4.34 TNNT1 Achchuthan Shanmugasundram Publications for gene: TNNT1 were set to 26296490; 25430424; 32994279
Congenital myopathy v4.33 SELENON Achchuthan Shanmugasundram edited their review of gene: SELENON: Changed phenotypes to: Muscular dystrophy, rigid spine, 1, OMIM:602771
Congenital muscular dystrophy v4.20 DAG1 Achchuthan Shanmugasundram Publications for gene: DAG1 were set to 26380289; 24052401; 25934851; 22810924
Congenital muscular dystrophy v4.19 EMD Achchuthan Shanmugasundram Tag Q2_21_expert_review was removed from gene: EMD.
Tag Q2_23_expert_review tag was added to gene: EMD.
Congenital muscular dystrophy v4.19 COL4A1 Eleanor Williams Tag Q3_23_NHS_review tag was added to gene: COL4A1.
Congenital myopathy v4.33 LETM1 Eleanor Williams Tag Q3_23_NHS_review tag was added to gene: LETM1.
Congenital muscular dystrophy v4.19 POGLUT1 Eleanor Williams Tag Q4_22_NHS_review tag was added to gene: POGLUT1.
Congenital muscular dystrophy v4.19 EMD Eleanor Williams commented on gene: EMD
Congenital muscular dystrophy v4.19 EMD Eleanor Williams Tag Q2_21_expert_review tag was added to gene: EMD.
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ATP5E.
Tag Q4_23_expert_review tag was added to gene: ATP5E.
Familial tumours of the nervous system v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2023-12-20
Familial tumours of the nervous system v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Hereditary isolated diabetes insipidus v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2023-12-20
Hereditary isolated diabetes insipidus v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Hereditary diffuse gastric cancer v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2023-12-20
Hereditary diffuse gastric cancer v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Hereditary diffuse gastric cancer v1.10 Eleanor Williams List of related panels changed from R215; CDH1-related cancer syndrome to CDH1-related cancer syndrome; R215
Hereditary isolated diabetes insipidus v1.9 Eleanor Williams List of related panels changed from R440; Neuropophyseal diabetes insipidus to Neuropophyseal diabetes insipidus; R440
Hereditary isolated diabetes insipidus v1.7 Achchuthan Shanmugasundram Panel name changed from Neuropophyseal diabetes insipidus to Hereditary isolated diabetes insipidus
List of related panels changed from R440 to R440; Neuropophyseal diabetes insipidus
Hereditary diffuse gastric cancer v1.6 Achchuthan Shanmugasundram Panel name changed from CDH1-related cancer syndrome to Hereditary diffuse gastric cancer
List of related panels changed from R215 to R215; CDH1-related cancer syndrome
Structural eye disease v3.72 SLC25A24 Achchuthan Shanmugasundram Classified gene: SLC25A24 as Amber List (moderate evidence)
Structural eye disease v3.72 SLC25A24 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Structural eye disease v3.72 SLC25A24 Achchuthan Shanmugasundram Gene: slc25a24 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.71 SLC25A24 Achchuthan Shanmugasundram Publications for gene: SLC25A24 were set to 29903433; 29100093; 29100094
Structural eye disease v3.70 SLC25A24 Achchuthan Shanmugasundram Mode of inheritance for gene: SLC25A24 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.69 SLC25A24 Achchuthan Shanmugasundram Tag Q4_23_NHS_review tag was added to gene: SLC25A24.
Structural eye disease v3.69 SLC25A24 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC25A24.
Structural eye disease v3.69 SLC25A24 Achchuthan Shanmugasundram changed review comment from: There are six unrelated cases reported in total, of which five cases had c.650G>A (p.Arg217His) variant and one patient had c.649C>T (p.Arg217Cys).; to: There are six unrelated cases reported in total, of which five cases had c.650G>A (p.Arg217His) variant and one patient had c.649C>T (p.Arg217Cys). Both these variants are on the same amino acid. However, these cases were from people of multiple descent/ geographic locations. Experiments from patient-derived fibroblasts demonstrated that SLC25A24 variants lead to mitochondrial dysfunction with increased sensitivity to oxidative stress.
Structural eye disease v3.69 SLC25A24 Achchuthan Shanmugasundram changed review comment from: There are six unrelated cases reported in total, of which five cases had c.650G>A (p.Arg217His) variant and one patient had c.649C>T p.Arg217Cys; to: There are six unrelated cases reported in total, of which five cases had c.650G>A (p.Arg217His) variant and one patient had c.649C>T (p.Arg217Cys).
Structural eye disease v3.69 SLC25A24 Achchuthan Shanmugasundram reviewed gene: SLC25A24: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100093, 31775791; Phenotypes: Fontaine progeroid syndrome, OMIM:612289; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.69 KIF11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KIF11.
Tag Q4_23_NHS_review tag was added to gene: KIF11.
Structural eye disease v3.69 KIF11 Achchuthan Shanmugasundram Classified gene: KIF11 as Amber List (moderate evidence)
Structural eye disease v3.69 KIF11 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Structural eye disease v3.69 KIF11 Achchuthan Shanmugasundram Gene: kif11 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.68 KIF11 Achchuthan Shanmugasundram Phenotypes for gene: KIF11 were changed from Chorioretinopathy, Lymphedema or Mental Retardation, MCLMR, 152950 to Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development, OMIM:152950
Structural eye disease v3.67 KIF11 Achchuthan Shanmugasundram Publications for gene: KIF11 were set to 27212378
Structural eye disease v3.66 KIF11 Achchuthan Shanmugasundram Mode of inheritance for gene: KIF11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.65 KIF11 Achchuthan Shanmugasundram reviewed gene: KIF11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development, OMIM:152950; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood solid tumours v4.9 CDKN2A Terri McVeigh gene: CDKN2A was added
gene: CDKN2A was added to Childhood solid tumours. Sources: Expert Review,Literature
Mode of inheritance for gene: CDKN2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDKN2A were set to 24451801; 30207590
Phenotypes for gene: CDKN2A were set to cutaneous melanoma; pancreatic cancer; astrocytomas
Penetrance for gene: CDKN2A were set to Incomplete
Review for gene: CDKN2A was set to GREEN
Added comment: Discussed at UKCGG/cancer leads meeting 06/07/2023 - agreed reasonable to include on panel
Sources: Expert Review, Literature
Childhood solid tumours v4.9 BAP1 Terri McVeigh gene: BAP1 was added
gene: BAP1 was added to Childhood solid tumours. Sources: Expert Review
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to 23552620; 30517737; 31382694; https://doi.org/10.1016/j.ejcped.2023.100023; 29981911
Phenotypes for gene: BAP1 were set to uveal melanoma; mesothelioma; cholangiocarcioma; cutaneous melanoma; renal cell carcinoma; meningioma
Penetrance for gene: BAP1 were set to Incomplete
Review for gene: BAP1 was set to GREEN
Added comment: Discussed at UKCGG/cancer leads meeting 06/07/2023 - agreed reasonable to include on panel
Sources: Expert Review
Structural eye disease v3.65 KIAA0586 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Structural eye disease v3.65 KIAA0586 Achchuthan Shanmugasundram Classified gene: KIAA0586 as Amber List (moderate evidence)
Structural eye disease v3.65 KIAA0586 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Structural eye disease v3.65 KIAA0586 Achchuthan Shanmugasundram Gene: kiaa0586 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.64 KIAA0586 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0586 were changed from to Joubert syndrome 23, OMIM:616490; Short-rib thoracic dysplasia 14 with polydactyly, OMIM:616546
Structural eye disease v3.63 KIAA0586 Achchuthan Shanmugasundram Publications for gene: KIAA0586 were set to 30055837
Structural eye disease v3.62 KIAA0586 Achchuthan Shanmugasundram Mode of inheritance for gene: KIAA0586 was changed from to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v3.61 KIAA0586 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KIAA0586.
Tag Q4_23_NHS_review tag was added to gene: KIAA0586.
Structural eye disease v3.61 KIAA0586 Achchuthan Shanmugasundram reviewed gene: KIAA0586: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 23, OMIM:616490, Short-rib thoracic dysplasia 14 with polydactyly, OMIM:616546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v3.61 CRYBB2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CRYBB2.
Tag Q4_23_NHS_review tag was added to gene: CRYBB2.
Structural eye disease v3.61 CRYBB2 Achchuthan Shanmugasundram Classified gene: CRYBB2 as Amber List (moderate evidence)
Structural eye disease v3.61 CRYBB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Structural eye disease v3.61 CRYBB2 Achchuthan Shanmugasundram Gene: crybb2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.60 CRYBB2 Achchuthan Shanmugasundram Publications for gene: CRYBB2 were set to 29386872
Structural eye disease v3.59 CRYBB2 Achchuthan Shanmugasundram Phenotypes for gene: CRYBB2 were changed from Cataract 3, multiple types, 601547 to Cataract 3, multiple types, OMIM:601547
Structural eye disease v3.58 CRYBB2 Achchuthan Shanmugasundram reviewed gene: CRYBB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v4.48 MVK Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MVK.
Tag Q4_23_NHS_review tag was added to gene: MVK.
Retinal disorders v4.48 MVK Achchuthan Shanmugasundram Classified gene: MVK as Amber List (moderate evidence)
Retinal disorders v4.48 MVK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Siying Lin, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Retinal disorders v4.48 MVK Achchuthan Shanmugasundram Gene: mvk has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.47 MVK Achchuthan Shanmugasundram Phenotypes for gene: MVK were changed from Hyper-IgD syndrome, OMIM:260920; Mevalonic aciduria, OMIM:610377 to Hyper-IgD syndrome, OMIM:260920; Mevalonic aciduria, OMIM:610377; retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.46 MVK Achchuthan Shanmugasundram edited their review of gene: MVK: Changed phenotypes to: retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.46 MVK Achchuthan Shanmugasundram Publications for gene: MVK were set to 24084495
Retinal disorders v4.45 MVK Achchuthan Shanmugasundram reviewed gene: MVK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gene therapy clinical trials v0.9 DDC vardha ismail reviewed gene: DDC: Rating: ; Mode of pathogenicity: None; Publications: PMID: 37402126; Phenotypes: Ptosis, Oculogyric crises, Poor feeding, Developmental delay, Truncal hypotonia, Limb dystonia, Orofacial dystonia, Autonomic abnormalities excessive sweating; Mode of inheritance: None
Gene therapy clinical trials v0.9 DDC vardha ismail gene: DDC was added
gene: DDC was added to Gene therapy clinical trials. Sources: Other
Mode of inheritance for gene: DDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDC were set to PMID: 37402126.
Penetrance for gene: DDC were set to Complete
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Gavin Ryan gene: RETREG1 was added
gene: RETREG1 was added to Childhood onset hereditary spastic paraplegia. Sources: NHS GMS
Mode of inheritance for gene: RETREG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RETREG1 were set to 24327336
Penetrance for gene: RETREG1 were set to unknown
Review for gene: RETREG1 was set to GREEN
Added comment: Aydinlar et al identified individuals with hereditary neuropathy caused by variant in this gene who also had spasticity. Further, LoF homozygous variant in this gene identified via Diagnostic Discovery in 100K and GMS WGS patient with features of Progressive spasticity, facial hypotonia, dysarthria, and fatiguable weakness.
Sources: NHS GMS
Intellectual disability v5.351 MYH10 Achchuthan Shanmugasundram Classified gene: MYH10 as Amber List (moderate evidence)
Intellectual disability v5.351 MYH10 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v5.351 MYH10 Achchuthan Shanmugasundram Gene: myh10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.350 MYH10 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MYH10.
Intellectual disability v5.350 MYH10 Achchuthan Shanmugasundram Phenotypes for gene: MYH10 were changed from Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; MYH10-related Multiple congenital anomalies to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; MYH10-related Multiple congenital anomalies
Intellectual disability v5.350 MYH10 Achchuthan Shanmugasundram Phenotypes for gene: MYH10 were changed from MYH10-related Multiple congenital anomalies, Intellectual disability to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; MYH10-related Multiple congenital anomalies
Intellectual disability v5.349 MYH10 Achchuthan Shanmugasundram Publications for gene: MYH10 were set to 25356899; 25003005
Intellectual disability v5.348 MYH10 Achchuthan Shanmugasundram Mode of inheritance for gene: MYH10 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.347 MYH10 Achchuthan Shanmugasundram reviewed gene: MYH10: Rating: GREEN; Mode of pathogenicity: None; Publications: 35980381; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v3.19 ABHD5 Tom Cullup gene: ABHD5 was added
gene: ABHD5 was added to Ichthyosis and erythrokeratoderma. Sources: Expert list
Mode of inheritance for gene: ABHD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD5 were set to PubMed: 11590543
Phenotypes for gene: ABHD5 were set to Chanarin-Dorfman syndrome
Penetrance for gene: ABHD5 were set to Complete
Review for gene: ABHD5 was set to GREEN
Added comment: Green gene on multiple panels including PPK. Request from Dr G Petrof, GOSH, to add this gene to ichthyosis, as this is part of presenting phenotype in Chanarin-Dorfman syndrome.
Sources: Expert list
Skeletal dysplasia v4.32 PSMC3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PSMC3.
Skeletal dysplasia v4.32 PSMC3 Achchuthan Shanmugasundram Classified gene: PSMC3 as Amber List (moderate evidence)
Skeletal dysplasia v4.32 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic PSMC3 variants with skeletal malformations and hence this gene can be promoted to green rating in the next GMS review.
Skeletal dysplasia v4.32 PSMC3 Achchuthan Shanmugasundram Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.31 PSMC3 Achchuthan Shanmugasundram changed review comment from: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Skeletal malformations were observed in 11/15 (73%) cases (scoliosis, acetabular dysplasia, brachymetatarsy)
Sources: Literature; to: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Skeletal malformations were observed in 11/15 (73%) cases (scoliosis, acetabular dysplasia, brachymetatarsy).

Monoallelic variants in PSMC3 are not yet associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v4.31 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to 37256937
Phenotypes for gene: PSMC3 were set to neurodevelopmental disorder, MONDO:0700092; scoliosis, MONDO:0005392; Acetabular dysplasia, HP:0008807; brachymetatarsy
Review for gene: PSMC3 was set to GREEN
Added comment: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Skeletal malformations were observed in 11/15 (73%) cases (scoliosis, acetabular dysplasia, brachymetatarsy)
Sources: Literature
Hereditary neuropathy or pain disorder v3.67 PSMC3 Achchuthan Shanmugasundram Classified gene: PSMC3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.67 PSMC3 Achchuthan Shanmugasundram Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.66 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354
Review for gene: PSMC3 was set to AMBER
Added comment: Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.
Sources: Literature
Severe microcephaly v4.48 PSMC3 Achchuthan Shanmugasundram Classified gene: PSMC3 as Amber List (moderate evidence)
Severe microcephaly v4.48 PSMC3 Achchuthan Shanmugasundram Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.47 PSMC3 Achchuthan Shanmugasundram changed review comment from: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Microcephaly was reported in in 6/17 (35%) cases, of which severe macrocephaly was in 2/16 (13%) cases.
Sources: Literature; to: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Microcephaly was reported in in 6/17 (35%) cases, of which severe macrocephaly was in 2/16 (13%) cases.
Sources: Literature
Severe microcephaly v4.47 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to 37256937
Phenotypes for gene: PSMC3 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: PSMC3 was set to AMBER
Added comment: 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Microcephaly was reported in in 6/17 (35%) cases, of which severe macrocephaly was in 2/16 (13%) cases.
Sources: Literature
Monogenic hearing loss v4.25 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: This gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: This gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".; to: Comment on mode of inheritance: There is sufficient evidence available for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene can be promoted to green rating at the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.
Monogenic hearing loss v4.25 PSMC3 Achchuthan Shanmugasundram Classified gene: PSMC3 as Amber List (moderate evidence)
Monogenic hearing loss v4.25 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with hearing loss and hence this gene can be promoted to green rating in the next GMS review.
Monogenic hearing loss v4.25 PSMC3 Achchuthan Shanmugasundram Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.24 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with hearing loss. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Monogenic hearing loss v4.24 PSMC3 Achchuthan Shanmugasundram Mode of inheritance for gene: PSMC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v4.23 PSMC3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PSMC3.
Monogenic hearing loss v4.23 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to 32500975; 37256937
Phenotypes for gene: PSMC3 were set to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092; autosomal dominant nonsyndromic hearing loss, MONDO:0019587
Review for gene: PSMC3 was set to GREEN
Added comment: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). 9/19 patients had hearing loss, of which two were labelled as sensorineural and one was labelled as conductive. In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Sources: Literature
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.; to: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Intellectual disability v5.347 PSMC3 Achchuthan Shanmugasundram changed review comment from: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.; to: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Ataxia and cerebellar anomalies - narrow panel v4.43 THG1L Achchuthan Shanmugasundram Classified gene: THG1L as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.43 THG1L Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.43 THG1L Achchuthan Shanmugasundram Gene: thg1l has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.42 THG1L Achchuthan Shanmugasundram Phenotypes for gene: THG1L were changed from Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800; Spinocerebellar ataxia, autosomal recessive 28, MONDO:0032923 to Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800, MONDO:0032923
Ataxia and cerebellar anomalies - narrow panel v4.41 THG1L Achchuthan Shanmugasundram Publications for gene: THG1L were set to 27307223; 30214071; 31168944
Ataxia and cerebellar anomalies - narrow panel v4.40 THG1L Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: THG1L.
Tag Q4_23_NHS_review tag was added to gene: THG1L.
Ataxia and cerebellar anomalies - narrow panel v4.40 THG1L Achchuthan Shanmugasundram reviewed gene: THG1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 27307223, 30214071, 31168944, 33682303, 37670026; Phenotypes: Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v4.19 COL4A1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM and Gene2Phenotype (Porencephaly 1 with 'definitive' rating in the DD panel).
Malformations of cortical development v4.19 COL4A1 Achchuthan Shanmugasundram Phenotypes for gene: COL4A1 were changed from Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:611773; Brain small vessel disease with or without ocular anomalies, OMIM:175780; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant, OMIM:618564; {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519 to Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:611773; Brain small vessel disease with or without ocular anomalies, OMIM:175780; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant, OMIM:618564; {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519
Malformations of cortical development v4.18 COL4A1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Malformations of cortical development v4.18 COL4A2 Achchuthan Shanmugasundram Classified gene: COL4A2 as Amber List (moderate evidence)
Malformations of cortical development v4.18 COL4A2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence for the promotion of this gene to green rating in the next GMS review.
Malformations of cortical development v4.18 COL4A2 Achchuthan Shanmugasundram Gene: col4a2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v4.17 COL4A2 Achchuthan Shanmugasundram changed review comment from: There are at least three unrelated cases of porencephaly reported with monoallelic variants in COL4A2.

This gene has also been associated with relevant phenotypes in both OMIM and Gene2Phenotype (with 'moderate' rating in the DD panel).; to: There are at least three unrelated cases of porencephaly reported with monoallelic variants in COL4A2.

This gene has also been associated with relevant phenotypes in both OMIM and Gene2Phenotype (Porencephaly 2 with 'moderate' rating in the DD panel).
Malformations of cortical development v4.17 COL4A2 Achchuthan Shanmugasundram Phenotypes for gene: COL4A2 were changed from Malformations of cortical development; Schizencephaly; porencephaly; polymicrogyria; focal cortical dysplasia; nodular heterotopia to Brain small vessel disease 2, OMIM:614483; {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519
Malformations of cortical development v4.16 COL4A2 Achchuthan Shanmugasundram Mode of inheritance for gene: COL4A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v4.15 COL4A2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: COL4A2.
Tag Q4_23_NHS_review tag was added to gene: COL4A2.
Malformations of cortical development v4.15 COL4A2 Achchuthan Shanmugasundram reviewed gene: COL4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain small vessel disease 2, OMIM:614483, {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v4.15 COL4A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: COL4A1.
Tag Q4_23_NHS_review tag was added to gene: COL4A1.
Malformations of cortical development v4.15 COL4A1 Achchuthan Shanmugasundram Classified gene: COL4A1 as Amber List (moderate evidence)
Malformations of cortical development v4.15 COL4A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Nour Elkhateeb, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Malformations of cortical development v4.15 COL4A1 Achchuthan Shanmugasundram Gene: col4a1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v4.14 COL4A1 Achchuthan Shanmugasundram Mode of inheritance for gene: COL4A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v4.13 COL4A1 Achchuthan Shanmugasundram Phenotypes for gene: COL4A1 were changed from Malformations of cortical development; Schizencephaly; porencephaly; polymicrogyria; focal cortical dysplasia; nodular heterotopia to Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:611773; Brain small vessel disease with or without ocular anomalies, OMIM:175780; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant, OMIM:618564; {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519
Malformations of cortical development v4.12 COL4A1 Achchuthan Shanmugasundram reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, OMIM:611773, Brain small vessel disease with or without ocular anomalies, OMIM:175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant, OMIM:618564, {Hemorrhage, intracerebral, susceptibility to}, OMIM:614519; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited polyposis and early onset colorectal cancer - germline testing v2.10 GREM1 Arina Puzriakova edited their review of gene: GREM1: Changed publications to: 25992589, 26947005, 28242209, 27984123, 9024286, 10092300, 12696020, 18084292, 21128281, 22561515, 24586997, 26493165, 29804199, 25419707
Inherited polyposis and early onset colorectal cancer - germline testing v2.10 GREM1 Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: GREM1.
Tag gene-duplication was removed from gene: GREM1.
Inherited polyposis and early onset colorectal cancer - germline testing v2.10 GREM1 Arina Puzriakova changed review comment from: Comment on list classification: Following review by the specialist service group, it has been agreed that this gene should be rated as Green at the next GMS panel update.

Upregulation of GREM1 expression in colorectal mucosa has been linked to hereditary mixed polyposis syndrome.
Most described patients are carriers of the Ashkenazi founder variant, a 40-kb upstream duplication that spans the 3' end of the neighbouring SCG5 gene. However, there are other duplications of different sizes that have been associated with disease (and some don’t incorporate the 3’ end of SCG5).

There is currently no evidence of small variants or a whole gene duplication of GREM1 causing a similar phenotype.

There is sufficient evidence to support a definitive gene-disease relationship but the providing GLH need to account for the upstream sequence location and size of reported variants in their primer design (as R211 (v2.10) is currently a purely wet-lab/non-WGS test).; to: Comment on list classification: Following review by the specialist service group, it has been agreed that this gene should be rated as Green at the next GMS panel update.

Upregulation of GREM1 expression in colorectal mucosa has been linked to hereditary mixed polyposis syndrome.
Most described patients are carriers of the Ashkenazi founder variant, a 40-kb upstream duplication that spans the 3' end of the neighbouring SCG5 gene. However, there are other duplications of different sizes that have been associated with disease (and some don’t incorporate the 3’ end of SCG5).

There is currently no evidence of small variants or a whole gene duplication of GREM1 causing a similar phenotype.

There is sufficient evidence to support a definitive gene-disease relationship but the providing GLH need to account for the upstream sequence location and size of reported variants in their primer design (as R211 v2.10 is currently a purely wet-lab/non-WGS test).
Inherited polyposis and early onset colorectal cancer - germline testing v2.10 GREM1 Arina Puzriakova changed review comment from: Comment on list classification: Following review by the specialist service group, it has been agreed that this gene should be rated as Green at the next GMS panel update.

Upregulation of GREM1 expression in colorectal mucosa has been linked to hereditary mixed polyposis syndrome. This is caused by a 40-kb upstream duplication that spans the 3' end of the neighbouring SCG5 gene. There is currently no evidence of small variants or a whole gene duplication of GREM1 (without SCG5 involvement) causing a similar phenotype.

There is sufficient evidence to support a definitive gene-disease relationship but the providing GLH will have to account for the upstream sequence location and size of reported variants in their primer design (as R211 is currently a purely wet-lab/non-WGS test).

The SCG5-GREM1 duplication would not be detected by the NGS pipeline and this should be considered if this clinical indication ever moves to WGS in the future.; to: Comment on list classification: Following review by the specialist service group, it has been agreed that this gene should be rated as Green at the next GMS panel update.

Upregulation of GREM1 expression in colorectal mucosa has been linked to hereditary mixed polyposis syndrome.
Most described patients are carriers of the Ashkenazi founder variant, a 40-kb upstream duplication that spans the 3' end of the neighbouring SCG5 gene. However, there are other duplications of different sizes that have been associated with disease (and some don’t incorporate the 3’ end of SCG5).

There is currently no evidence of small variants or a whole gene duplication of GREM1 causing a similar phenotype.

There is sufficient evidence to support a definitive gene-disease relationship but the providing GLH need to account for the upstream sequence location and size of reported variants in their primer design (as R211 (v2.10) is currently a purely wet-lab/non-WGS test).
Mitochondrial disorders v4.127 SLC25A36 Achchuthan Shanmugasundram Classified gene: SLC25A36 as Amber List (moderate evidence)
Mitochondrial disorders v4.127 SLC25A36 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the association of this gene with green rating in the next GMS review.
Mitochondrial disorders v4.127 SLC25A36 Achchuthan Shanmugasundram Gene: slc25a36 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.126 SLC25A36 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A36 were changed from Hyperinsulinemic hypoglycemia, familial, 8 to Hyperinsulinemic hypoglycemia, familial, 8, OMIM:620211
Mitochondrial disorders v4.125 SLC25A36 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC25A36.
Tag Q4_23_NHS_review tag was added to gene: SLC25A36.
Mitochondrial disorders v4.125 SLC25A36 Achchuthan Shanmugasundram reviewed gene: SLC25A36: Rating: GREEN; Mode of pathogenicity: None; Publications: 34576089, 34971397, 36695547; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 8, OMIM:620211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.45 MVK Siying Lin reviewed gene: MVK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35916082; Phenotypes: Retinal dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.125 PCK2 Achchuthan Shanmugasundram Classified gene: PCK2 as Amber List (moderate evidence)
Mitochondrial disorders v4.125 PCK2 Achchuthan Shanmugasundram Gene: pck2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.124 PCK2 Achchuthan Shanmugasundram Phenotypes for gene: PCK2 were changed from PEPCK deficiency, mitochondrial, OMIM:261650; Abnormal gait; peripheral neuropathy to PEPCK deficiency, mitochondrial, OMIM:261650; Abnormal gait; peripheral neuropathy
Mitochondrial disorders v4.124 PCK2 Achchuthan Shanmugasundram Phenotypes for gene: PCK2 were changed from Abnormal gait; peripheral neuropathy to PEPCK deficiency, mitochondrial, OMIM:261650; Abnormal gait; peripheral neuropathy
Mitochondrial disorders v4.123 PCK2 Achchuthan Shanmugasundram reviewed gene: PCK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36845668; Phenotypes: PEPCK deficiency, mitochondrial, OMIM:261650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.123 MRPS28 Achchuthan Shanmugasundram Classified gene: MRPS28 as Red List (low evidence)
Mitochondrial disorders v4.123 MRPS28 Achchuthan Shanmugasundram Gene: mrps28 has been classified as Red List (Low Evidence).
Mitochondrial disorders v4.122 MRPS28 Achchuthan Shanmugasundram Phenotypes for gene: MRPS28 were changed from ?Combined oxidative phosphorylation deficiency 47 to ?Combined oxidative phosphorylation deficiency 47, OMIM:618958
Mitochondrial disorders v4.121 MRPS28 Achchuthan Shanmugasundram changed review comment from: PMID:30566640 reported a single patient with intrauterine growth retardation, craniofacial dysmorphism and developmental delay and identified with a seemingly homozygous missense variant c.356A>G/ p.Lys119Arg. The variant was present in the mother in a heterozygous state, but not in the father who likely carried a large deletion spanning exon 2 and parts of introns 1 and 2 that could account for the apparent homozygosity of the patient.; to: PMID:30566640 reported a single patient with intrauterine growth retardation, craniofacial dysmorphism and developmental delay and identified with biallelic MRPS28 variants.
Mitochondrial disorders v4.121 MRPS28 Achchuthan Shanmugasundram reviewed gene: MRPS28: Rating: RED; Mode of pathogenicity: None; Publications: 30566640; Phenotypes: ?Combined oxidative phosphorylation deficiency 47, OMIM:618958; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.121 MRPS25 Achchuthan Shanmugasundram Classified gene: MRPS25 as Red List (low evidence)
Mitochondrial disorders v4.121 MRPS25 Achchuthan Shanmugasundram Gene: mrps25 has been classified as Red List (Low Evidence).
Mitochondrial disorders v4.120 MRPS25 Achchuthan Shanmugasundram Phenotypes for gene: MRPS25 were changed from ?Combined oxidative phosphorylation deficiency 50 to ?Combined oxidative phosphorylation deficiency 50, OMIM:619025
Mitochondrial disorders v4.119 MRPS25 Achchuthan Shanmugasundram reviewed gene: MRPS25: Rating: RED; Mode of pathogenicity: None; Publications: 31039582; Phenotypes: ?Combined oxidative phosphorylation deficiency 50, OMIM:619025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.119 MIEF2 Achchuthan Shanmugasundram Phenotypes for gene: MIEF2 were changed from ?Combined oxidative phosphorylation deficiency 49 to ?Combined oxidative phosphorylation deficiency 49, OMIM:619024
Mitochondrial disorders v4.118 MIEF2 Achchuthan Shanmugasundram Classified gene: MIEF2 as Red List (low evidence)
Mitochondrial disorders v4.118 MIEF2 Achchuthan Shanmugasundram Gene: mief2 has been classified as Red List (Low Evidence).
Mitochondrial disorders v4.117 MIEF2 Achchuthan Shanmugasundram reviewed gene: MIEF2: Rating: RED; Mode of pathogenicity: None; Publications: 29361167; Phenotypes: ?Combined oxidative phosphorylation deficiency 49, OMIM:619024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (five unrelated families) for the association of this gene with green rating in the next GMS review.
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (five unrelated families) for the association of this gene with green rating in the next GMS review.
Mitochondrial disorders v4.117 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.116 TEFM Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TEFM.
Tag Q4_23_NHS_review tag was added to gene: TEFM.
Mitochondrial disorders v4.116 TEFM Achchuthan Shanmugasundram reviewed gene: TEFM: Rating: GREEN; Mode of pathogenicity: None; Publications: 36823193; Phenotypes: Combined oxidative phosphorylation deficiency 58, OMIM:620451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.347 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Intellectual disability v5.347 TEFM Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.347 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.346 TEFM Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TEFM.
Intellectual disability v5.346 TEFM Achchuthan Shanmugasundram reviewed gene: TEFM: Rating: GREEN; Mode of pathogenicity: None; Publications: 36823193; Phenotypes: Combined oxidative phosphorylation deficiency 58, OMIM:620451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.135 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.135 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram changed review comment from: Three patients from two unrelated families with biallelic TEFM variants had seizures.; to: PMID:36823193 reported seven individuals from five unrelated families presenting with mitochondrial respiratory chain deficiency and they were identified with biallelic TEFM variants. Three of these patients from two unrelated families had seizures.
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram reviewed gene: TEFM: Rating: AMBER; Mode of pathogenicity: None; Publications: 36823193; Phenotypes: Combined oxidative phosphorylation deficiency 58, OMIM:620451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited polyposis and early onset colorectal cancer - germline testing v2.10 GREM1 Arina Puzriakova Publications for gene: GREM1 were set to
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v4.116
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram gene: TEFM was added
gene: TEFM was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58, OMIM:620451
Intellectual disability v5.346 TEFM Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v4.116
Intellectual disability v5.346 TEFM Achchuthan Shanmugasundram gene: TEFM was added
gene: TEFM was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58, OMIM:620451
Mitochondrial disorders v4.116 TEFM Achchuthan Shanmugasundram Phenotypes for gene: TEFM were changed from Combined oxidative phosphorylation deficiency 58 to Combined oxidative phosphorylation deficiency 58, OMIM:620451
Inherited polyposis and early onset colorectal cancer - germline testing v2.9 GREM1 Arina Puzriakova edited their review of gene: GREM1: Changed rating: GREEN
Rhabdomyolysis and metabolic muscle disorders v3.46 TAMM41 Achchuthan Shanmugasundram Classified gene: TAMM41 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.46 TAMM41 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Rhabdomyolysis and metabolic muscle disorders v3.46 TAMM41 Achchuthan Shanmugasundram Gene: tamm41 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.45 TAMM41 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TAMM41.
Rhabdomyolysis and metabolic muscle disorders v3.45 TAMM41 Achchuthan Shanmugasundram gene: TAMM41 was added
gene: TAMM41 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: TAMM41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAMM41 were set to 35321494
Phenotypes for gene: TAMM41 were set to Combined oxidative phosphorylation deficiency 56, OMIM:620139
Review for gene: TAMM41 was set to GREEN
Added comment: PMID:35321494 reported three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Two of these three individuals were reported with myopathy (proximal and distal in one and proximal in other). They were identified with compound heterozygous variants in TAMM41 gene. In addition, tissue-specific observations on OXPHOS were identified, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. The missense variants identified were defective in yeast models.
Sources: Literature
Mitochondrial disorders v4.115 TAMM41 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TAMM41.
Tag Q4_23_NHS_review tag was added to gene: TAMM41.
Mitochondrial disorders v4.115 TAMM41 Achchuthan Shanmugasundram Classified gene: TAMM41 as Amber List (moderate evidence)
Mitochondrial disorders v4.115 TAMM41 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Mitochondrial disorders v4.115 TAMM41 Achchuthan Shanmugasundram Gene: tamm41 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.114 TAMM41 Achchuthan Shanmugasundram Phenotypes for gene: TAMM41 were changed from Combined oxidative phosphorylation deficiency 56 to Combined oxidative phosphorylation deficiency 56, OMIM:620139
Mitochondrial disorders v4.113 TAMM41 Achchuthan Shanmugasundram reviewed gene: TAMM41: Rating: GREEN; Mode of pathogenicity: None; Publications: 35321494; Phenotypes: Combined oxidative phosphorylation deficiency 56, OMIM:620139; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v3.9 SPEF2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SPEF2.
Tag Q4_23_NHS_review tag was added to gene: SPEF2.
Respiratory ciliopathies including non-CF bronchiectasis v3.9 SPEF2 Achchuthan Shanmugasundram Classified gene: SPEF2 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v3.9 SPEF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Steven Cowman, there is sufficient evidence available for this gene to be promoted to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v3.9 SPEF2 Achchuthan Shanmugasundram Gene: spef2 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.27 ABHD5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ABHD5.
Tag Q4_23_NHS_review tag was added to gene: ABHD5.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.27 ABHD5 Achchuthan Shanmugasundram changed review comment from: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465). ; to: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465).

This gene should therefore be added with green rating in this panel and also in panel 66 (as myopathy is caused by enzyme deficiency/ metabolic disorder).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.27 ABHD5 Achchuthan Shanmugasundram Classified gene: ABHD5 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.27 ABHD5 Achchuthan Shanmugasundram Gene: abhd5 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.26 ABHD5 Achchuthan Shanmugasundram Phenotypes for gene: ABHD5 were changed from OMIM 604780 (Chanarin-Dorfman syndrome) to Chanarin-Dorfman syndrome, OMIM:275630
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.25 ABHD5 Achchuthan Shanmugasundram changed review comment from: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465). However, this gene should be included as part of Rhabdomyolysis and metabolic muscle disorders panel (66) rather than this panel. This is because I cannot see any evidence of limb-girdle muscular dystrophy/ weakness and the myopathy caused was due to enzyme deficiency/ metabolic disorder.; to: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.25 ABHD5 Achchuthan Shanmugasundram edited their review of gene: ABHD5: Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.25 ABHD5 Achchuthan Shanmugasundram changed review comment from: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465). However, this gene should be included as part of Rhabdomyolysis and metabolic muscle disorders panel (66) rather than this panel. This is because I cannot see any evidence of limb-girdle dystrophy/ weakness and the myopathy caused was due to metabolic disorder.; to: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465). However, this gene should be included as part of Rhabdomyolysis and metabolic muscle disorders panel (66) rather than this panel. This is because I cannot see any evidence of limb-girdle muscular dystrophy/ weakness and the myopathy caused was due to enzyme deficiency/ metabolic disorder.
Inherited polyposis and early onset colorectal cancer - germline testing v2.9 GREM1 Arina Puzriakova Classified gene: GREM1 as Amber List (moderate evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v2.9 GREM1 Arina Puzriakova Added comment: Comment on list classification: Following review by the specialist service group, it has been agreed that this gene should be rated as Green at the next GMS panel update.

Upregulation of GREM1 expression in colorectal mucosa has been linked to hereditary mixed polyposis syndrome. This is caused by a 40-kb upstream duplication that spans the 3' end of the neighbouring SCG5 gene. There is currently no evidence of small variants or a whole gene duplication of GREM1 (without SCG5 involvement) causing a similar phenotype.

There is sufficient evidence to support a definitive gene-disease relationship but the providing GLH will have to account for the upstream sequence location and size of reported variants in their primer design (as R211 is currently a purely wet-lab/non-WGS test).

The SCG5-GREM1 duplication would not be detected by the NGS pipeline and this should be considered if this clinical indication ever moves to WGS in the future.
Inherited polyposis and early onset colorectal cancer - germline testing v2.9 GREM1 Arina Puzriakova Gene: grem1 has been classified as Amber List (Moderate Evidence).
Inherited polyposis and early onset colorectal cancer - germline testing v2.8 GREM1 Arina Puzriakova Tag regulatory-region tag was added to gene: GREM1.
Inherited polyposis and early onset colorectal cancer - germline testing v2.8 GREM1 Arina Puzriakova Tag regulatory-region was removed from gene: GREM1.
Tag Q4_23_promote_green tag was added to gene: GREM1.
Tag Q4_23_NHS_review tag was added to gene: GREM1.
Inherited polyposis and early onset colorectal cancer - germline testing v2.8 GREM1 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: GREM1.
Tag gene-duplication tag was added to gene: GREM1.
Tag regulatory-region tag was added to gene: GREM1.
Respiratory ciliopathies including non-CF bronchiectasis v3.8 NME5 Achchuthan Shanmugasundram Classified gene: NME5 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v3.8 NME5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and zebrafish model) for the promotion of this gene to green rating in the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v3.8 NME5 Achchuthan Shanmugasundram Gene: nme5 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v3.7 NME5 Achchuthan Shanmugasundram Phenotypes for gene: NME5 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 48, without situs inversus, OMIM:620032
Respiratory ciliopathies including non-CF bronchiectasis v3.6 NME5 Achchuthan Shanmugasundram Publications for gene: NME5 were set to 32185794; 31479451
Respiratory ciliopathies including non-CF bronchiectasis v3.5 NME5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NME5.
Tag Q4_23_NHS_review tag was added to gene: NME5.
Respiratory ciliopathies including non-CF bronchiectasis v3.5 NME5 Achchuthan Shanmugasundram changed review comment from: Two unrelated cases were reported with biallelic NME5 variants. One patient was homozygous for p.Trp191Ter variant, while other was compound heterozygous with the same variant and p.Tyr160PhefsTer11. In addition, morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy.; to: Two unrelated cases were reported with biallelic NME5 variants. One patient was homozygous for p.Trp191Ter variant, while other was compound heterozygous with the same variant and p.Tyr160PhefsTer11. In addition, morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620032) and Gene2Phenotype (with 'definitive' rating in the DD panel).
Respiratory ciliopathies including non-CF bronchiectasis v3.5 NME5 Achchuthan Shanmugasundram reviewed gene: NME5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32185794, 37957793; Phenotypes: Ciliary dyskinesia, primary, 48, without situs inversus, OMIM:620032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.5 FOXJ1 Achchuthan Shanmugasundram Classified gene: FOXJ1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v3.5 FOXJ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Steven Cowman, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Respiratory ciliopathies including non-CF bronchiectasis v3.5 FOXJ1 Achchuthan Shanmugasundram Gene: foxj1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v3.4 FOXJ1 Achchuthan Shanmugasundram Publications for gene: FOXJ1 were set to 31630787
Respiratory ciliopathies including non-CF bronchiectasis v3.3 FOXJ1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FOXJ1.
Tag Q4_23_NHS_review tag was added to gene: FOXJ1.
Respiratory ciliopathies including non-CF bronchiectasis v3.3 FOXJ1 Achchuthan Shanmugasundram reviewed gene: FOXJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rhabdomyolysis and metabolic muscle disorders v3.44 ABHD5 Achchuthan Shanmugasundram changed review comment from: Chanarin-Dorfman is a neutral lipid storage disorder. Myopathy, identified through raised CK levels and muscle biopsy, was a commonly observed finding in 59% (86/147) cases with ABHD5 deficiency. The myopathy tends to generally be a slowly progressive muscle weakness and rarely culminates in cardiomyopathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #275630) and Gene2Phenotype (with 'definitive' rating in the DD panel), and muscle weakness has been recorded as one of the features in both resources.

As the myopathy was caused by metabolic deficiency, this gene should be added to this panel.
Sources: Literature; to: Chanarin-Dorfman is a neutral lipid storage disorder. Myopathy, identified through raised CK levels and muscle biopsy, was a commonly observed finding in 59% (86/147) cases with ABHD5 deficiency. The myopathy tends to generally be a slowly progressive muscle weakness and rarely culminates in cardiomyopathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #275630) and Gene2Phenotype (with 'definitive' rating in the DD panel), and muscle weakness has been recorded as one of the features in both resources.

As myopathy is caused by metabolic deficiency, this gene should be added to this panel.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v3.44 ABHD5 Achchuthan Shanmugasundram changed review comment from: Chanarin-Dorfman is a neutral lipid storage disorder. Myopathy, identified through raised CK levels and muscle biopsy, was a commonly observed finding in 59% (86/147) cases with ABHD5 deficiency. The myopathy tends to generally be a slowly progressive muscle weakness and rarely culminates in cardiomyopathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #275630) and Gene2Phenotype (with 'definitive' rating in the DD panel), and muscle weakness has been recorded as one of the features in both resources.
Sources: Literature; to: Chanarin-Dorfman is a neutral lipid storage disorder. Myopathy, identified through raised CK levels and muscle biopsy, was a commonly observed finding in 59% (86/147) cases with ABHD5 deficiency. The myopathy tends to generally be a slowly progressive muscle weakness and rarely culminates in cardiomyopathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #275630) and Gene2Phenotype (with 'definitive' rating in the DD panel), and muscle weakness has been recorded as one of the features in both resources.

As the myopathy was caused by metabolic deficiency, this gene should be added to this panel.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v3.44 ABHD5 Achchuthan Shanmugasundram Classified gene: ABHD5 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.44 ABHD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in this panel in the next GMS review.
Rhabdomyolysis and metabolic muscle disorders v3.44 ABHD5 Achchuthan Shanmugasundram Gene: abhd5 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.43 ABHD5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ABHD5.
Rhabdomyolysis and metabolic muscle disorders v3.43 ABHD5 Achchuthan Shanmugasundram gene: ABHD5 was added
gene: ABHD5 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: ABHD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD5 were set to 33455044
Phenotypes for gene: ABHD5 were set to Chanarin-Dorfman syndrome, OMIM:275630
Review for gene: ABHD5 was set to GREEN
Added comment: Chanarin-Dorfman is a neutral lipid storage disorder. Myopathy, identified through raised CK levels and muscle biopsy, was a commonly observed finding in 59% (86/147) cases with ABHD5 deficiency. The myopathy tends to generally be a slowly progressive muscle weakness and rarely culminates in cardiomyopathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #275630) and Gene2Phenotype (with 'definitive' rating in the DD panel), and muscle weakness has been recorded as one of the features in both resources.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.25 ABHD5 Achchuthan Shanmugasundram edited their review of gene: ABHD5: Added comment: As reviewed by Oliver Watkinson, Chanarin-Dorfman is a neutral lipid storage disorder and myopathy(generally tends to be slowly progressive muscle weakness) is part of the phenotype in 59% of reported cases (PMID:33455044). I agree with him that it should be included as part of R381 - Other rare neuromuscular disorders super panel (465). However, this gene should be included as part of Rhabdomyolysis and metabolic muscle disorders panel (66) rather than this panel. This is because I cannot see any evidence of limb-girdle dystrophy/ weakness and the myopathy caused was due to metabolic disorder.; Changed publications to: 33455044; Changed phenotypes to: Chanarin-Dorfman syndrome, OMIM:275630
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.25 ABHD5 Achchuthan Shanmugasundram reviewed gene: ABHD5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chanarin-Dorfman syndrome, OMIM<; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.25 PNPLA2 Achchuthan Shanmugasundram Phenotypes for gene: PNPLA2 were changed from Neutral lipid storage disease with myopathy 610717 to Neutral lipid storage disease with myopathy, OMIM:610717
Rhabdomyolysis and metabolic muscle disorders v3.42 PNPLA2 Achchuthan Shanmugasundram Classified gene: PNPLA2 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.42 PNPLA2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are sufficient number of cases associating biallelic PNPLA2 variants to muscle and upper and lower limb weakness and dystrophy of shoulder girdle. Hence, this gene can be promoted to GREEN in this panel at the next GMS update.

This gene has also been associated with phenotypes in both OMIM (MIM #610717) and Gene2Phenotype (with 'strong' rating in DD panel).
Rhabdomyolysis and metabolic muscle disorders v3.42 PNPLA2 Achchuthan Shanmugasundram Gene: pnpla2 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.41 PNPLA2 Achchuthan Shanmugasundram Deleted their comment
Rhabdomyolysis and metabolic muscle disorders v3.41 PNPLA2 Achchuthan Shanmugasundram Phenotypes for gene: PNPLA2 were changed from Neutral lipid storage disease with myopathy 610717 to Neutral lipid storage disease with myopathy, OMIM:610717
Rhabdomyolysis and metabolic muscle disorders v3.40 PNPLA2 Achchuthan Shanmugasundram Tag Q2_23_promote_green was removed from gene: PNPLA2.
Tag Q4_23_promote_green tag was added to gene: PNPLA2.
Rhabdomyolysis and metabolic muscle disorders v3.40 PNPLA2 Achchuthan Shanmugasundram Entity copied from Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.24
Rhabdomyolysis and metabolic muscle disorders v3.40 PNPLA2 Achchuthan Shanmugasundram gene: PNPLA2 was added
gene: PNPLA2 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review Amber
Q2_23_promote_green tags were added to gene: PNPLA2.
Mode of inheritance for gene: PNPLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA2 were set to 18952067; 21544567; 25956450; 32269696
Phenotypes for gene: PNPLA2 were set to Neutral lipid storage disease with myopathy 610717
Congenital muscular dystrophy v4.19 GOLGA2 Achchuthan Shanmugasundram Phenotypes for gene: GOLGA2 were changed from Secondary dystroglycanopathy; Developmental delay with hypotonia, myopathy, and brain abnormalities to Developmental delay with hypotonia, myopathy, and brain abnormalities, OMIM:620240
Congenital muscular dystrophy v4.18 GOLGA2 Achchuthan Shanmugasundram edited their review of gene: GOLGA2: Changed phenotypes to: Developmental delay with hypotonia, myopathy, and brain abnormalities, OMIM:620240
Congenital muscular dystrophy v4.18 GOLGA2 Achchuthan Shanmugasundram Classified gene: GOLGA2 as Amber List (moderate evidence)
Congenital muscular dystrophy v4.18 GOLGA2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are three unrelated cases and zebrafish model in support of the disease association. Hence, this gene can be promoted to green rating in the next GMS review.
Congenital muscular dystrophy v4.18 GOLGA2 Achchuthan Shanmugasundram Gene: golga2 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v4.17 GOLGA2 Achchuthan Shanmugasundram Phenotypes for gene: GOLGA2 were changed from Secondary dystroglycanopathy to Secondary dystroglycanopathy; Developmental delay with hypotonia, myopathy, and brain abnormalities
Congenital muscular dystrophy v4.16 GOLGA2 Achchuthan Shanmugasundram Publications for gene: GOLGA2 were set to 26742501; 30237576
Congenital muscular dystrophy v4.15 GOLGA2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GOLGA2.
Tag Q4_23_NHS_review tag was added to gene: GOLGA2.
Congenital muscular dystrophy v4.15 GOLGA2 Achchuthan Shanmugasundram reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v2.20 FKRP Achchuthan Shanmugasundram Classified gene: FKRP as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v2.20 FKRP Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be considered for promotion to green rating in this panel in the next GMS review.
Dilated and arrhythmogenic cardiomyopathy v2.20 FKRP Achchuthan Shanmugasundram Gene: fkrp has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v2.19 FKRP Achchuthan Shanmugasundram Phenotypes for gene: FKRP were changed from to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5, OMIM:607155
Dilated and arrhythmogenic cardiomyopathy v2.18 FKRP Achchuthan Shanmugasundram Publications for gene: FKRP were set to
Dilated and arrhythmogenic cardiomyopathy v2.17 FKRP Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FKRP.
Tag Q4_23_NHS_review tag was added to gene: FKRP.
Dilated and arrhythmogenic cardiomyopathy v2.17 FKRP Achchuthan Shanmugasundram changed review comment from: PMID:32914449 reviewed 56 patients with limb-girdle muscular dystrophy and biallelic FKRP variants, of which 45% of patients had dilated cardiomyopathy as part of the phenotype with a median age of 54 years for patients homozygous for the common founder c.826C>A, compared to 18 years of age for other variants.

Dilated cardiomyopathy was also reported as part of the LGMD phenotype in both OMIM (MIM #607155) and Gene2Phenotype.; to: As reviewed by Oliver Watkinson, the limb-girdle muscular dystrophy phenotype caused by biallelic FKRP variants includes dilated cardiomyopathy as part of the phenotype.

PMID:32914449 reviewed 56 patients with limb-girdle muscular dystrophy and biallelic FKRP variants, of which 45% of patients had dilated cardiomyopathy as part of the phenotype with a median age of 54 years for patients homozygous for the common founder c.826C>A, compared to 18 years of age for other variants.

There were also a number of cases reported with dilated cardiomyopathy being the presenting condition and preceding overt skeletal muscle disease as noted by Oliver Watkinson including the recent case that he has seen in hospital.

Dilated cardiomyopathy was also reported as part of the LGMD phenotype in both OMIM (MIM #607155) and Gene2Phenotype.
Dilated and arrhythmogenic cardiomyopathy v2.17 FKRP Achchuthan Shanmugasundram reviewed gene: FKRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32914449; Phenotypes: Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5, OMIM:607155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.46 KMT2B Arina Puzriakova Tag Q3_23_promote_green was removed from gene: KMT2B.
Tag Q4_23_promote_green tag was added to gene: KMT2B.
Intellectual disability v5.345 KMT2B Arina Puzriakova Tag Q3_23_promote_green was removed from gene: KMT2B.
Tag Q4_23_promote_green tag was added to gene: KMT2B.
Retinal disorders v4.45 RPE65 Arina Puzriakova Tag Q4_23_promote_green was removed from gene: RPE65.
Tag Q4_23_MOI tag was added to gene: RPE65.
Retinal disorders v4.45 RPE65 Arina Puzriakova Tag Q3_23_MOI was removed from gene: RPE65.
Tag Q4_23_promote_green tag was added to gene: RPE65.
Ataxia and cerebellar anomalies - narrow panel v4.40 ASL Nour Elkhateeb gene: ASL was added
gene: ASL was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: ASL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASL were set to 38044746; 36994644; 28251416
Phenotypes for gene: ASL were set to Ataxia
Added comment: Ataxia has been reported in multiple individuals with argininosuccinic aciduria (PMID 38044746, 36994644, 28251416).
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v3.56 ASL Nour Elkhateeb reviewed gene: ASL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38044746, 36994644, 28251416; Phenotypes: Movement disorder, tremor, dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.45 RPE65 Arina Puzriakova Phenotypes for gene: RPE65 were changed from Leber congenital amaurosis 2; Retinitis pigmentosa 20; Leber Congenital Amaurosis; Leber congenital amaurosis 2, 204100; Eye Disorders; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa to Leber congenital amaurosis 2, OMIM:204100 (AR); Retinitis pigmentosa 20, OMIM:613794 (AR); Retinitis pigmentosa 87 with choroidal involvement, OMIM:618697 (AD)
Retinal disorders v4.44 RPE65 Arina Puzriakova Publications for gene: RPE65 were set to
Retinal disorders v4.43 RPE65 Arina Puzriakova Tag Q3_23_MOI tag was added to gene: RPE65.
Retinal disorders v4.43 RPE65 Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic variants cause retinitis pigmentosa and leber congenital amaurosis. Heterozygous variants have also been found in at least 4 unrelated families with choroid/retinal atrophy that mimics certain aspects of choroideremia (PMIDs: 21654732; 27307694; 29947567).

This supports a change in MOI from biallelic to both mono- and biallelic at the next GMS panel update.
Retinal disorders v4.43 RPE65 Arina Puzriakova Mode of inheritance for gene: RPE65 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.56 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from Dystonia 28, childhood-onset 617284; early-onset dystonia to Dystonia 28, childhood-onset, OMIM:617284; Complex early-onset dystonia
Fetal anomalies v3.122 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from Complex early-onset dystonia to Dystonia 28, childhood-onset, OMIM:617284; Complex early-onset dystonia
Adult onset neurodegenerative disorder v4.42 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from early-onset dystonia to Dystonia 28, childhood-onset, OMIM:617284; early-onset dystonia
Structural basal ganglia disorders v1.39 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from Dystonia 28, childhood-onset 617284 to Dystonia 28, childhood-onset, OMIM:617284; early-onset dystonia
Early onset dystonia v1.147 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from early-onset dystonia to Dystonia 28, childhood-onset, OMIM:617284; early-onset dystonia
Severe microcephaly v4.46 KMT2B Arina Puzriakova changed review comment from: At least 80 patients have been reported with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia.

Microcephaly of relevant severity to this panel has been reported in a sufficient number of cases to warrant inclusion on this panel with a Green rating.
Sources: Literature; to: At least 80 patients have been reported with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia.

Microcephaly of relevant severity to this panel has been reported in a sufficient number of cases to warrant inclusion on this panel with a Green rating at the next GMS panel update.
Sources: Literature
Severe microcephaly v4.46 KMT2B Arina Puzriakova Classified gene: KMT2B as Amber List (moderate evidence)
Severe microcephaly v4.46 KMT2B Arina Puzriakova Gene: kmt2b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.45 KMT2B Arina Puzriakova gene: KMT2B was added
gene: KMT2B was added to Severe microcephaly. Sources: Literature
Q3_23_promote_green tags were added to gene: KMT2B.
Mode of inheritance for gene: KMT2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT2B were set to 27839873; 27839873; 33150406
Phenotypes for gene: KMT2B were set to Dystonia 28, childhood-onset, OMIM:617284; Intellectual developmental disorder, autosomal dominant 68, OMIM:619934
Review for gene: KMT2B was set to GREEN
Added comment: At least 80 patients have been reported with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia.

Microcephaly of relevant severity to this panel has been reported in a sufficient number of cases to warrant inclusion on this panel with a Green rating.
Sources: Literature
Intellectual disability v5.345 KMT2B Arina Puzriakova Classified gene: KMT2B as Amber List (moderate evidence)
Intellectual disability v5.345 KMT2B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Inclusion on this panel would also ensure this gene is included on the Paediatric disorders super panel which is appropriate for the phenotype.
Intellectual disability v5.345 KMT2B Arina Puzriakova Gene: kmt2b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.344 KMT2B Arina Puzriakova Phenotypes for gene: KMT2B were changed from Dystonia 28, childhood-onset, 617284 to Dystonia 28, childhood-onset, OMIM:617284; Intellectual developmental disorder, autosomal dominant 68, OMIM:619934
Intellectual disability v5.343 KMT2B Arina Puzriakova Publications for gene: KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525; 29697234; 31216378
Intellectual disability v5.342 KMT2B Arina Puzriakova Tag watchlist was removed from gene: KMT2B.
Tag Q3_23_promote_green tag was added to gene: KMT2B.
Intellectual disability v5.342 KMT2B Arina Puzriakova reviewed gene: KMT2B: Rating: ; Mode of pathogenicity: None; Publications: 33150406; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v4.44 NSD2 Sarah Leigh changed review comment from: Microcephaly is well recognized as a feature associated with pathogenic NSD2 variants. Of the published reports of microcephaly 50% (7/14) can be regarded as being severe, with a occipitofrontal circumference (OFC) below -3.0 standard deviations below the mean for age (PMID: 33941880 (including a review of previously published reports S4 table, PMID: 33276791).; to: Microcephaly is well recognized as a feature associated with pathogenic NSD2 variants. PMID: 33941880 reports three NSD2 variants in three unrelated cases of Rauch-Steindl syndrome (OMIM:619695), who have severe microcephaly (Occipitofrontal circumference (OFC) below >3.0 SD). Similarly, PMID: 33276791 reports a case with
OFC of 44 cm (<−3SD). Further cases are examined in the supplementary table 4 in PMID: 33941880
Severe microcephaly v4.44 NSD2 Sarah Leigh Classified gene: NSD2 as Amber List (moderate evidence)
Severe microcephaly v4.44 NSD2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Severe microcephaly v4.44 NSD2 Sarah Leigh Gene: nsd2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.43 NSD2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: NSD2.
Severe microcephaly v4.43 NSD2 Sarah Leigh reviewed gene: NSD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.342 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from Intrauterine growth retardation; Growth delay; Microcephaly; Muscular hypotonia; Neurodevelopmental delay; Intellectual disability; No OMIM number to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
Severe Paediatric Disorders v1.178 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from Wolf-Hirschhorn syndrome to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
DDG2P v3.79 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from NSD2-related developmental disorder (monoallelic) to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
Laterality disorders and isomerism v3.8 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
Severe microcephaly v4.43 NSD2 Sarah Leigh Phenotypes for gene: NSD2 were changed from microcephaly, MONDO:0001149 to Rauch-Steindl syndrome, OMIM:619695; Rauch-Steindl syndrome, MONDO:0859219
Severe microcephaly v4.42 NSD2 Sarah Leigh Publications for gene: NSD2 were set to 30345613; 31171569; 29760529; 29892088
Intellectual disability v5.341 C20orf24 Hannah Knight gene: C20orf24 was added
gene: C20orf24 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C20orf24 were set to 35614220
Phenotypes for gene: C20orf24 were set to ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2
Added comment: HGNC Approved Gene Symbol: RAB5IF
PMID: 35614220 (2022) identified a homozygous nonsense variant (p.W25X) in a Turkish boy previously reported by PMID: 24194475 to have bilateral cleft lip, complete cleft palate, moderate to severe intellectual delay and dysmorphic features. FHx of cleft lip/cleft palate as well in relatives who were heterozygous for the reported variant
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 DUT Hannah Knight gene: DUT was added
gene: DUT was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome
Review for gene: DUT was set to AMBER
Added comment: PMID: 28073829 (2017) - two unrelated consanguineous families with diabetes and bone marrow aplasia, both homozygous for p.Y142C
PMID: 35611808 (2022) - another family, two affected children with thrombocytopenia, macrocytosis, with or without anemia, followed by non-autoimmune diabetes. Same homozygous missense variant identified as before
PMID: 35931051 (2022) - identified probands who came from two independent families, had bi-allelic DUT variants, and presented with severe pancytopenia and mucocutaneous skin features. Information in supplementary materials. One patient homozygous for p.Tyr142Cys and the other compound het for p.Arg173Trp and p.Tyr227Cys
Sources: Literature
Mitochondrial disorders v4.113 PCK2 Hannah Knight gene: PCK2 was added
gene: PCK2 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: PCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCK2 were set to 36845668
Phenotypes for gene: PCK2 were set to Abnormal gait; peripheral neuropathy
Review for gene: PCK2 was set to AMBER
Added comment: PMID: 36845668 (2023) identified three patients in two families with a common phenotype and likely pathogenic variants in PCK2:
A 3-year-old girl with ataxia and weakness, who was found to be compound heterozygous for p.Ser23Ter and p.Pro170Leu
Two siblings with abnormal gait and weakness who were found to both be homozygous for p.Arg193Ter. Unaffected sibling did not carry the variant
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v4.77 LDHD Hannah Knight gene: LDHD was added
gene: LDHD was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature
Mode of inheritance for gene: LDHD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDHD were set to 30931947; 31638601
Phenotypes for gene: LDHD were set to D-lactic aciduria with susceptibility to gout
Review for gene: LDHD was set to AMBER
Added comment: PMID: 30931947 (2019) reported two unrelated patients with homozygous missense variants in LDHD (p.Thr463Met and p.Trp374Cys)
PMID: 31638601 (2019) reported a 4-generation consanguineous Bedouin-Israeli family with autosomal recessive hyperuricemia. A homozygous missense variant in LDHD was identified (p.R370W)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 IFNGR2 Arina Puzriakova Publications for gene: IFNGR2 were set to 9616207; 15924140; 18625743; 30264912
Primary immunodeficiency or monogenic inflammatory bowel disease v4.124 IFNGR2 Arina Puzriakova Phenotypes for gene: IFNGR2 were changed from Immunodeficiency 28, Mycobacteriosis, 614889; Defects with susceptibility to mycobacterial infection (MSMD); Susceptibility to mycobacteria and Salmonella; Defects in Intrinsic and Innate Immunity to Immunodeficiency 28, mycobacteriosis, OMIM:614889
Mitochondrial disorders v4.113 SLC25A36 Hannah Knight gene: SLC25A36 was added
gene: SLC25A36 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34576089; 34971397; 36695547
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8
Review for gene: SLC25A36 was set to GREEN
Added comment: More than three cases reported in past three years
PMID: 34576089 (2021) - first case, a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Homozygous frameshift variant identified c.803dupT, p.Ser269llefs*35
PMID: 34971397 (2022) - two siblings with homozygous splice site variant
PMID: 36695547 (2023) - four individuals of two Bedouin Israeli related families - same homozygous splice site variant identified
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v4.40 THG1L Hannah Knight reviewed gene: THG1L: Rating: AMBER; Mode of pathogenicity: None; Publications: 33682303, 33682303; Phenotypes: Spinocerebellar ataxia, autosomal recessive 28; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.77 ACACA Hannah Knight gene: ACACA was added
gene: ACACA was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature
Mode of inheritance for gene: ACACA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACACA were set to 34552920
Phenotypes for gene: ACACA were set to Acetyl-CoA carboxylase deficiency
Review for gene: ACACA was set to AMBER
Added comment: PMID: 34552920 (2021) reported a baby who presented in her first two years of life with global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. Two VUS's in ACACA were identified, and a decreased level of ACC1 and ACC1 enzyme activity was detected in patient-derived lymphocytes. In vitro studies revealed a disruption of lipid homeostasis in patient-derived lymphocytes, further inducing the deficit of cell motility capacity and that the deficiency could be partly attenuated by palmitate.
Sources: Literature
Mitochondrial disorders v4.113 MRPS28 Hannah Knight gene: MRPS28 was added
gene: MRPS28 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: MRPS28 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS28 were set to 30566640
Phenotypes for gene: MRPS28 were set to ?Combined oxidative phosphorylation deficiency 47
Review for gene: MRPS28 was set to AMBER
Added comment: PMID: 30566640 (2019) reported a 30-year-old man with a multisystemic mitochondrial disorder and compound heterozygous variants in the MRPS28 gene. Patient fibroblasts showed decreased MRPS28 protein levels compared to controls. There were variable deficiencies of complexes I, III, IV, and V activities and complex assembly associated with decreased mitochondrial respiration activity in vitro. Additional studies of patient fibroblasts showed impaired assembly of the small mitoribosomal subunit (bS1m, encoded by MRPS28), decreased levels of 12S rRNA, and impaired mitochondrial translation. These defects could be rescued by expression of wildtype MRPS28
Sources: Literature
Mitochondrial disorders v4.113 MRPS25 Hannah Knight gene: MRPS25 was added
gene: MRPS25 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: MRPS25 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS25 were set to 31039582
Phenotypes for gene: MRPS25 were set to ?Combined oxidative phosphorylation deficiency 50
Review for gene: MRPS25 was set to AMBER
Added comment: PMID: 31039582 (2019) reported a 25-year-old man, born of unrelated parents, with a mitochondrial encephalomyopathy and a homozygous missense variant in the MRPS25 gene (P72L). Patient fibroblasts showed decreased protein levels of MRPS25, about one-tenth of controls. Levels of other polypeptides of the 28S ribosomal subunit were also decreased, suggesting that the mutation adversely affected assembly or stability of the 28S subunit. Further in vitro studies of patient fibroblasts showed impaired mitochondrial translation and decreased protein levels of respiratory chain complexes I, III, and IV. Expression of wildtype MRPS25 in patient fibroblasts resulted in partial restoration of OXPHOS protein levels. The findings suggested that MRPS25 is required for mitochondrial protein synthesis, and that this defect causes decreased levels of mitochondrial respiratory chain subunits and impaired mitochondrial translation.
Sources: Literature
Mitochondrial disorders v4.113 MIEF2 Hannah Knight gene: MIEF2 was added
gene: MIEF2 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: MIEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIEF2 were set to 29361167
Phenotypes for gene: MIEF2 were set to ?Combined oxidative phosphorylation deficiency 49
Review for gene: MIEF2 was set to AMBER
Added comment: PMID: 29361167 (2018) reported a 15-year-old boy, born of consanguineous Jewish parents, with combined oxidative phosphorylation deficiency-49 and a homozygous nonsense variant in the MIEF2 gene (Q92X). Patient skeletal muscle and fibroblasts showed a combined decrease in mitochondrial respiratory chain enzymes, particularly complexes I and IV, elongated mitochondria with abnormal cristae, decreased mitochondrial fission, and increased fusion events. The cellular phenotype could be rescued by expression of wildtype MIEF2. The findings were consistent with a defect in mitochondrial dynamics
Sources: Literature
Mitochondrial disorders v4.113 TAMM41 Hannah Knight gene: TAMM41 was added
gene: TAMM41 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: TAMM41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAMM41 were set to 35321494
Phenotypes for gene: TAMM41 were set to Combined oxidative phosphorylation deficiency 56
Review for gene: TAMM41 was set to GREEN
Added comment: PMID: 35321494 (2022) report three unrelated individuals with mitochondrial disease and compound heterozygous variants in this gene + functional studies
Sources: Literature
Mitochondrial disorders v4.113 TEFM Hannah Knight gene: TEFM was added
gene: TEFM was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58
Review for gene: TEFM was set to GREEN
Added comment: PMID: 36823193 (2023) report seven TEFM variants (four missense, two frameshift and one in-frame 2-amino acid deletion) in seven individuals from five unrelated families who present with mitochondrial respiratory chain deficiency and a wide range of infantile or childhood-onset neurological and neuromuscular symptoms, due to abnormal mitochondrial transcription. Zebrafish model as well
Sources: Literature
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Edoardo Monfrini gene: STAB1 was added
gene: STAB1 was added to Iron metabolism disorders - NOT common HFE mutations. Sources: Literature
Mode of inheritance for gene: STAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAB1 were set to 37490907
Phenotypes for gene: STAB1 were set to Hyperferritinemia without iron overload
Penetrance for gene: STAB1 were set to Complete
Review for gene: STAB1 was set to GREEN
Added comment: Sources: Literature
Malformations of cortical development v4.12 COL4A2 Nour Elkhateeb edited their review of gene: COL4A2: Changed rating: GREEN
Paediatric or syndromic cardiomyopathy v3.43 RRAGC Achchuthan Shanmugasundram Phenotypes for gene: RRAGC were changed from Dilated cardiomyopathy, hepatopathy and brain abnormalities to Long-Olsen syndrome, OMIM:620609
Paediatric or syndromic cardiomyopathy v3.42 RRAGC Achchuthan Shanmugasundram reviewed gene: RRAGC: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Long-Olsen syndrome, OMIM:620609; Mode of inheritance: None
Paediatric or syndromic cardiomyopathy v3.42 RRAGC Achchuthan Shanmugasundram Tag gene-checked was removed from gene: RRAGC.
Early onset or syndromic epilepsy v4.133 ASL Nour Elkhateeb changed review comment from: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60% (PMID 36994644, 21744316, 28251416). The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients (PMID: 36994644).
Sources: Literature, ClinGen; to: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60% (PMID 36994644, 21744316, 28251416). The epilepsy phenotype occurs early in the natural history of ASA, with a median between at 2-5.5 years (PMID 36994644, 21744316, 28251416). The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients (PMID: 36994644).
Sources: Literature, ClinGen
Early onset or syndromic epilepsy v4.133 ASL Nour Elkhateeb changed review comment from: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60%. The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients.
Sources: Literature, ClinGen; to: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60% (PMID 36994644, 21744316, 28251416). The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients (PMID: 36994644).
Sources: Literature, ClinGen
Early onset or syndromic epilepsy v4.133 ASL Nour Elkhateeb gene: ASL was added
gene: ASL was added to Early onset or syndromic epilepsy. Sources: Literature,ClinGen
Mode of inheritance for gene: ASL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASL were set to 36994644; 21744316; 28251416
Phenotypes for gene: ASL were set to Seizure; Neurodevelopmental delay; Intellectual disability; Autism; Abnormality of movement; Ataxia; Hepatomegaly; Elevated hepatic transaminase; Renal tubular dysfunction; Abnormal hair morphology
Penetrance for gene: ASL were set to Complete
Review for gene: ASL was set to GREEN
Added comment: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60%. The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients.
Sources: Literature, ClinGen
COVID-19 research v1.140 IKBKB Arina Puzriakova Phenotypes for gene: IKBKB were changed from Immunodeficiency 15, 615592; Immunodeficiencies affecting cellular and humoral immunity; Combined immunodeficiency; Recurrent bacterial, viral, fungal infections, opportunistic infections to Immunodeficiency 15A, OMIM:618204 (AD); Immunodeficiency 15B, OMIM:615592 (AR); Combined immunodeficiency; Recurrent bacterial, viral, fungal infections, opportunistic infections; Immunodeficiencies affecting cellular and humoral immunity
COVID-19 research v1.139 IKBKB Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic' as both inheritance patterns are associated with a relevant phenotype of primary immunodeficiency, but AR disease is more severe with earlier onset.
COVID-19 research v1.139 IKBKB Arina Puzriakova Mode of inheritance for gene: IKBKB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital hypothyroidism v2.18 IYD Arina Puzriakova Added comment: Comment on publications: Previous phenotypes - PMID:18434651 (Moreno et al., 2008): 2 missense mutations and a 3bp deletion were identified in 4 patients with hypothryoidism from 3 unrelated families;PMID:22535972 (Burniat et al., 2012) identified a homozygous IYD mutation in a child born to first-cousins. A 4.5-yr-old unaffected sister was found homozygous for the mutation;24629858 (Review);18765512
Congenital hypothyroidism v2.18 IYD Arina Puzriakova Publications for gene: IYD were set to PMID:18434651 (Moreno et al., 2008): 2 missense mutations and a 3bp deletion were identified in 4 patients with hypothryoidism from 3 unrelated families; PMID:22535972 (Burniat et al., 2012) identified a homozygous IYD mutation in a child born to first-cousins. A 4.5-yr-old unaffected sister was found homozygous for the mutation; 24629858 (Review); 18765512
Congenital hypothyroidism v2.17 IYD Arina Puzriakova Phenotypes for gene: IYD were changed from Congenital hypothyroidism; Thyroid dyshormonogenesis 4, 274800; goitre; childhood/adolescent onset hypothyroidism; normal iodide organification; raised urinary MIT and DIT to Thyroid dyshormonogenesis 4, OMIM:274800
Hypogonadotropic hypogonadism v1.40 NSMF Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this only partially explains the phenotype in some cases due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1.; to: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this only partially explains the phenotype in some cases due to oligogenic variants in other genes such as FGFR1 and HS6ST1.
Hypogonadotropic hypogonadism v1.40 NSMF Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this is only partially explains the phenotype due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1.; to: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this only partially explains the phenotype in some cases due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1.
Hypogonadotropic hypogonadism v1.40 NSMF Arina Puzriakova Classified gene: NSMF as Red List (low evidence)
Hypogonadotropic hypogonadism v1.40 NSMF Arina Puzriakova Added comment: Comment on list classification: Downgrading from Green to Red to align with the classification on the GMS equivalent panel (https://panelapp.genomicsengland.co.uk/panels/650/gene/NSMF/).

Review by Zornitza Stark (Australian Genomics) - 18 Jul 2020
"Rare variants reported in individuals with IHH; however, variants in other IHH genes also present, and at least one of the variants has a very high population frequency in gnomad (intronic 8-bp deletion ending 14 bp before exon 10 (1159-14_-22del), present in 258 individuals)."

Review by Ivone Leong (Genomics England Curator) - 24 Mar 2021
"This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. PMID:27803842 describes a murine Nsmf knockout model that shows that Nsmf does not have a role in the migration of GnRH-positive neurons during early development.
Given the available evidence, this gene should be demoted to Red status."
Hypogonadotropic hypogonadism v1.40 NSMF Arina Puzriakova Gene: nsmf has been classified as Red List (Low Evidence).
Hypogonadotropic hypogonadism v1.39 NSMF Arina Puzriakova Publications for gene: NSMF were set to 15362570; 17235395; 21300340
Hypogonadotropic hypogonadism v1.38 NSMF Arina Puzriakova Phenotypes for gene: NSMF were changed from Hypogonadotropic hypogonadism 9 with or without anosmia, 614838; Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory) to Hypogonadotropic hypogonadism 9 with or without anosmia, OMIM:614838
Hypogonadotropic hypogonadism v1.37 NSMF Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this is only partially explains the phenotype due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1.
Hypogonadotropic hypogonadism v1.37 NSMF Arina Puzriakova Mode of inheritance for gene: NSMF was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v3.14 NSMF Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this is only partially explains the phenotype due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1.
Hypogonadotropic hypogonadism (GMS) v3.14 NSMF Arina Puzriakova Mode of inheritance for gene: NSMF was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v3.121 NSMF Arina Puzriakova Mode of pathogenicity for gene: NSMF was changed from to Other
Fetal anomalies v3.120 NSMF Arina Puzriakova Phenotypes for gene: NSMF were changed from Hypogonadotropic hypogonadism 9 with or without anosmia 614838 to Hypogonadotropic hypogonadism 9 with or without anosmia, OMIM:614838
Autoinflammatory disorders v1.11 UBA1 Arina Puzriakova Publications for gene: UBA1 were set to 33108101; 33690815; 34048852; 34077651; 34196684
Autoinflammatory disorders v1.10 UBA1 Arina Puzriakova Tag to_be_confirmed_NHSE was removed from gene: UBA1.
Autoinflammatory disorders v1.10 UBA1 Arina Puzriakova Classified gene: UBA1 as Green List (high evidence)
Autoinflammatory disorders v1.10 UBA1 Arina Puzriakova Added comment: Comment on list classification: Following further discussions with the GMS specialist group, it was agreed that the coverage of this test does include somatic variant detection. Therefore, the rating of this gene has been updated to green and the mode of inheritance set to "Other" following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v1.10 UBA1 Arina Puzriakova Gene: uba1 has been classified as Green List (High Evidence).
Autoinflammatory disorders v1.9 UBA1 Arina Puzriakova Mode of pathogenicity for gene: UBA1 was changed from to Other
Early onset or syndromic epilepsy v4.133 CLCN2 Sarah Leigh commented on gene: CLCN2: The association between CLCN2 and epilepsy has been refuted by ClinGen Epilepsy Expert Panel on the meeting date March 15, 2022 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba2a1616-b3d7-4762-a546-c838333db683-2022-03-15T040000.000Z)
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh commented on gene: MAGI2: Sarah Leigh commented on gene: MAGI2: Clingen refuted association with epilepsy https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2023-10-17T190000.000Z?page=1&size=25&search=
Malformations of cortical development v4.12 CASP2 Achchuthan Shanmugasundram Classified gene: CASP2 as Amber List (moderate evidence)
Malformations of cortical development v4.12 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence available (three unrelated families) for the association of biallelic CASP2 variants with lissencephaly. Hence, this gene can be promoted to green rating in the next GMS update.
Malformations of cortical development v4.12 CASP2 Achchuthan Shanmugasundram Gene: casp2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v4.11 CASP2 Achchuthan Shanmugasundram Phenotypes for gene: CASP2 were changed from neurodevelopmental disorder MONDO:0700092, CASP2-related to neurodevelopmental disorder, MONDO:0700092; hereditary cerebral malformation, MONDO:0957008
Malformations of cortical development v4.10 CASP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CASP2.
Malformations of cortical development v4.10 CASP2 Achchuthan Shanmugasundram reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37880421; Phenotypes: neurodevelopmental disorder, MONDO:0700092, hereditary cerebral malformation, MONDO:0957008; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe Paediatric Disorders v1.177 CPA6 Sarah Leigh Classified gene: CPA6 as Red List (low evidence)
Severe Paediatric Disorders v1.177 CPA6 Sarah Leigh Gene: cpa6 has been classified as Red List (Low Evidence).
Severe Paediatric Disorders v1.176 CPA6 Sarah Leigh reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Classified gene: CASP2 as Amber List (moderate evidence)
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are at least three unrelated families reported with biallelic CASP2 variants and intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Gene: casp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Classified gene: CASP2 as Amber List (moderate evidence)
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are at least three unrelated families reported with biallelic CASP2 variants and intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Gene: casp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Classified gene: CASP2 as Amber List (moderate evidence)
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are at least three unrelated families reported with biallelic CASP2 variants and intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.341 CASP2 Achchuthan Shanmugasundram Gene: casp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.340 CASP2 Achchuthan Shanmugasundram Phenotypes for gene: CASP2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.340 CASP2 Achchuthan Shanmugasundram Phenotypes for gene: CASP2 were changed from Autosomal recessive mental retardation to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.339 CASP2 Achchuthan Shanmugasundram Publications for gene: CASP2 were set to 26350204; 24896178; 21937992
Intellectual disability v5.338 CASP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CASP2.
Intellectual disability v5.338 CASP2 Achchuthan Shanmugasundram reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37880421; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.133 CACNB4 Sarah Leigh Tag refuted tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v4.133 CACNB4 Sarah Leigh Tag Q4_23_demote_red tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v4.133 CACNB4 Sarah Leigh edited their review of gene: CACNB4: Added comment: The gene disease association between CACNB4 and epilepsy has been refuted by ClinGen Epilepsy Gene Curation Expert Panel on July 5, 2022 (SOP Version 9)(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2fad131-8e91-4874-9394-8b86d6d62abb-2022-07-05T160000.000Z?page=1&size=25&search= ); Changed rating: RED
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh Tag disputed was removed from gene: MAGI2.
Tag refuted tag was added to gene: MAGI2.
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh commented on gene: MAGI2: Clingen refuted association with epilepsy https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2023-10-17T190000.000Z?page=1&size=25&search=
Structural eye disease v3.58 KIF11 Hannah Knight reviewed gene: KIF11: Rating: GREEN; Mode of pathogenicity: None; Publications: 24281367; Phenotypes: Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.58 KIAA0586 Hannah Knight reviewed gene: KIAA0586: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055837, 36580738, 28125082; Phenotypes: Joubert syndrome 23; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v3.58 CRYBB2 Hannah Knight reviewed gene: CRYBB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29386872, 25489230, 21402992, 2240043, 9158139; Phenotypes: Cataract 3, multiple types; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.58 SLC25A24 Hannah Knight reviewed gene: SLC25A24: Rating: AMBER; Mode of pathogenicity: None; Publications: 31775791; Phenotypes: Fontaine progeroid syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.113 ATP5B Sarah Leigh commented on gene: ATP5B: In the opinion of Helen Brittain (Clinical Fellow, Genomics England) is "There is a lack of clarity over the penetrance, plus also the phenotypes are somewhat disparate (the twins had DD with episodic hyperthermia, whereas the other cases presented with dystonia). A gene:disease association cannot be made at this time".
Mitochondrial disorder with complex V deficiency v2.12 ATP5B Sarah Leigh commented on gene: ATP5B: In the opinion of Helen Brittain (Clinical Fellow, Genomics England) is "There is a lack of clarity over the penetrance, plus also the phenotypes are somewhat disparate (the twins had DD with episodic hyperthermia, whereas the other cases presented with dystonia). A gene:disease association cannot be made at this time".
Likely inborn error of metabolism - targeted testing not possible v4.77 ATP5B Sarah Leigh commented on gene: ATP5B: In the opinion of Helen Brittain (Clinical Fellow, Genomics England) is "There is a lack of clarity over the penetrance, plus also the phenotypes are somewhat disparate (the twins had DD with episodic hyperthermia, whereas the other cases presented with dystonia). A gene:disease association cannot be made at this time".
Possible mitochondrial disorder - nuclear genes v3.68 ATP5B Sarah Leigh commented on gene: ATP5B: In the opinion of Helen Brittain (Clinical Fellow, Genomics England) is "There is a lack of clarity over the penetrance, plus also the phenotypes are somewhat disparate (the twins had DD with episodic hyperthermia, whereas the other cases presented with dystonia). A gene:disease association cannot be made at this time".
Early onset or syndromic epilepsy v4.133 ZBTB47 Sarah Leigh changed review comment from: Asked the opinion of Helen Brittain (Genomics England, Clinical Fellow), regarding the recommended rating of ZBTB47.; to: The opinion of Helen Brittain (Genomics England, Clinical Fellow), was that ZBTB47 should be green on the Intellectual disability and Early onset or syndromic epilepsy panels.
Intellectual disability v5.338 ZBTB47 Sarah Leigh commented on gene: ZBTB47: The opinion of Helen Brittain (Genomics England, Clinical Fellow), was that ZBTB47 should be green on the Intellectual disability and Early onset or syndromic epilepsy panels.
Early onset or syndromic epilepsy v4.133 ZBTB47 Sarah Leigh edited their review of gene: ZBTB47: Added comment: ZBTB47 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37743782 reports five unrelated patients with de novo missense variants in ZBTB47 (c.2039A>G, p.(Glu680Gly) in one patient and c.1429G>A, p.(Glu477Lys) in four others), with a phenotype that included developmental delay, intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities.; Changed rating: GREEN
Intellectual disability v5.338 ZBTB47 Sarah Leigh edited their review of gene: ZBTB47: Added comment: ZBTB47 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37743782 reports five unrelated patients with de novo missense variants in ZBTB47 (c.2039A>G, p.(Glu680Gly) in one patient and c.1429G>A, p.(Glu477Lys) in four others), with a phenotype that included developmental delay, intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities.; Changed rating: GREEN
Early onset or syndromic epilepsy v4.133 ZBTB47 Sarah Leigh Phenotypes for gene: ZBTB47 were changed from Neurodevelopmental disorder, MONDO; 0700092 to Neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v4.132 ZBTB47 Sarah Leigh Phenotypes for gene: ZBTB47 were changed from Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related to Neurodevelopmental disorder, MONDO; 0700092
Intellectual disability v5.338 ZBTB47 Sarah Leigh Phenotypes for gene: ZBTB47 were changed from Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related to Neurodevelopmental disorder, MONDO; 0700092
Intellectual disability v5.337 ZBTB47 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ZBTB47.
Early onset or syndromic epilepsy v4.131 ZBTB47 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ZBTB47.
Early onset or syndromic epilepsy v4.131 ZBTB47 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.337
Early onset or syndromic epilepsy v4.131 ZBTB47 Sarah Leigh gene: ZBTB47 was added
gene: ZBTB47 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Early onset or syndromic epilepsy v4.130 MAST4 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.337
Early onset or syndromic epilepsy v4.130 MAST4 Sarah Leigh gene: MAST4 was added
gene: MAST4 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: MAST4.
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Severe Paediatric Disorders v1.176 CSF1R Tracy Lester reviewed gene: CSF1R: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v3.3 FOXJ1 Steven Cowman reviewed gene: FOXJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630787, 37469238, 37813609; Phenotypes: Motile ciliopathy, situs inversus, hydrocephalus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Respiratory ciliopathies including non-CF bronchiectasis v3.3 NME5 Steven Cowman reviewed gene: NME5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37957793; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.3 SPEF2 Steven Cowman reviewed gene: SPEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31942643, 31942643, 31545650; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.3 SPEF2 Steven Cowman Deleted their review
Respiratory ciliopathies including non-CF bronchiectasis v3.3 SPEF2 Steven Cowman reviewed gene: SPEF2: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31942643; Phenotypes: ; Mode of inheritance: None
COVID-19 research v1.138 IL21R Arina Puzriakova Phenotypes for gene: IL21R were changed from Combined immunodeficiency; Atypical Severe Combined Immunodeficiency (Atypical SCID); Immunodeficiency 56, 615207; Immunodeficiencies affecting cellular and humoral immunity; Omenn syndrome; Immunodeficiency, primary, autosomal recessive, IL21R-related; IL-21R deficiency; Severe combined immunodeficiency (SCID); Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease to Immunodeficiency 56, OMIM:615207; Atypical Severe Combined Immunodeficiency (Atypical SCID); Combined immunodeficiency; Omenn syndrome; Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v4.123 IL21R Arina Puzriakova Phenotypes for gene: IL21R were changed from Immunodeficiency 56, 615207; Immunodeficiency, primary, autosomal recessive, IL21R-related; Atypical Severe Combined Immunodeficiency (Atypical SCID); Combined immunodeficiency; Omenn syndrome; Severe combined immunodeficiency (SCID); IL-21R deficiency; Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease; Immunodeficiencies affecting cellular and humoral immunity to Immunodeficiency 56, OMIM:615207
Retinal disorders v4.42 NRL Arina Puzriakova Phenotypes for gene: NRL were changed from Retinal degeneration, autosomal recessive, clumped pigment type (AR); Retinitis pigmentosa 27 (AD); Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa; Retinitis pigmentosa 27, 613750 to Retinal degeneration, autosomal recessive, clumped pigment type (AR); Retinitis pigmentosa 27, OMIM:613750
Structural eye disease v3.58 NRL Arina Puzriakova Phenotypes for gene: NRL were changed from Retinitis pigmentosa 27, 613750; Eye Disorders to Retinitis pigmentosa 27, OMIM:613750
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.24 ABHD5 Oliver Watkinson gene: ABHD5 was added
gene: ABHD5 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: ABHD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD5 were set to 33455044
Phenotypes for gene: ABHD5 were set to OMIM 604780 (Chanarin-Dorfman syndrome)
Penetrance for gene: ABHD5 were set to Complete
Review for gene: ABHD5 was set to GREEN
Added comment: Chanarin-Dorfman is a neutral lipid storage disorder. The review here summarises the world literature to date, with a good paragraph about myopathy towards the end of the discussion. The phenotype is quite variable, and can include multiple organ systems, but overall 59% of patients have high CK and muscle weakness. Skeletal muscle biopsy findings of lipid storage in this disorder are well described. Thus, this gene probably ought to be part of R381, and this seems like the best sub-panel to put it in, given that PNPLA2, a similar disorder, is also on this panel.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v3.20 TUBA8 Hannah Knight gene: TUBA8 was added
gene: TUBA8 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: TUBA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA8 were set to 34704371
Phenotypes for gene: TUBA8 were set to Macrothrombocytopenia, isolated, 2, autosomal dominant
Review for gene: TUBA8 was set to AMBER
Added comment: PMID: 34704371 (2022) identified rare variants in this gene in patients with macrothrombocytopenia. Associated with a phenotype on OMIM
Sources: Literature
Cytopenia - NOT Fanconi anaemia v3.20 TUBA4A Hannah Knight gene: TUBA4A was added
gene: TUBA4A was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA4A were set to 30760556
Phenotypes for gene: TUBA4A were set to Thrombocytopenia
Review for gene: TUBA4A was set to RED
Added comment: Linked to thrombocytopenia (PMID: 30760556, 2019) - only one patient reported
Sources: Literature
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh Tag Q4_23_NHS_review was removed from gene: PIGM.
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).
Absence seizures were apparent in 5/7 individuals from 5/6 families with OMIM:610293 biallelic for rs587776528 (table 1, PMID: 31445883).
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.77
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh gene: PIGM was added
gene: PIGM was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber,London North GLH
promoter, non-coding-known-pathogenic, Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: PIGM.
Mode of inheritance for gene: PIGM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906; 31445883
Phenotypes for gene: PIGM were set to Glycosylphosphatidylinositol deficiency, OMIM:610293
Undiagnosed metabolic disorders v1.607 PIGM Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: PIGM.
Likely inborn error of metabolism - targeted testing not possible v4.77 PIGM Sarah Leigh Tag promoter tag was added to gene: PIGM.
Congenital disorders of glycosylation v4.13 PIGM Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: PIGM.
Tag Q4_23_promote_green tag was added to gene: PIGM.
Congenital disorders of glycosylation v4.13 PIGM Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).
Likely inborn error of metabolism - targeted testing not possible v4.77 PIGM Sarah Leigh edited their review of gene: PIGM: Added comment: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; Changed rating: GREEN
Undiagnosed metabolic disorders v1.607 PIGM Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).
Likely inborn error of metabolism - targeted testing not possible v4.77 PIGM Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: PIGM.
Tag Q4_23_promote_green tag was added to gene: PIGM.
Tag Q4_23_NHS_review tag was added to gene: PIGM.
Undiagnosed metabolic disorders v1.607 PIGM Sarah Leigh Classified gene: PIGM as Green List (high evidence)
Undiagnosed metabolic disorders v1.607 PIGM Sarah Leigh Gene: pigm has been classified as Green List (High Evidence).
Congenital disorders of glycosylation v4.13 PIGM Sarah Leigh Classified gene: PIGM as Amber List (moderate evidence)
Congenital disorders of glycosylation v4.13 PIGM Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital disorders of glycosylation v4.13 PIGM Sarah Leigh Gene: pigm has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.77 PIGM Sarah Leigh Classified gene: PIGM as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.77 PIGM Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.77 PIGM Sarah Leigh Gene: pigm has been classified as Amber List (Moderate Evidence).
Severe Paediatric Disorders v1.176 SQSTM1 Tracy Lester reviewed gene: SQSTM1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, ataxia, dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v4.12 PIGM Sarah Leigh edited their review of gene: PIGM: Added comment: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; Changed rating: GREEN
Undiagnosed metabolic disorders v1.606 PIGM Sarah Leigh edited their review of gene: PIGM: Added comment: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; Changed rating: GREEN
Congenital disorders of glycosylation v4.12 PIGM Sarah Leigh Publications for gene: PIGM were set to 27604308; 16767100; 25293775
Undiagnosed metabolic disorders v1.606 PIGM Sarah Leigh Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906
Congenital disorders of glycosylation v4.11 PIGM Sarah Leigh Added comment: Comment on phenotypes: Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency;Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation
Congenital disorders of glycosylation v4.11 PIGM Sarah Leigh Phenotypes for gene: PIGM were changed from Glycosylphosphatidylinositol deficiency, 610293; Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency; Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation to Glycosylphosphatidylinositol deficiency, OMIM:610293
Undiagnosed metabolic disorders v1.605 PIGM Sarah Leigh Phenotypes for gene: PIGM were changed from Glycosylphosphatidylinositol deficiency 610293 to Glycosylphosphatidylinositol deficiency, OMIM:610293
Likely inborn error of metabolism - targeted testing not possible v4.76 PIGM Sarah Leigh Phenotypes for gene: PIGM were changed from Glycosylphosphatidylinositol deficiency 610293 to Glycosylphosphatidylinositol deficiency, OMIM:610293
Likely inborn error of metabolism - targeted testing not possible v4.75 PIGM Sarah Leigh Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906
Ataxia and cerebellar anomalies - narrow panel v4.40 DLG4 Dmitrijs Rots gene: DLG4 was added
gene: DLG4 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: DLG4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DLG4 were set to PMID: 33597769
Phenotypes for gene: DLG4 were set to Intellectual developmental disorder, autosomal dominant 62
Penetrance for gene: DLG4 were set to Complete
Review for gene: DLG4 was set to GREEN
Added comment: PMID: 33597769 described a large cohort with DLG4-synaptopathy, where at least 19 individuals are with movement disorders, and 9 are with ataxia.
Sources: Literature
Adult onset neurodegenerative disorder v4.41 DAO Ivone Leong Tag refuted tag was added to gene: DAO.
Adult onset neurodegenerative disorder v4.41 DAO Ivone Leong Classified gene: DAO as Red List (low evidence)
Adult onset neurodegenerative disorder v4.41 DAO Ivone Leong Added comment: Comment on list classification: This gene has been demoted from Amber to Red. This gene has been refuted by ClinGen ALS spectrum disorders (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_35ac00ac-3279-4c7e-89b6-8a75e3cae414-2022-04-12T103808.867Z?page=1&size=25&search=) (4/12/2022)
Adult onset neurodegenerative disorder v4.41 DAO Ivone Leong Gene: dao has been classified as Red List (Low Evidence).
Adult onset neurodegenerative disorder v4.40 DAO Ivone Leong Publications for gene: DAO were set to 29194436; 20368421
Rhabdomyolysis and metabolic muscle disorders v3.39 HADHB Dmitrijs Rots reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35403730; Phenotypes: episodic myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.113 HADHB Dmitrijs Rots reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35403730; Phenotypes: episodic myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.113 HADHB Dmitrijs Rots Deleted their review
Mitochondrial disorders v4.113 HADHB Dmitrijs Rots reviewed gene: HADHB: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 35403730; Phenotypes: episodic myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.337 CASP2 Dmitrijs Rots reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37880421; Phenotypes: neurodevelopmental disorder with lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v2.17 FKRP Oliver Watkinson reviewed gene: FKRP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32914449, 19705481, 18060779, 15833432; Phenotypes: Dilated cardiomyopathy, Limb girdle muscular dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v3.57 GDF3 Sarah Leigh Tag Q4_23_demote_amber tag was added to gene: GDF3.
Tag Q4_23_expert_review tag was added to gene: GDF3.
Structural eye disease v3.57 GDF3 Sarah Leigh changed review comment from: A total of GDF3 variants have been reported in PMID: 19864492, 24281366 & 29260090 in patients with ocular phenotypes. It has been noted, that some of the variants have been found in gnomAD v4.0.0 at a high frequency and in unaffected relatives of the patients. A summary of the allele frequencies and other information is presented below.
NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)
• rs140926412
• https://gnomad.broadinstitute.org/variant/12-7690177-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 4046/1614130 = allele frequency of 0.002507 which could be considered as scoring BS1 depending on the frequency of the disease
• PMID: 19864492; 29260090
NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)
• rs146973734
• https://gnomad.broadinstitute.org/variant/12-7690389-C-T?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 239/1614062 = allele frequency 0.0001481 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia
NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)
• rs387906946
• https://gnomad.broadinstitute.org/variant/12-7690153-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 156/1614148 = allele frequency 0.00009665 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia and coloboma
NM_020634.3(GDF3):c.914T>C (p.Leu305Pro)
• rs387906945
• https://gnomad.broadinstitute.org/variant/12-7690059-A-G?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 349/1614130 = allele frequency 0.0002162 which could be considered slightly too frequent to score PM2 depending on the frequency of the disease
• PMID: 19864492 three cases:
o 1 patient (2.1) with Unilateral microphthalmia and incomplete penetrance.
o 1 patient (2.2) unaffected father of 2.1
o 1 patient with Bilateral iris coloboma
NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)
• rs566697767
• https://gnomad.broadinstitute.org/variant/12-7689999-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 77/1613890 = allele frequency 0.00004771 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 24281366
o 1 patient 11 with microphthalmia and coloboma, also compound heterozygote for two missense mutations in CYP1B1, c.1103G>A, p.(Arg368His), and c.685G>A, p.(Glu229Lys), which is associated with ocular phenotypes (OMIM: 231300 & OMIM: 617315) and is Green on Structural eye disease panel
o 1 patient unaffected father of the patient above

As a result of this analysis, it seems unlikely that c.796C>T (p.Arg266Cys) is disease causing, due to its high frequency in gnomAD v4.0.0. The contribution of c.974C>T (p.Pro325Leu) to the disease is unknown, as it has only been seen in a patient who was also compound heterozygous for CYP1B1 variants. Plus, c.974C>T (p.Pro325Leu) was also seen in the unaffected father of the patient, as was c.914T>C (p.Leu305Pro); leading to the assertion that the effects of GDF3 variants of is subject to reduced penetrance. The variants c.584G>A (p.Arg195Gln) and c.820C>T (p.Arg274Trp) were found at low frequency in gnomAD v4.0.0. and there were no reports of unaffected carriers of these variants in the cited publications.; to: A total of five GDF3 variants have been reported in PMID: 19864492, 24281366 & 29260090 in patients with ocular phenotypes. It has been noted, that some of the variants have been found in gnomAD v4.0.0 at a high frequency and in unaffected relatives of the patients. A summary of the allele frequencies and other information is presented below.
NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)
• rs140926412
• https://gnomad.broadinstitute.org/variant/12-7690177-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 4046/1614130 = allele frequency of 0.002507 which could be considered as scoring BS1 depending on the frequency of the disease
• PMID: 19864492; 29260090
NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)
• rs146973734
• https://gnomad.broadinstitute.org/variant/12-7690389-C-T?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 239/1614062 = allele frequency 0.0001481 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia
NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)
• rs387906946
• https://gnomad.broadinstitute.org/variant/12-7690153-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 156/1614148 = allele frequency 0.00009665 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia and coloboma
NM_020634.3(GDF3):c.914T>C (p.Leu305Pro)
• rs387906945
• https://gnomad.broadinstitute.org/variant/12-7690059-A-G?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 349/1614130 = allele frequency 0.0002162 which could be considered slightly too frequent to score PM2 depending on the frequency of the disease
• PMID: 19864492 three cases:
o 1 patient (2.1) with Unilateral microphthalmia and incomplete penetrance.
o 1 patient (2.2) unaffected father of 2.1
o 1 patient with Bilateral iris coloboma
NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)
• rs566697767
• https://gnomad.broadinstitute.org/variant/12-7689999-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 77/1613890 = allele frequency 0.00004771 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 24281366
o 1 patient 11 with microphthalmia and coloboma, also compound heterozygote for two missense mutations in CYP1B1, c.1103G>A, p.(Arg368His), and c.685G>A, p.(Glu229Lys), which is associated with ocular phenotypes (OMIM: 231300 & OMIM: 617315) and is Green on Structural eye disease panel
o 1 patient unaffected father of the patient above

As a result of this analysis, it seems unlikely that c.796C>T (p.Arg266Cys) is disease causing, due to its high frequency in gnomAD v4.0.0. The contribution of c.974C>T (p.Pro325Leu) to the disease is unknown, as it has only been seen in a patient who was also compound heterozygous for CYP1B1 variants. Plus, c.974C>T (p.Pro325Leu) was also seen in the unaffected father of the patient, as was c.914T>C (p.Leu305Pro); leading to the assertion that the effects of GDF3 variants of is subject to reduced penetrance. The variants c.584G>A (p.Arg195Gln) and c.820C>T (p.Arg274Trp) were found at low frequency in gnomAD v4.0.0. and there were no reports of unaffected carriers of these variants in the cited publications.
Structural eye disease v3.57 GDF3 Sarah Leigh changed review comment from: A total of GDF3 variants have been reported in PMID: 19864492, 24281366 & 29260090 in patients with ocular phenotypes. It has been noted, that some of the variants have been found in gnomAD v4.0.0 at a high frequency and in unaffected relatives of the patients. A summary of the allele frequencies and other information is presented below.
NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)
• rs140926412
• https://gnomad.broadinstitute.org/variant/12-7690177-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 4046/1614130 = allele frequency of 0.002507 which could be considered as scoring BS1 depending on the frequency of the disease
• PMID: 19864492; 29260090
NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)
• rs146973734
• https://gnomad.broadinstitute.org/variant/12-7690389-C-T?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 239/1614062 = allele frequency 0.0001481 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia
NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)
• rs387906946
• https://gnomad.broadinstitute.org/variant/12-7690153-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 156/1614148 = allele frequency 0.00009665 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia and coloboma
NM_020634.3(GDF3):c.914T>C (p.Leu305Pro)
• rs387906945
• https://gnomad.broadinstitute.org/variant/12-7690059-A-G?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 349/1614130 = allele frequency 0.0002162 which could be considered slightly too frequent to score PM2 depending on the frequency of the disease
• PMID: 19864492 three cases:
o 1 patient (2.1) with Unilateral microphthalmia and incomplete penetrance.
o 1 patient (2.2) unaffected father of 2.1
o 1 patient with Bilateral iris coloboma
NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)
• rs566697767
• https://gnomad.broadinstitute.org/variant/12-7689999-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 77/1613890 = allele frequency 0.00004771 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 24281366
o 1 patient 11 with microphthalmia and coloboma, also compound heterozygote for two missense mutations in CYP1B1, c.1103G>A, p.(Arg368His), and c.685G>A, p.(Glu229Lys), which is associated with ocular phenotypes (OMIM: 231300 & OMIM: 617315) and is Green on Structural eye disease panel
o 1 patient unaffected father of the patient above

As a result of this analysis, it seems unlikely that c.796C>T (p.Arg266Cys) is disease causing, due to its high frequency in gnomAD v4.0.0. The contribution of c.974C>T (p.Pro325Leu) to the disease is unknown, as it has only been seen in a patient who was also compound heterozygous for CYP1B1 variants. Plus, c.974C>T (p.Pro325Leu) was also seen in the unaffected father of the patient, as was c.914T>C (p.Leu305Pro), leading to the assertion the effects of GDF3 variants of is subject to reduced penetrance. The variants c.584G>A (p.Arg195Gln) and c.820C>T (p.Arg274Trp) were found at low frequency in gnomAD v4.0.0. and there were no reports of unaffected carriers in these publications.; to: A total of GDF3 variants have been reported in PMID: 19864492, 24281366 & 29260090 in patients with ocular phenotypes. It has been noted, that some of the variants have been found in gnomAD v4.0.0 at a high frequency and in unaffected relatives of the patients. A summary of the allele frequencies and other information is presented below.
NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)
• rs140926412
• https://gnomad.broadinstitute.org/variant/12-7690177-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 4046/1614130 = allele frequency of 0.002507 which could be considered as scoring BS1 depending on the frequency of the disease
• PMID: 19864492; 29260090
NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)
• rs146973734
• https://gnomad.broadinstitute.org/variant/12-7690389-C-T?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 239/1614062 = allele frequency 0.0001481 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia
NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)
• rs387906946
• https://gnomad.broadinstitute.org/variant/12-7690153-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 156/1614148 = allele frequency 0.00009665 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia and coloboma
NM_020634.3(GDF3):c.914T>C (p.Leu305Pro)
• rs387906945
• https://gnomad.broadinstitute.org/variant/12-7690059-A-G?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 349/1614130 = allele frequency 0.0002162 which could be considered slightly too frequent to score PM2 depending on the frequency of the disease
• PMID: 19864492 three cases:
o 1 patient (2.1) with Unilateral microphthalmia and incomplete penetrance.
o 1 patient (2.2) unaffected father of 2.1
o 1 patient with Bilateral iris coloboma
NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)
• rs566697767
• https://gnomad.broadinstitute.org/variant/12-7689999-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 77/1613890 = allele frequency 0.00004771 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 24281366
o 1 patient 11 with microphthalmia and coloboma, also compound heterozygote for two missense mutations in CYP1B1, c.1103G>A, p.(Arg368His), and c.685G>A, p.(Glu229Lys), which is associated with ocular phenotypes (OMIM: 231300 & OMIM: 617315) and is Green on Structural eye disease panel
o 1 patient unaffected father of the patient above

As a result of this analysis, it seems unlikely that c.796C>T (p.Arg266Cys) is disease causing, due to its high frequency in gnomAD v4.0.0. The contribution of c.974C>T (p.Pro325Leu) to the disease is unknown, as it has only been seen in a patient who was also compound heterozygous for CYP1B1 variants. Plus, c.974C>T (p.Pro325Leu) was also seen in the unaffected father of the patient, as was c.914T>C (p.Leu305Pro); leading to the assertion that the effects of GDF3 variants of is subject to reduced penetrance. The variants c.584G>A (p.Arg195Gln) and c.820C>T (p.Arg274Trp) were found at low frequency in gnomAD v4.0.0. and there were no reports of unaffected carriers of these variants in the cited publications.
Structural eye disease v3.57 GDF3 Sarah Leigh Deleted their comment
Structural eye disease v3.57 GDF3 Sarah Leigh edited their review of gene: GDF3: Added comment: A total of GDF3 variants have been reported in PMID: 19864492, 24281366 & 29260090 in patients with ocular phenotypes. It has been noted, that some of the variants have been found in gnomAD v4.0.0 at a high frequency and in unaffected relatives of the patients. A summary of the allele frequencies and other information is presented below.
NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)
• rs140926412
• https://gnomad.broadinstitute.org/variant/12-7690177-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 4046/1614130 = allele frequency of 0.002507 which could be considered as scoring BS1 depending on the frequency of the disease
• PMID: 19864492; 29260090
NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)
• rs146973734
• https://gnomad.broadinstitute.org/variant/12-7690389-C-T?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 239/1614062 = allele frequency 0.0001481 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia
NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)
• rs387906946
• https://gnomad.broadinstitute.org/variant/12-7690153-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 156/1614148 = allele frequency 0.00009665 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia and coloboma
NM_020634.3(GDF3):c.914T>C (p.Leu305Pro)
• rs387906945
• https://gnomad.broadinstitute.org/variant/12-7690059-A-G?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 349/1614130 = allele frequency 0.0002162 which could be considered slightly too frequent to score PM2 depending on the frequency of the disease
• PMID: 19864492 three cases:
o 1 patient (2.1) with Unilateral microphthalmia and incomplete penetrance.
o 1 patient (2.2) unaffected father of 2.1
o 1 patient with Bilateral iris coloboma
NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)
• rs566697767
• https://gnomad.broadinstitute.org/variant/12-7689999-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 77/1613890 = allele frequency 0.00004771 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 24281366
o 1 patient 11 with microphthalmia and coloboma, also compound heterozygote for two missense mutations in CYP1B1, c.1103G>A, p.(Arg368His), and c.685G>A, p.(Glu229Lys), which is associated with ocular phenotypes (OMIM: 231300 & OMIM: 617315) and is Green on Structural eye disease panel
o 1 patient unaffected father of the patient above

As a result of this analysis, it seems unlikely that c.796C>T (p.Arg266Cys) is disease causing, due to its high frequency in gnomAD v4.0.0. The contribution of c.974C>T (p.Pro325Leu) to the disease is unknown, as it has only been seen in a patient who was also compound heterozygous for CYP1B1 variants. Plus, c.974C>T (p.Pro325Leu) was also seen in the unaffected father of the patient, as was c.914T>C (p.Leu305Pro), leading to the assertion the effects of GDF3 variants of is subject to reduced penetrance. The variants c.584G>A (p.Arg195Gln) and c.820C>T (p.Arg274Trp) were found at low frequency in gnomAD v4.0.0. and there were no reports of unaffected carriers in these publications.; Changed rating: AMBER
Hereditary neuropathy or pain disorder v3.65 SARS Achchuthan Shanmugasundram Classified gene: SARS as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.65 SARS Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of SARS1 gene in this panel in the next GMS review.
Hereditary neuropathy or pain disorder v3.65 SARS Achchuthan Shanmugasundram Gene: sars has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.64 SARS Achchuthan Shanmugasundram Phenotypes for gene: SARS were changed from CMTi to hereditary peripheral neuropathy, MONDO:0020127
Hereditary neuropathy or pain disorder v3.63 SARS Achchuthan Shanmugasundram Publications for gene: SARS were set to 37706277,36088542
Hereditary neuropathy or pain disorder v3.62 SARS Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: SARS.
Tag Q4_23_promote_green tag was added to gene: SARS.
Tag Q4_23_NHS_review tag was added to gene: SARS.
Hereditary neuropathy or pain disorder v3.62 SARS Achchuthan Shanmugasundram commented on gene: SARS: Added new-gene-name tag, new approved HGNC gene symbol for SARS is SARS1.
Hereditary neuropathy or pain disorder v3.62 SARS Achchuthan Shanmugasundram changed review comment from: PMID:36088542 - Two different heterozygous missense variants within the aminoacylation domain of SARS1 gene was identified in 16 affected individuals from three unrelated families with Charcot-Marie-Tooth (CMT) disease. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.

PMID:37706277 - A female patient with demyelinating CMT was identified with a heterozygous variant in SARS1 gene.


Biallelic variants in this gene have already been associated with relevant phenotypes in both OMIM (MIM #617709) and Gene2Phenotype, while monoallelic variants are associated with phenotype only in Gene2Phenotype (with 'limited' rating in the DD panel).; to: PMID:36088542 - Two different heterozygous missense variants within the aminoacylation domain of SARS1 gene was identified in 16 affected individuals from three unrelated families with Charcot-Marie-Tooth (CMT) disease. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.

PMID:37706277 - A female patient with demyelinating CMT was identified with a heterozygous variant in SARS1 gene.

Biallelic variants in this gene have already been associated with relevant phenotypes in both OMIM (MIM #617709) and Gene2Phenotype, while monoallelic variants are associated with phenotype only in Gene2Phenotype (with 'limited' rating in the DD panel).
Hereditary neuropathy or pain disorder v3.62 SARS Achchuthan Shanmugasundram reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 36088542, 37706277; Phenotypes: hereditary peripheral neuropathy, MONDO:0020127; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.57 GDF3 Sarah Leigh Publications for gene: GDF3 were set to 19864492; 29260090
Retinal disorders v4.41 VWA8 Hannah Knight gene: VWA8 was added
gene: VWA8 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to 37012052
Phenotypes for gene: VWA8 were set to ?Retinitis pigmentosa 97
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052 (2023) identified VWA8 as a novel cause of adRP in a four generation family with 11 affected family members.
6 of the affected members appear to have been tested and confirmed to carry the variant, while 5 unaffected members appear to have been confirmed NOT to
Sources: Literature
Congenital muscular dystrophy v4.15 GOLGA2 Hannah Knight reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.74 PIGM Hannah Knight reviewed gene: PIGM: Rating: GREEN; Mode of pathogenicity: None; Publications: 31445883; Phenotypes: Glycosylphosphatidylinositol deficiency 610293; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.24 POPDC3 Hannah Knight reviewed gene: POPDC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 35075722, 35842834, 37104941; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 26; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.68 HSPA9 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HSPA9.
Tag Q4_23_NHS_review tag was added to gene: HSPA9.
Possible mitochondrial disorder - nuclear genes v3.68 HSPA9 Achchuthan Shanmugasundram Classified gene: HSPA9 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.68 HSPA9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic variants in HSPA9 gene to Even-plus syndrome. Hence, this gene should be promoted to green rating in the next GMS review.
Possible mitochondrial disorder - nuclear genes v3.68 HSPA9 Achchuthan Shanmugasundram Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.67 HSPA9 Achchuthan Shanmugasundram Mode of inheritance for gene: HSPA9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.66 HSPA9 Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to 26598328; 32869452; 35779070; 36052765
Possible mitochondrial disorder - nuclear genes v3.65 HSPA9 Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, there are more than three unrelated cases identified with biallelic HSPA9 variants and reported with Even-plus syndrome (MIM #616854).

However, there are only two unrelated families identified with monoallelic HSPA9 variants and reported with sideroblastic anemia-4 (PMID:26491070).; to: As reviewed by Hannah Knight, there are more than three unrelated cases identified with biallelic HSPA9 variants and reported with Even-plus syndrome (MIM #616854).

However, there are only two unrelated families identified with monoallelic HSPA9 variants and reported with sideroblastic anemia-4 (MIM #182170) (PMID:26491070).
Possible mitochondrial disorder - nuclear genes v3.65 HSPA9 Achchuthan Shanmugasundram reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26491070, 26598328, 32869452, 35779070, 36052765; Phenotypes: Even-plus syndrome, OMIM:616854, Anemia, sideroblastic, 4, OMIM:182170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.65 HSPA9 Achchuthan Shanmugasundram Deleted their review
Likely inborn error of metabolism - targeted testing not possible v4.74 HSPA9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Corneal dystrophy v3.9 LTBP2 Arina Puzriakova Classified gene: LTBP2 as Amber List (moderate evidence)
Corneal dystrophy v3.9 LTBP2 Arina Puzriakova Added comment: Comment on list classification: This gene could be promoted to Green at the next GMS panel update.
Corneal dystrophy v3.9 LTBP2 Arina Puzriakova Gene: ltbp2 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v3.8 LTBP2 Arina Puzriakova gene: LTBP2 was added
gene: LTBP2 was added to Corneal dystrophy. Sources: Literature
Q4_23_promote_green tags were added to gene: LTBP2.
Mode of inheritance for gene: LTBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP2 were set to 19656777; 19361779; 21081970; 20179738; 22539340; 20617341; 22025892
Phenotypes for gene: LTBP2 were set to Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, OMIM:251750; Glaucoma 3, primary congenital, D, OMIM:613086; Weill-Marchesani syndrome 3, recessive, OMIM:614819
Review for gene: LTBP2 was set to GREEN
Added comment: Variants in this gene are typically associated with ocular abnormalities, including microspherophakia, megalocornea, ectopia lentis and glaucoma. At least three unrelated individual cases have been associated with megalocornea. This gene was rated as green on the Corneal abnormalities 100K panel and is associated with a relevant phenotype in OMIM and Gene2Phenotype.
Sources: Literature
Intellectual disability v5.337 CLEC16A Dmitrijs Rots gene: CLEC16A was added
gene: CLEC16A was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CLEC16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLEC16A were set to PMID: 36538041
Phenotypes for gene: CLEC16A were set to severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation
Penetrance for gene: CLEC16A were set to Complete
Review for gene: CLEC16A was set to GREEN
Added comment: Two independent cases reported PMID: 36538041with biallelic variants and functional evidence. Sufficient for the green rating.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v3.9 LTBP2 Arina Puzriakova Publications for gene: LTBP2 were set to PMID: 20179738; PMID: 20617341
Monogenic diabetes v2.53 SMPD4 Dmitrijs Rots gene: SMPD4 was added
gene: SMPD4 was added to Monogenic diabetes. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 36732302
Phenotypes for gene: SMPD4 were set to NDD, microcephaly and diabetes
Penetrance for gene: SMPD4 were set to Complete
Review for gene: SMPD4 was set to AMBER
Added comment: PMID: 36732302 reported three independent families with multiple affected individuals with biallelic SMPD4 variants with severe NDD and insulin-dependent diabetes. Given the syndromic presentation - not sure about the relevancy for the panel.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v3.8 LTBP2 Arina Puzriakova Phenotypes for gene: LTBP2 were changed from Inreased arm-span-to-height ratio; Decreased upper-to-lower body ratio; Lens dislocation; Pectus excavatum; Myopia to Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, OMIM:251750; Glaucoma 3, primary congenital, D, OMIM:613086; Weill-Marchesani syndrome 3, recessive, OMIM:614819
Ehlers Danlos syndrome with a likely monogenic cause v3.7 LTBP2 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: LTBP2.
Ehlers Danlos syndrome with a likely monogenic cause v3.7 LTBP2 Arina Puzriakova Classified gene: LTBP2 as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v3.7 LTBP2 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Andžela Lazdāne. Variants are typically associated with ocular abnormalities, and in a subset of cases (>3) marfanoid features may be observed. Marfan syndrome is an important differential diagnosis for this panel and therefore this gene could be promoted to Green at the next GMS review.
Ehlers Danlos syndrome with a likely monogenic cause v3.7 LTBP2 Arina Puzriakova Gene: ltbp2 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.65 HSPA9 Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to
Possible mitochondrial disorder - nuclear genes v3.64 HSPA9 Achchuthan Shanmugasundram Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, 616854; Anemia, sideroblastic, 4, 182170; Also Parkinson disease association? to Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170
Possible mitochondrial disorder - nuclear genes v3.63 HSPA9 Achchuthan Shanmugasundram reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Even-plus syndrome, OMIM:616854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.74 HSPA9 Achchuthan Shanmugasundram Classified gene: HSPA9 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.74 HSPA9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Likely inborn error of metabolism - targeted testing not possible v4.74 HSPA9 Achchuthan Shanmugasundram Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.73 HSPA9 Achchuthan Shanmugasundram Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854 to Even-plus syndrome, OMIM:616854
Likely inborn error of metabolism - targeted testing not possible v4.72 HSPA9 Achchuthan Shanmugasundram Phenotypes for gene: HSPA9 were changed from Even-plus syndrome 616854 to Even-plus syndrome, OMIM:616854
Likely inborn error of metabolism - targeted testing not possible v4.71 HSPA9 Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to 26598328; 32869452; 35779070; 36052765
Likely inborn error of metabolism - targeted testing not possible v4.71 HSPA9 Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to 26598328; 32869452; 35779070; 36052765
Likely inborn error of metabolism - targeted testing not possible v4.70 HSPA9 Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to PMID: 26598328
Likely inborn error of metabolism - targeted testing not possible v4.69 HSPA9 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HSPA9.
Tag Q4_23_NHS_review tag was added to gene: HSPA9.
Likely inborn error of metabolism - targeted testing not possible v4.69 HSPA9 Achchuthan Shanmugasundram reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Even-plus syndrome, OMIM:616854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v3.20 SRPRA Achchuthan Shanmugasundram Classified gene: SRPRA as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.20 SRPRA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is one case and functional studies (including zebrafish model) available in support of the association of this gene with severe congenital neutropenia. Hence, this gene can be rated amber with current evidence.
Cytopenia - NOT Fanconi anaemia v3.20 SRPRA Achchuthan Shanmugasundram Gene: srpra has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.19 SRPRA Achchuthan Shanmugasundram Phenotypes for gene: SRPRA were changed from Severe congenital neutropenia to severe congenital neutropenia, MONDO:0018542
Cytopenia - NOT Fanconi anaemia v3.18 SRPRA Achchuthan Shanmugasundram reviewed gene: SRPRA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: severe congenital neutropenia, MONDO:0018542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v3.18 SRP19 Achchuthan Shanmugasundram Classified gene: SRP19 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.18 SRP19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two related families with severe congenital neutropenia and functional studies in support of this association. Hence, this gene can be rated amber with current evidence.
Cytopenia - NOT Fanconi anaemia v3.18 SRP19 Achchuthan Shanmugasundram Gene: srp19 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.17 SRP19 Achchuthan Shanmugasundram Phenotypes for gene: SRP19 were changed from Severe congenital neutropenia to severe congenital neutropenia, MONDO:0018542
Cytopenia - NOT Fanconi anaemia v3.16 SRP19 Achchuthan Shanmugasundram reviewed gene: SRP19: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: severe congenital neutropenia, MONDO:0018542; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v3.16 SEC61A1 Achchuthan Shanmugasundram Publications for gene: SEC61A1 were set to 32325141; 27392076
Cytopenia - NOT Fanconi anaemia v3.15 SEC61A1 Achchuthan Shanmugasundram Phenotypes for gene: SEC61A1 were changed from Severe congenital neutropenia; Tubulointerstitial kidney disease, autosomal dominant, 5 to severe congenital neutropenia, MONDO:0018542; Tubulointerstitial kidney disease, autosomal dominant, 5, OMIM:617056
Cytopenia - NOT Fanconi anaemia v3.14 SEC61A1 Achchuthan Shanmugasundram Classified gene: SEC61A1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.14 SEC61A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases reported with neutropenia. Hence, this gene can be rated amber with the current evidence.
Cytopenia - NOT Fanconi anaemia v3.14 SEC61A1 Achchuthan Shanmugasundram Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.13 SEC61A1 Achchuthan Shanmugasundram reviewed gene: SEC61A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: severe congenital neutropenia, MONDO:0018542, Tubulointerstitial kidney disease, autosomal dominant, 5, OMIM:617056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v3.13 PROP1 Achchuthan Shanmugasundram Phenotypes for gene: PROP1 were changed from Combined Pituitary Hormone deficiency (OMIM 262600) to Pituitary hormone deficiency, combined, 2, OMIM:262600
Hypogonadotropic hypogonadism (GMS) v3.12 PROP1 Achchuthan Shanmugasundram Publications for gene: PROP1 were set to
Hypogonadotropic hypogonadism (GMS) v3.11 PROP1 Achchuthan Shanmugasundram Classified gene: PROP1 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v3.11 PROP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Hypogonadotropic hypogonadism (GMS) v3.11 PROP1 Achchuthan Shanmugasundram Gene: prop1 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.10 PROP1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PROP1.
Hypogonadotropic hypogonadism (GMS) v3.10 PROP1 Achchuthan Shanmugasundram reviewed gene: PROP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11549703, 15941866; Phenotypes: Pituitary hormone deficiency, combined, 2, OMIM:262600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.337 VCP Achchuthan Shanmugasundram Phenotypes for gene: VCP were changed from Neurodevelopmental disorder (MONDO: 0700092) to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.336 VCP Achchuthan Shanmugasundram edited their review of gene: VCP: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v5.336 VCP Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: VCP.
Intellectual disability v5.336 VCP Achchuthan Shanmugasundram Classified gene: VCP as Amber List (moderate evidence)
Intellectual disability v5.336 VCP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence available for adding this gene with green rating in the next GMS update.
Intellectual disability v5.336 VCP Achchuthan Shanmugasundram Gene: vcp has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.335 VCP Achchuthan Shanmugasundram reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: None; Publications: 37883978; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.62 SLC12A6 Christopher Record reviewed gene: SLC12A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 27485015, 36542484, 35733399, 31439721, 33323309; Phenotypes: CMT1, CMT2, CMTi, dHMN; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.62 SARS Christopher Record gene: SARS was added
gene: SARS was added to Hereditary neuropathy or pain disorder. Sources: Expert Review
Mode of inheritance for gene: SARS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SARS were set to 37706277,36088542
Phenotypes for gene: SARS were set to CMTi
Penetrance for gene: SARS were set to Complete
Review for gene: SARS was set to GREEN
Added comment: Dominant or de novo dominant plausibly causing CMT in four unrelated families. Another amino-acyl tRNA synthetase causing CMT
Sources: Expert Review
Hypogonadotropic hypogonadism (GMS) v3.10 CUL4B Achchuthan Shanmugasundram Classified gene: CUL4B as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v3.10 CUL4B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Hypogonadotropic hypogonadism (GMS) v3.10 CUL4B Achchuthan Shanmugasundram Gene: cul4b has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.9 CUL4B Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CUL4B.
Hypogonadotropic hypogonadism (GMS) v3.9 CUL4B Achchuthan Shanmugasundram reviewed gene: CUL4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25385192; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Cabezas type, OMIM:300354; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital adrenal hypoplasia v3.9 KDM1A Lauma Freimane edited their review of gene: KDM1A: Changed publications to: 34906447, 34655521
Haematological malignancies cancer susceptibility v4.4 POT1 Lauma Freimane reviewed gene: POT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Haematological malignancies cancer susceptibility v4.4 POT1 Lauma Freimane gene: POT1 was added
gene: POT1 was added to Haematological malignancies cancer susceptibility. Sources: Expert Review
Mode of inheritance for gene: POT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POT1 were set to PMID: 36467798; 30213928
Phenotypes for gene: POT1 were set to Multiple myeloma
Penetrance for gene: POT1 were set to unknown
gene: POT1 was marked as current diagnostic
Congenital adrenal hypoplasia v3.9 KDM1A Lauma Freimane gene: KDM1A was added
gene: KDM1A was added to Congenital adrenal hypoplasia. Sources: Expert Review
Mode of inheritance for gene: KDM1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM1A were set to 34906447
Phenotypes for gene: KDM1A were set to Food-dependent Cushing syndrome (FDCS)
Review for gene: KDM1A was set to GREEN
gene: KDM1A was marked as current diagnostic
Added comment: KDM1A inactivation explains about 90% of food-dependent Cushing syndrome observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) (PMID: 34906447).
Sources: Expert Review
Haematological malignancies cancer susceptibility v4.4 KDM1A Lauma Freimane gene: KDM1A was added
gene: KDM1A was added to Haematological malignancies cancer susceptibility. Sources: Expert list
Mode of inheritance for gene: KDM1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM1A were set to 29559475
Phenotypes for gene: KDM1A were set to Multiple myeloma
Review for gene: KDM1A was set to GREEN
gene: KDM1A was marked as current diagnostic
Added comment: KDM1A is the first autosomal dominant MM germline predisposition gene, providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B cell differentiation (PMID: 29559475).
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v3.13 TCIRG1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: TCIRG1.
Cytopenia - NOT Fanconi anaemia v3.13 TCIRG1 Achchuthan Shanmugasundram Classified gene: TCIRG1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.13 TCIRG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three cases reported so far, only two of these cases were reported in peer-reviewed publications. Hence, this gene is currently rated amber. In addition, watchlist tag has been added.
Cytopenia - NOT Fanconi anaemia v3.13 TCIRG1 Achchuthan Shanmugasundram Gene: tcirg1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.12 TCIRG1 Achchuthan Shanmugasundram Phenotypes for gene: TCIRG1 were changed from Congenital neutropenia to severe congenital neutropenia, MONDO:0018542
Cytopenia - NOT Fanconi anaemia v3.11 TCIRG1 Achchuthan Shanmugasundram Publications for gene: TCIRG1 were set to 24753205
Cytopenia - NOT Fanconi anaemia v3.10 TCIRG1 Achchuthan Shanmugasundram reviewed gene: TCIRG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24753205, 35573728; Phenotypes: severe congenital neutropenia, MONDO:0018542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy v4.6 TULP3 Achchuthan Shanmugasundram Tag Q2_23_NHS_review tag was added to gene: TULP3.
Structural eye disease v3.56 GDF3 Sarah Leigh Deleted their comment
Structural eye disease v3.56 GDF3 Sarah Leigh Tag Q4_23_promote_green was removed from gene: GDF3.
Tag Q4_23_NHS_review was removed from gene: GDF3.
Mitochondrial disorders v4.113 ATP5B Sarah Leigh Classified gene: ATP5B as Amber List (moderate evidence)
Mitochondrial disorders v4.113 ATP5B Sarah Leigh Gene: atp5b has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.69 ATP5B Sarah Leigh Classified gene: ATP5B as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.69 ATP5B Sarah Leigh Gene: atp5b has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.63 ATP5B Sarah Leigh reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.68 ATP5B Sarah Leigh reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v4.112 ATP5B Sarah Leigh reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorder with complex V deficiency v2.12 ATP5B Sarah Leigh reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorder with complex V deficiency v2.12 ATP5B Sarah Leigh Penetrance for gene ATP5B was set from to None
Mitochondrial disorders v4.112 ATP5B Sarah Leigh Penetrance for gene ATP5B was set from to Complete
Likely inborn error of metabolism - targeted testing not possible v4.68 ATP5B Sarah Leigh Penetrance for gene ATP5B was set from to None
Possible mitochondrial disorder - nuclear genes v3.63 ATP5B Sarah Leigh Penetrance for gene ATP5B was set from to None
Likely inborn error of metabolism - targeted testing not possible v4.67 ATP5B Sarah Leigh Mode of inheritance for gene: ATP5B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.62 ATP5B Sarah Leigh Mode of inheritance for gene: ATP5B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.111 ATP5B Sarah Leigh Mode of inheritance for gene: ATP5B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorder with complex V deficiency v2.11 ATP5B Sarah Leigh Mode of inheritance for gene: ATP5B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism - targeted testing not possible v4.66 ATP5B Sarah Leigh Phenotypes for gene: ATP5B were changed from No OMIM phenotype to ?Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2, OMIM: 620085
Possible mitochondrial disorder - nuclear genes v3.61 ATP5B Sarah Leigh Phenotypes for gene: ATP5B were changed from No OMIM phenotype to ?Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2, OMIM: 620085
Mitochondrial disorders v4.110 ATP5B Sarah Leigh Phenotypes for gene: ATP5B were changed from No OMIM phenotype to ?Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2, OMIM: 620085
Mitochondrial disorder with complex V deficiency v2.10 ATP5B Sarah Leigh Phenotypes for gene: ATP5B were changed from No OMIM phenotype to ?Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2, OMIM: 620085
Mitochondrial disorders v4.109 ATP5B Sarah Leigh Publications for gene: ATP5B were set to
Mitochondrial disorder with complex V deficiency v2.9 ATP5B Sarah Leigh Publications for gene: ATP5B were set to
Likely inborn error of metabolism - targeted testing not possible v4.65 ATP5B Sarah Leigh Publications for gene: ATP5B were set to
Possible mitochondrial disorder - nuclear genes v3.60 ATP5B Sarah Leigh Publications for gene: ATP5B were set to
Early onset or syndromic epilepsy v4.128 PTCD3 Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.64
Early onset or syndromic epilepsy v4.128 PTCD3 Sarah Leigh gene: PTCD3 was added
gene: PTCD3 was added to Early onset or syndromic epilepsy. Sources: Expert list,Expert Review Amber
Q4_23_promote_green tags were added to gene: PTCD3.
Mode of inheritance for gene: PTCD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCD3 were set to 30607703; 30706245; 36450274
Phenotypes for gene: PTCD3 were set to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057; combined oxidative phosphorylation deficiency 51, MONDO:0033631
Likely inborn error of metabolism - targeted testing not possible v4.64 PTCD3 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: PTCD3.
Mitochondrial disorders v4.108 PTCD3 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: PTCD3.
Mitochondrial disorders v4.108 PTCD3 Sarah Leigh edited their review of gene: PTCD3: Added comment: PTCD3 variants are associated with ?Combined oxidative phosphorylation deficiency 51 (OMIM:619057), but not associated with phenotype in Gen2Phen. At least six variants have been reported in three unrelated cases, with OMIM:619057 (PMID: 30607703; 36450274). Functional studies also support the involvement of PTCD3 variants in this condition (PMID: 30607703; 36450274).; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.64 PTCD3 Sarah Leigh edited their review of gene: PTCD3: Added comment: PTCD3 variants are associated with ?Combined oxidative phosphorylation deficiency 51 (OMIM:619057), but not associated with phenotype in Gen2Phen. At least six variants have been reported in three unrelated cases, with OMIM:619057 (PMID: 30607703; 36450274). Functional studies also support the involvement of PTCD3 variants in this condition (PMID: 30607703; 36450274).; Changed rating: GREEN
Mitochondrial disorders v4.108 PTCD3 Sarah Leigh Phenotypes for gene: PTCD3 were changed from ?Combined oxidative phosphorylation deficiency 51, OMIM:619057 to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057; combined oxidative phosphorylation deficiency 51, MONDO:0033631
Likely inborn error of metabolism - targeted testing not possible v4.64 PTCD3 Sarah Leigh Phenotypes for gene: PTCD3 were changed from ?Combined oxidative phosphorylation deficiency 51, OMIM:619057 to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057; combined oxidative phosphorylation deficiency 51, MONDO:0033631
Possible mitochondrial disorder - nuclear genes v3.59 PTCD3 Sarah Leigh Phenotypes for gene: PTCD3 were changed from ?Combined oxidative phosphorylation deficiency 51, OMIM:619057 to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057; combined oxidative phosphorylation deficiency 51, MONDO:0033631
Possible mitochondrial disorder - nuclear genes v3.58 PTCD3 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: PTCD3.
Tag Q4_23_NHS_review tag was added to gene: PTCD3.
Possible mitochondrial disorder - nuclear genes v3.58 PTCD3 Sarah Leigh edited their review of gene: PTCD3: Added comment: PTCD3 variants are associated with ?Combined oxidative phosphorylation deficiency 51 (OMIM:619057), but not associated with phenotype in Gen2Phen. At least six variants have been reported in three unrelated cases, with OMIM:619057 (PMID: 30607703; 36450274). Functional studies also support the involvement of PTCD3 variants in this condition (PMID: 30607703; 36450274).; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.63 PTCD3 Sarah Leigh Classified gene: PTCD3 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.63 PTCD3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.63 PTCD3 Sarah Leigh Gene: ptcd3 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.58 PTCD3 Sarah Leigh Classified gene: PTCD3 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.58 PTCD3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.58 PTCD3 Sarah Leigh Gene: ptcd3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.107 PTCD3 Sarah Leigh Classified gene: PTCD3 as Amber List (moderate evidence)
Mitochondrial disorders v4.107 PTCD3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.107 PTCD3 Sarah Leigh Gene: ptcd3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.41 CFAP20 Ivone Leong Tag Q4_23_promote_green tag was added to gene: CFAP20.
Retinal disorders v4.41 CFAP20 Ivone Leong Classified gene: CFAP20 as Amber List (moderate evidence)
Retinal disorders v4.41 CFAP20 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene has been given an Amber rating; however, this gene should be promoted to Green at the next GMS review.
Retinal disorders v4.41 CFAP20 Ivone Leong Gene: cfap20 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.106 PTCD3 Sarah Leigh Phenotypes for gene: PTCD3 were changed from No OMIM phenotype to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057
Likely inborn error of metabolism - targeted testing not possible v4.62 PTCD3 Sarah Leigh Phenotypes for gene: PTCD3 were changed from low birth weight, mental retardation, and optic atrophy to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057
Possible mitochondrial disorder - nuclear genes v3.57 PTCD3 Sarah Leigh Phenotypes for gene: PTCD3 were changed from No OMIM phenotype to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057
Mitochondrial disorders v4.105 PTCD3 Sarah Leigh Publications for gene: PTCD3 were set to 30607703
Likely inborn error of metabolism - targeted testing not possible v4.61 PTCD3 Sarah Leigh Publications for gene: PTCD3 were set to 30607703; 30706245
Possible mitochondrial disorder - nuclear genes v3.56 PTCD3 Sarah Leigh Publications for gene: PTCD3 were set to 30607703; 36450274
Possible mitochondrial disorder - nuclear genes v3.55 PTCD3 Sarah Leigh Publications for gene: PTCD3 were set to 30607703
Likely inborn error of metabolism - targeted testing not possible v4.60 MRM2 Sarah Leigh Publications for gene: MRM2 were set to 28973171
Mitochondrial disorders v4.104 MRM2 Sarah Leigh Publications for gene: MRM2 were set to 28973171
Hereditary neuropathy v1.472 VRK1 Dmitrijs Rots reviewed gene: VRK1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37257665; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.22 PTPRQ Arina Puzriakova Phenotypes for gene: PTPRQ were changed from Deafness, autosomal recessive 84A, 613391; Deafness,autosomalrecessive84A,613391 to Deafness, autosomal dominant 73, OMIM:617663; Deafness, autosomal recessive 84A, OMIM:613391
Monogenic hearing loss v4.21 PTPRQ Arina Puzriakova Added comment: Comment on publications: Previous publications listed: "PMID: 20346435 report a homozygous variant resulting in Tyr497Ter in 2 Dutch siblings with AR nonsyndromic hearing loss, and not found in matched controls. A homozygous variant resulting in Arg457Gly identified in 2 Moroccan siblings with AR nonsyndromic hearing loss, was also not found in matched controls."
Monogenic hearing loss v4.21 PTPRQ Arina Puzriakova Publications for gene: PTPRQ were set to PMID: 20346435 report a homozygous variant resulting in Tyr497Ter in 2 Dutch siblings with AR nonsyndromic hearing loss, and not found in matched controls. A homozygous variant resulting in Arg457Gly identified in 2 Moroccan siblings with AR nonsyndromic hearing loss, was also not found in matched controls.
Retinal disorders v4.40 RCBTB1 Arina Puzriakova Phenotypes for gene: RCBTB1 were changed from familial exudative vitreoretinopathy; Coats disease; Retinal dystrophy with or without extraocular anomalies, 617175 to Familial exudative vitreoretinopathy; Coats disease; Retinal dystrophy with or without extraocular anomalies, OMIM:617175
Retinal disorders v4.39 RP1L1 Arina Puzriakova Phenotypes for gene: RP1L1 were changed from Occult Macular Dystrophy; Occult macular dystrophy, 613587 to Occult macular dystrophy, OMIM:613587 (AD); Retinitis pigmentosa 88, OMIM:618826 (AR)
Likely inborn error of metabolism - targeted testing not possible v4.59 MRM2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: MRM2.
Mitochondrial disorders v4.103 MRM2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: MRM2.
Possible mitochondrial disorder - nuclear genes v3.54 MRM2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: MRM2.
Tag Q4_23_NHS_review tag was added to gene: MRM2.
Palmoplantar keratodermas v3.17 SASH1 Arina Puzriakova Mode of inheritance for gene: SASH1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.59 MRM2 Sarah Leigh edited their review of gene: MRM2: Added comment: MRM2 variants have been associated with ?Mitochondrial DNA depletion syndrome 17 (OMIM:618567), but not associated with phenotype in Gen2Phen. To date three biallelic MRM2 variants have been reported three unrelated cases (PMID: 28973171;36002240), supportive yeast functional studies have also been presented (PMID: 36002240).; Changed rating: GREEN
Mitochondrial disorders v4.103 MRM2 Sarah Leigh edited their review of gene: MRM2: Added comment: MRM2 variants have been associated with ?Mitochondrial DNA depletion syndrome 17 (OMIM:618567), but not associated with phenotype in Gen2Phen. To date three biallelic MRM2 variants have been reported three unrelated cases (PMID: 28973171;36002240), supportive yeast functional studies have also been presented (PMID: 36002240).; Changed rating: GREEN
Intellectual disability v5.335 DPP6 Ivone Leong commented on gene: DPP6
Palmoplantar keratodermas v3.16 SASH1 Arina Puzriakova Phenotypes for gene: SASH1 were changed from Dyschromatosis (het); Pigmentation defects, palmoplantar keratoderma, spinocellular carcinoma (homo) to ?Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma, OMIM:618373
Possible mitochondrial disorder - nuclear genes v3.54 MRM2 Sarah Leigh edited their review of gene: MRM2: Added comment: MRM2 variants have been associated with ?Mitochondrial DNA depletion syndrome 17 (OMIM:618567), but not associated with phenotype in Gen2Phen. To date three biallelic MRM2 variants have been reported three unrelated cases (PMID: 28973171;36002240), supportive yeast functional studies have also been presented (PMID: 36002240).; Changed rating: GREEN
Ichthyosis and erythrokeratoderma v3.19 SASH1 Arina Puzriakova Phenotypes for gene: SASH1 were changed from Pigmentation defects, palmoplantar keratoderma and skin carcinoma to ?Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma, OMIM:618373
Palmoplantar keratoderma and erythrokeratodermas v1.29 SASH1 Arina Puzriakova Phenotypes for gene: SASH1 were changed from Pigmentation defects, palmoplantar keratoderma and skin carcinoma to ?Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma, OMIM:618373
Intellectual disability v5.335 DPP6 Ivone Leong Tag Q4_23_demote_red tag was added to gene: DPP6.
Tag Q4_23_NHS_review tag was added to gene: DPP6.
Tag Q4_23_expert_review tag was added to gene: DPP6.
Pigmentary skin disorders v3.5 SASH1 Arina Puzriakova Phenotypes for gene: SASH1 were changed from Pigmentation defects, palmoplantar keratoderma, spinocellular carcinoma (homo); DYSCHROMATOSIS UNIVERSALIS HEREDITARIA 1; DUH1; Dyschromatosis (het) to Dyschromatosis universalis hereditaria 1, OMIM:127500 (AD); ?Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma, OMIM:618373 (AR)
Pigmentary skin disorders v3.4 SASH1 Arina Puzriakova Tag watchlist_moi tag was added to gene: SASH1.
Likely inborn error of metabolism - targeted testing not possible v4.59 MRM2 Sarah Leigh Classified gene: MRM2 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.59 MRM2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.59 MRM2 Sarah Leigh Gene: mrm2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.103 MRM2 Sarah Leigh Classified gene: MRM2 as Amber List (moderate evidence)
Mitochondrial disorders v4.103 MRM2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.103 MRM2 Sarah Leigh Gene: mrm2 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.54 MRM2 Sarah Leigh Classified gene: MRM2 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.54 MRM2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.54 MRM2 Sarah Leigh Gene: mrm2 has been classified as Amber List (Moderate Evidence).
Congenital fibrosis of the extraocular muscles v1.16 MYF5 Ivone Leong Tag watchlist was removed from gene: MYF5.
Tag Q4_23_promote_green tag was added to gene: MYF5.
Tag Q4_23_NHS_review tag was added to gene: MYF5.
Congenital fibrosis of the extraocular muscles v1.16 MYF5 Ivone Leong commented on gene: MYF5: There is now enough evidence for this gene to be promoted to Green status. This gene should be promoted to Green at the next GMS review.
Possible mitochondrial disorder - nuclear genes v3.53 MRM2 Sarah Leigh Publications for gene: MRM2 were set to 28973171
Congenital fibrosis of the extraocular muscles v1.16 MYF5 Ivone Leong Publications for gene: MYF5 were set to 29887215
Bleeding and platelet disorders v3.7 BLOC1S5 Ivone Leong Tag Q4_23_promote_green tag was added to gene: BLOC1S5.
Tag Q4_23_NHS_review tag was added to gene: BLOC1S5.
Bleeding and platelet disorders v3.7 BLOC1S5 Ivone Leong commented on gene: BLOC1S5
Bleeding and platelet disorders v3.7 BLOC1S5 Ivone Leong Phenotypes for gene: BLOC1S5 were changed from Hermansky–Pudlak syndrome to Hermansky–Pudlak syndrome 11, OMIM:619172; Hermansky-Pudlak syndrome 11, MONDO:0030903
Bleeding and platelet disorders v3.6 BLOC1S5 Ivone Leong Publications for gene: BLOC1S5 were set to 32565547
Possible mitochondrial disorder - nuclear genes v3.52 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 25954304
Likely inborn error of metabolism - targeted testing not possible v4.58 SEC23B Arina Puzriakova Tag Q4_23_MOI tag was added to gene: SEC23B.
Intellectual disability v5.335 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from Dyserythropoietic anemia, congenital, type II, 224100 to Dyserythropoietic anemia, congenital, type II, OMIM:224100
Fetal anomalies v3.119 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from ANEMIA, DYSERYTHROPOIETIC CONGENITAL, TYPE II to Dyserythropoietic anemia, congenital, type II, OMIM:224100
Rare anaemia v3.4 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from 224100 ANEMIA, DYSERYTHROPOIETIC CONGENITAL, TYPE II; Congenital Dyserythropoietic Anemia; 224100 Congenital dyserythropoietic anaemia type 2; ANEMIA, DYSERYTHROPOIETIC CONGENITAL, TYPE II; Anemia, dyserythropoieticcongenital, type II, 224100; Congenital dyserythropoietic anemia type II to Dyserythropoietic anemia, congenital, type II, OMIM:224100
Likely inborn error of metabolism - targeted testing not possible v4.58 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from Dyserythropoietic anemia, congenital, type II 224100; COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies) to Dyserythropoietic anemia, congenital, type II, OMIM:224100; COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies)
Cytopenias and congenital anaemias v1.112 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from Congenital dyserythropoietic anemia type II; Congenital Dyserythropoietic Anemia; Anemia, dyserythropoieticcongenital, type II, 224100; ANEMIA, DYSERYTHROPOIETIC CONGENITAL, TYPE II to Dyserythropoietic anemia, congenital, type II, OMIM:224100
Undiagnosed metabolic disorders v1.604 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies); Dyserythropoietic anemia, congenital, type II 224100 to Dyserythropoietic anemia, congenital, type II, OMIM:224100; COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies)
Congenital disorders of glycosylation v4.10 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from Dyserythropoietic anemia, congenital, type II 224100; COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies) to Dyserythropoietic anemia, congenital, type II, OMIM:224100; COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies)
Inherited non-medullary thyroid cancer v1.7 SEC23B Arina Puzriakova Classified gene: SEC23B as Red List (low evidence)
Inherited non-medullary thyroid cancer v1.7 SEC23B Arina Puzriakova Added comment: Comment on list classification: There is limited evidence linking this gene with Cowden syndrome (monoallelic variants). Only one family has been reported to date (PMID:26522472). The other variant identified in 2 unrelated women discussed in previous reviews, has since been reclassified as a VUS.

This gene:disease association is provisional in OMIM, 'limited' disease confidence category in G2P and is not listed in ClinGen (whereas CDAII is).

On this basis, downgrading the rating of this gene from Green to Red.
Inherited non-medullary thyroid cancer v1.7 SEC23B Arina Puzriakova Gene: sec23b has been classified as Red List (Low Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.57 SEC23B Arina Puzriakova Added comment: Comment on mode of inheritance: There is limited evidence linking this gene with Cowden syndrome (monoallelic variants). Only one family has been reported to date (PMID:26522472). This gene:disease association is provisional in OMIM, 'limited' disease confidence category in G2P and is not listed in ClinGen (whereas CDAII is). Biallelic phenotype remains relevant to this panel (PMID: 35163229).

On this basis, the MOI should be updated from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS panel update.
Likely inborn error of metabolism - targeted testing not possible v4.57 SEC23B Arina Puzriakova Mode of inheritance for gene: SEC23B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital disorders of glycosylation v4.9 SEC23B Arina Puzriakova Tag Q4_23_MOI tag was added to gene: SEC23B.
Undiagnosed metabolic disorders v1.603 SEC23B Arina Puzriakova Added comment: Comment on mode of inheritance: There is limited evidence linking this gene with Cowden syndrome (monoallelic variants). Only one family has been reported to date (PMID:26522472). This gene:disease association is provisional in OMIM, 'limited' disease confidence category in G2P and is not listed in ClinGen (whereas CDAII is). Biallelic phenotype remains relevant to this panel (PMID: 35163229).

On this basis, updating the MOI from 'Both mono- and biallelic' to 'Biallelic' only.
Undiagnosed metabolic disorders v1.603 SEC23B Arina Puzriakova Mode of inheritance for gene: SEC23B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v4.9 SEC23B Arina Puzriakova Added comment: Comment on mode of inheritance: There is limited evidence linking this gene with Cowden syndrome (monoallelic variants). Only one family has been reported to date (PMID:26522472). This gene:disease association is provisional in OMIM, 'limited' disease confidence category in G2P and is not listed in ClinGen (whereas CDAII is). Biallelic phenotype remains relevant to this panel (PMID: 35163229).

On this basis, the MOI should be updated from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS panel update.
Congenital disorders of glycosylation v4.9 SEC23B Arina Puzriakova Mode of inheritance for gene: SEC23B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.56 SEC23B Arina Puzriakova Publications for gene: SEC23B were set to 22208203
Undiagnosed metabolic disorders v1.602 SEC23B Arina Puzriakova Publications for gene: SEC23B were set to 27604308
Congenital disorders of glycosylation v4.8 SEC23B Arina Puzriakova Publications for gene: SEC23B were set to 22208203
Inherited non-medullary thyroid cancer v1.6 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from Cowden syndrome 7 616858 to Cowden syndrome 7, OMIM:616858
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Classified gene: RAP1B as Amber List (moderate evidence)
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Gene: rap1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Classified gene: RAP1B as Amber List (moderate evidence)
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.334 RAP1B Achchuthan Shanmugasundram Gene: rap1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.333 RAP1B Achchuthan Shanmugasundram Publications for gene: RAP1B were set to 32627184; 26280580
Autoinflammatory disorders v1.8 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from Dyserythropoietic anemia, congenital, type II to Dyserythropoietic anemia, congenital, type II, OMIM:224100
Intellectual disability v5.332 RAP1B Achchuthan Shanmugasundram Tag watchlist was removed from gene: RAP1B.
Tag Q4_23_promote_green tag was added to gene: RAP1B.
Autoinflammatory disorders v1.7 SEC23B Arina Puzriakova changed review comment from: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with congenital dyserythropoietic anemia (CDA) type II with multiple unrelated cases reported. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs. Could not find evidence of an autoinflammatory component of this disorder and therefore rating as red on this panel.; to: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with congenital dyserythropoietic anemia (CDA) type II with multiple unrelated cases reported. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs. Could not find strong evidence of an autoinflammatory component of this disorder and therefore rating as red on this panel.
Intellectual disability v5.332 RAP1B Achchuthan Shanmugasundram changed review comment from: PMID:35451551 - New patient reported with mild intellectual disability, bicuspid aortic valve, dilation of aortic root and ascending aorta, hearing loss, and long‐standing thrombocytopenia with lymphopenia. A novel, missense RAP1B variant (p.Ala59Gly) has been identified in this patient. This variant is on the neighbouring amino acid to one of the previously reported variants (p.Gly60Arg). This variant is confirmed de novo and not in gnomAD; to: PMID:35451551 - New patient reported with mild intellectual disability, bicuspid aortic valve, dilation of aortic root and ascending aorta, hearing loss, and long‐standing thrombocytopenia with lymphopenia. A novel, missense RAP1B variant (p.Ala59Gly) has been identified in this patient. This variant is on the neighbouring amino acid to one of the previously reported variants (p.Gly60Arg). This variant is confirmed de novo and not in gnomAD.

This gene has been associated with relevant phenotype in Gene2Phenotype database (with 'limited' rating in the DD panel), but not yet been associated with phenotypes in OMIM.
Intellectual disability v5.332 RAP1B Achchuthan Shanmugasundram reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35451551; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v1.7 SEC23B Arina Puzriakova Classified gene: SEC23B as Red List (low evidence)
Autoinflammatory disorders v1.7 SEC23B Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with congenital dyserythropoietic anemia (CDA) type II with multiple unrelated cases reported. These defective erythroblasts cannot develop into functional mature red blood cells. The resulting shortage of healthy red blood cells leads to the characteristic signs and symptoms of anemia, as well as complications including an enlarged liver and spleen (hepatosplenomegaly) and an abnormal buildup of iron that can damage the body's organs. Could not find evidence of an autoinflammatory component of this disorder and therefore rating as red on this panel.
Autoinflammatory disorders v1.7 SEC23B Arina Puzriakova Gene: sec23b has been classified as Red List (Low Evidence).
Autoinflammatory disorders v1.6 PRF1 Arina Puzriakova Publications for gene: PRF1 were set to 32098966
Autoinflammatory disorders v1.5 PRF1 Arina Puzriakova Classified gene: PRF1 as Amber List (moderate evidence)
Autoinflammatory disorders v1.5 PRF1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with
Hemophagocytic Lymphohistiocytosis (HLH) with multiple unrelated cases reported. This is a hyperinflammatory disorder which leads to to impaired function of cytotoxic T cells and NK cells, consistent with a defect in cellular cytotoxicity. Acquired HLH can be caused by autoinflammatory and autoimmune diseases; however, familial HLH caused by biallelic variants in this gene do not necessarily cause autoinflammation.

For this reason, rating this gene:disease association as amber on this panel. Cases should be picked up via the 'R15 Primary immunodeficiency or monogenic inflammatory bowel disease' panel, where it is already green.
Autoinflammatory disorders v1.5 PRF1 Arina Puzriakova Gene: prf1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.10 RAP1B Achchuthan Shanmugasundram Tag watchlist was removed from gene: RAP1B.
Tag Q4_23_promote_green tag was added to gene: RAP1B.
Tag Q4_23_NHS_review tag was added to gene: RAP1B.
Cytopenia - NOT Fanconi anaemia v3.10 RAP1B Achchuthan Shanmugasundram Classified gene: RAP1B as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.10 RAP1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases with cytopenia and hence this gene can be promoted to green rating in the next GMS review.

This gene has been associated with relevant phenotype in Gene2Phenotype database (with 'limited' rating in the DD panel), but not yet been associated with phenotypes in OMIM.
Cytopenia - NOT Fanconi anaemia v3.10 RAP1B Achchuthan Shanmugasundram Gene: rap1b has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.9 RAP1B Achchuthan Shanmugasundram Publications for gene: RAP1B were set to 32627184; 26280580
Cytopenia - NOT Fanconi anaemia v3.8 RAP1B Achchuthan Shanmugasundram Mode of inheritance for gene: RAP1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v3.7 RAP1B Achchuthan Shanmugasundram reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32627184, 35451551; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haemophagocytic syndrome with absent perforin expression v1.2 PRF1 Arina Puzriakova Phenotypes for gene: PRF1 were changed from to Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553
Autoinflammatory disorders v1.4 PRF1 Arina Puzriakova Phenotypes for gene: PRF1 were changed from Familial hemophagocytic lymphohistiocytosis-2 (FHL2) (OMIM: 603553) to Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553
Primary immunodeficiency or monogenic inflammatory bowel disease v4.122 PRF1 Arina Puzriakova Phenotypes for gene: PRF1 were changed from Hemophagocytic lymphohistiocytosis, familial 2, 603553; FHL2; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH2; HLH2; Fever, HSM, Hemophagocytic lymphohistiocytosis (HLH), cytopenias; Diseases of Immune Dysregulation to Hemophagocytic lymphohistiocytosis, familial, 2, OMIM:603553
Fetal anomalies v3.118 ESAM Achchuthan Shanmugasundram Phenotypes for gene: ESAM were changed from intracranial hemorrhage; cerebral anomalies to Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371
Fetal anomalies v3.117 ESAM Achchuthan Shanmugasundram Publications for gene: ESAM were set to PMID: 36996813
Fetal anomalies v3.116 ESAM Achchuthan Shanmugasundram Classified gene: ESAM as Amber List (moderate evidence)
Fetal anomalies v3.116 ESAM Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julia Baptista, PMID:36996813 reported foetal intracranial hemorrhage in four foetuses from three unrelated families. Hence, there is sufficient evidence for this gene to be promoted to green rating in this panel in the next GMS review.
Fetal anomalies v3.116 ESAM Achchuthan Shanmugasundram Gene: esam has been classified as Amber List (Moderate Evidence).
Fetal anomalies v3.115 ESAM Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: ESAM.
Fetal anomalies v3.115 ESAM Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ESAM.
Fetal anomalies v3.115 ESAM Achchuthan Shanmugasundram reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 36996813; Phenotypes: Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v3.22 KRT83 Arina Puzriakova Tag watchlist tag was added to gene: KRT83.
Ectodermal dysplasia v3.22 KRT83 Arina Puzriakova Classified gene: KRT83 as Amber List (moderate evidence)
Ectodermal dysplasia v3.22 KRT83 Arina Puzriakova Added comment: Comment on list classification: KRT81 is associated with two relevant phenotypes in OMIM (MIM# 158000) and G2P with a 'definitive' disease confidence classification for monilethrix. Monoallelic variant have been linked to monilethrix in two families (PMID: 15744029; 25557232) while biallelic variants were found in one family with EKVP5 (PMID: 27965375).

Overall no additional evidence has been published since the last review and therefore going to maintain the amber rating for now, but adding a 'watchlist' tag to monitor for additional evidence that may lead to future upgrade to green.

Other keratin genes, like KRT81 and KRT86 have been added as amber with the recommendation of being made green at the next review.
Ectodermal dysplasia v3.22 KRT83 Arina Puzriakova Gene: krt83 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v3.21 KRT86 Arina Puzriakova Publications for gene: KRT86 were set to 10469314; 10594761; 10504448; 12653715; 10878478; 25557232
Ectodermal dysplasia v3.20 KRT81 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: KRT81.
Tag Q4_23_NHS_review tag was added to gene: KRT81.
Ectodermal dysplasia v3.20 KRT81 Arina Puzriakova Publications for gene: KRT81 were set to
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 DLST Ivone Leong Tag Q4_23_demote_red tag was added to gene: DLST.
Ectodermal dysplasia v3.19 KRT81 Arina Puzriakova Classified gene: KRT81 as Amber List (moderate evidence)
Ectodermal dysplasia v3.19 KRT81 Arina Puzriakova Added comment: Comment on list classification: KRT81 is associated with a relevant phenotype in OMIM (MIM# 158000) and G2P with a 'definitive' disease confidence classification. Monoallelic variant have been linked to monilethrix. In addition to the two families previously discussed (PMID: 9665406; 9402962), there are an additional three unrelated cases reported in the literature (PMID: 10504448; 14714571; 25557232), particularly for recurrent variants at p.Glu413. KRT81 variants have been found in unaffected family members, suggesting reduced penetrance.
Overall there are sufficient cases to support an association with monilethrix, and therefore this gene can be promoted to Green at the next GMS panel update.
Ectodermal dysplasia v3.19 KRT81 Arina Puzriakova Gene: krt81 has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 MDH2 Ivone Leong Tag Q4_23_demote_red tag was added to gene: MDH2.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 SLC25A11 Ivone Leong Tag Q4_23_demote_red tag was added to gene: SLC25A11.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 DLST Ivone Leong commented on gene: DLST: This gene has been tagged for additional expert review due to conflicting reviews. The gene rating will remain Green pending the results of the expert review.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 DLST Ivone Leong Tag Q4_23_NHS_review tag was added to gene: DLST.
Tag Q4_23_expert_review tag was added to gene: DLST.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 MDH2 Ivone Leong Tag Q4_23_NHS_review tag was added to gene: MDH2.
Tag Q4_23_expert_review tag was added to gene: MDH2.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 MDH2 Ivone Leong commented on gene: MDH2: This gene has been tagged for additional expert review due to conflicting reviews. The gene rating will remain Green pending the results of the expert review.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 SLC25A11 Ivone Leong commented on gene: SLC25A11: This gene has been tagged for additional expert review due to conflicting reviews. The gene rating will remain Green pending the results of the expert review.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 SLC25A11 Ivone Leong Tag Q4_23_NHS_review tag was added to gene: SLC25A11.
Tag Q4_23_expert_review tag was added to gene: SLC25A11.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.6 DLST Ivone Leong Phenotypes for gene: DLST were changed from Paragangliomas 7, OMIM:618475 to Paragangliomas 7, OMIM:618475; Paragangliomas 7, MONDO:0032771
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.5 MDH2 Ivone Leong Phenotypes for gene: MDH2 were changed from PPGL to PPGL; pheochromocytoma-paraganglioma, MONDO:0035540
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.4 SLC25A11 Ivone Leong Phenotypes for gene: SLC25A11 were changed from Paragangliomas 6, OMIM:618464 to Paragangliomas 6, OMIM:618464; Paragangliomas 6, MONDO:0032767
Optic neuropathy v4.16 MCAT Ivone Leong Phenotypes for gene: MCAT were changed from progressive autosomal recessive optic neuropathy to progressive autosomal recessive optic neuropathy; Hereditary optic neuropathy, MONDO:0020249
Optic neuropathy v4.15 MCAT Ivone Leong Publications for gene: MCAT were set to 31915829
Optic neuropathy v4.14 MCAT Ivone Leong Classified gene: MCAT as Amber List (moderate evidence)
Optic neuropathy v4.14 MCAT Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber, based on new evidence of a second case (PMID:33918393).
Optic neuropathy v4.14 MCAT Ivone Leong Gene: mcat has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v3.18 KRT86 Arina Puzriakova Publications for gene: KRT86 were set to PMID: 10469314; 10594761; 10504448; 12653715
Ectodermal dysplasia v3.17 KRT86 Arina Puzriakova Classified gene: KRT86 as Amber List (moderate evidence)
Ectodermal dysplasia v3.17 KRT86 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Ronnie Wright (NWGLH). KRT86 is associated with a relevant phenotype in OMIM (MIM# 158000) and G2P with a 'definitive' disease confidence classification. Monoallelic variant have been linked to monilethrix and multiple (>3) families have been reported in the literature. Overall there is enough evidence to promote this gene to Green at the next GMS panel update.
Ectodermal dysplasia v3.17 KRT86 Arina Puzriakova Gene: krt86 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v3.16 KRT86 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: KRT86.
Tag Q4_23_NHS_review tag was added to gene: KRT86.
Ectodermal dysplasia v3.16 KRT83 Arina Puzriakova Phenotypes for gene: KRT83 were changed from to Monilethrix, OMIM:158000
Ectodermal dysplasia v3.15 KRT81 Arina Puzriakova Phenotypes for gene: KRT81 were changed from to Monilethrix, OMIM:158000
Ectodermal dysplasia v3.14 KRT86 Arina Puzriakova Phenotypes for gene: KRT86 were changed from Monilethrix to Monilethrix, OMIM:158000
Thoracic aortic aneurysm or dissection (GMS) v3.7 PMEPA1 Ivone Leong Phenotypes for gene: PMEPA1 were changed from thoracic aortic aneurysm; tall stature; dolichocephaly; abnormal axial skeletal morphology; pes planus to thoracic aortic aneurysm, MONDO:0005396; tall stature; dolichocephaly; abnormal axial skeletal morphology; pes planus; Loeys-Dietz syndrome, MONDO:0018954
Thoracic aortic aneurysm or dissection (GMS) v3.6 PMEPA1 Ivone Leong Tag Q4_23_promote_green tag was added to gene: PMEPA1.
Tag Q4_23_NHS_review tag was added to gene: PMEPA1.
Thoracic aortic aneurysm or dissection (GMS) v3.6 PMEPA1 Ivone Leong Classified gene: PMEPA1 as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v3.6 PMEPA1 Ivone Leong Added comment: Comment on list classification: New gene submitted by Andrew Mumford (University of Bristol). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 36928819 describes 8 families with truncating variants affecting the same polycytosine area in this gene. In the 100KGP cohort, three families of European ancestry with FTAAD have the same variant. This same variant was identified independently in 3 families of Japanese ancestry in a separate Japanese patient group. A second variant in the same polycycstine stretch was identified in a different FTAAD case enrolled in the 100KGP pilot programme. A third variant (5 bp deletion in the same stretch which caused a frameshift mutation) was identified in a family in Belgium.

"All pedigrees exhibited dominant inheritance of aortic aneurysm disease with incomplete penetrance and skeletal features including pectus deformity, scoliosis and arachnodactyly with complete penetrance". The authors found four HPO terms related to the musculoskeletal system were significantly enriched, which suggested the phenotypic characteristics of the syndromic aortopathy Loeys–Dietz syndrome.

Based on the above evidence this gene has been given an Amber gene rating and should be promoted to Green at the next GMS review.
Thoracic aortic aneurysm or dissection (GMS) v3.6 PMEPA1 Ivone Leong Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v3.5 PMEPA1 Ivone Leong Publications for gene: PMEPA1 were set to PMID:36928819
Primary lymphoedema v3.9 ERG Ivone Leong Phenotypes for gene: ERG were changed from primary lymphoedema to primary lymphoedema, MONDO:0019175
Primary lymphoedema v3.8 ERG Ivone Leong Tag Q4_23_promote_green tag was added to gene: ERG.
Tag Q4_23_NHS_review tag was added to gene: ERG.
Primary lymphoedema v3.8 ERG Ivone Leong Classified gene: ERG as Amber List (moderate evidence)
Primary lymphoedema v3.8 ERG Ivone Leong Added comment: Comment on list classification: New gene submitted by Andrew Mumford (University of Bristol). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 36928819 describes 3 families with frameshift variants (2 nonsense-mediated decay variants and 1 protein truncating variant). There is also a fourth family with a protein truncating variant; however, there are other clinical features and lymphoedema was only identified during chart review. Over expression of mutant cDNA caused mislocalisation of ERG in the cytoplasm, preventing it from binding to DNA and functioning as a transcription factor.

Based on the above evidence this gene has been given an Amber gene rating and should be promoted to Green at the next GMS review.
Primary lymphoedema v3.8 ERG Ivone Leong Gene: erg has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v3.7 ERG Ivone Leong Publications for gene: ERG were set to
Intellectual disability v5.332 DPP6 Gavin Ryan reviewed gene: DPP6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.56 GDF3 Zornitza Stark changed review comment from: p.Arg266Cys is present in >4,000 individuals in gnomad v4, casting serious doubts about pathogenicity.; to: p.Arg266Cys is present in >4,000 individuals in gnomad v4, casting serious doubts about pathogenicity.

p.Arg195Gln is present in 239 individuals which is also very high even for 'variable penetrance'.

p.Arg274Trp is present in 156.

p.Leu305Pro in 349. Also classified 'benign' in ClinVar.

p.Pro325Leu in 77.
Structural eye disease v3.56 GDF3 Zornitza Stark reviewed gene: GDF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Malformations of cortical development v4.10 CASP2 Zornitza Stark gene: CASP2 was added
gene: CASP2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: CASP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP2 were set to 37880421
Phenotypes for gene: CASP2 were set to neurodevelopmental disorder MONDO:0700092, CASP2-related
Review for gene: CASP2 was set to GREEN
Added comment: 7 individuals from 5 families:
- 4 families homozygous for PTC.
- 1 family compound heterozygote for splice site + PTC. RNA studies indicate usage of 2 cryptic splice donor sites.

5/5 have ID/dev delay
1/5 seizures
2/5 hypotonia
3/5 Lissencephaly (pachygyria + cortical thickening)
Sources: Literature
Intellectual disability v5.332 SGSM3 Zornitza Stark gene: SGSM3 was added
gene: SGSM3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SGSM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSM3 were set to 37833060
Phenotypes for gene: SGSM3 were set to Neurodevelopmental disorder (MONDO:0700092), SGSM3-related
Review for gene: SGSM3 was set to AMBER
Added comment: PMID: 37833060
- 13 patients from 8 families of Ashkenazi Jewish origin all had the same homozygous frameshift variant (c.981dup). Predicted to cause NMD. The variant co-segregated with disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional features observed included hypotonia, behavioural challenges and short stature. Considered a founder variant (1 in 52 Ashkenazi Jews carry the variant). Also present in other populations but no homozygotes in gnomAD.
Sources: Literature
Intellectual disability v5.332 AGPAT3 Zornitza Stark gene: AGPAT3 was added
gene: AGPAT3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT3 were set to 37821758
Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related
Review for gene: AGPAT3 was set to AMBER
Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa
- All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant
- Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis
- KO AGPAT3 mouse demonstrated impaired neuronal migration
Sources: Literature
Intellectual disability v5.332 VCP Zornitza Stark gene: VCP was added
gene: VCP was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 37883978
Phenotypes for gene: VCP were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: VCP was set to GREEN
Added comment: 13 unrelated individuals with childhood onset ID/DD disorder including macrocephaly, hypotonia and dysmorphic features. Non-specific / mild MRI findings.
12 de novo - 1 inherited
Sources: Literature
Intellectual disability v5.332 ZBTB47 Sarah Leigh reviewed gene: ZBTB47: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.332 ZBTB47 Sarah Leigh Classified gene: ZBTB47 as Amber List (moderate evidence)
Intellectual disability v5.332 ZBTB47 Sarah Leigh Gene: zbtb47 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Classified gene: POLD3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is one patient identified with homozygous POLD3 variant (p.Ile10Thr) and reported with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. In addition, there is also functional evidence for this variant. Hence, this gene is promoted to amber rating.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Gene: pold3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Classified gene: POLD3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is one patient identified with homozygous POLD3 variant (p.Ile10Thr) and reported with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. In addition, there is also functional evidence for this variant. Hence, this gene is promoted to amber rating.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.121 POLD3 Achchuthan Shanmugasundram Gene: pold3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.120 POLD3 Achchuthan Shanmugasundram Phenotypes for gene: POLD3 were changed from Immunodeficiency with neurodevelopmental delay and hearing loss to severe combined immunodeficiency, MONDO:0015974
Primary immunodeficiency or monogenic inflammatory bowel disease v4.119 POLD3 Achchuthan Shanmugasundram reviewed gene: POLD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 37030525; Phenotypes: severe combined immunodeficiency, MONDO:0015974; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.331 MYCN Sarah Leigh Publications for gene: MYCN were set to 37710961; 21224895; 8470948; 16906565; 18671284; 15821734; 18470948
Intellectual disability v5.330 MYCN Sarah Leigh Added comment: Comment on mode of pathogenicity: Gain-of-function MYCN variants have been reported (PMID: 30573562; 37710961) where the phenotypic features are to an extent opposite the phenotype of Feingold syndrome 1 (OMIM:164280) caused by loss-of-function MYCN variants.
Intellectual disability v5.330 MYCN Sarah Leigh Mode of pathogenicity for gene: MYCN was changed from to None
Intellectual disability v5.329 MYCN Sarah Leigh Publications for gene: MYCN were set to 21224895; 8470948; 16906565; 18671284; 15821734; 18470948
Primary immunodeficiency or monogenic inflammatory bowel disease v4.119 FMNL2 Achchuthan Shanmugasundram Phenotypes for gene: FMNL2 were changed from Severe very early onset inflammatory bowel disease to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v4.118 FMNL2 Achchuthan Shanmugasundram Classified gene: FMNL2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.118 FMNL2 Achchuthan Shanmugasundram Gene: fmnl2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.117 FMNL2 Achchuthan Shanmugasundram Mode of pathogenicity for gene: FMNL2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v4.116 FMNL2 Achchuthan Shanmugasundram reviewed gene: FMNL2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 34043722; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.328 MAST4 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: MAST4.
Intellectual disability v5.328 MAST4 Sarah Leigh edited their review of gene: MAST4: Added comment: MAST4 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO to date. PMID: 36910266 reports three de novo heterozygous MAST4 missense variants in four unrelated cases, with a neurodevelopmental disorder, including cognitive delay/intellectual disability and PMID: 33057194 reports four heterozygous MAST4 missense variants in four unrelated cases and a terminating variant in an additional case, from a cohort of 31,058 parent-offspring trios of individuals with developmental disorders. Between these two publications there are five missense MAST4 variants and one terminating variant. Variant c.4412C>T (p.Thr1471Ile) was seen in three unrelated cases.; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v4.116 PTPN2 Achchuthan Shanmugasundram Classified gene: PTPN2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.116 PTPN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and a Ptpn2 deficient mouse model in support of the association of PTPN2 to this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.116 PTPN2 Achchuthan Shanmugasundram Gene: ptpn2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.115 PTPN2 Achchuthan Shanmugasundram Phenotypes for gene: PTPN2 were changed from Lupus; arthritis; common variable immunodeficiency to Lupus; arthritis; common variable immunodeficiency; Very early onset inflammatory bowel disease
Primary immunodeficiency or monogenic inflammatory bowel disease v4.114 PTPN2 Achchuthan Shanmugasundram Publications for gene: PTPN2 were set to 32499645; 27658548
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 PTPN2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PTPN2.
Tag Q4_23_NHS_review tag was added to gene: PTPN2.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 PTPN2 Achchuthan Shanmugasundram reviewed gene: PTPN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27658548, 32499645, 32721438; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare genetic inflammatory skin disorders v3.5 NLRP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of monoallelic NLRP1 variants to this panel with green rating. However, the evidence is not sufficient enough (two unrelated cases) for biallelic variants. Hence, the MOI should be changed to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' and this gene should be recommended for upgrade to green rating in the next GMS review.
Rare genetic inflammatory skin disorders v3.5 NLRP1 Achchuthan Shanmugasundram Mode of inheritance for gene: NLRP1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare genetic inflammatory skin disorders v3.4 NLRP1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NLRP1.
Rare genetic inflammatory skin disorders v3.4 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and two unrelated cases with biallelic NLRP1 variants reported with inflammatory skin conditions. Some of these variants are reported to be gain-of-function.; to: There are five unrelated cases with monoallelic NLRP1 variants and two unrelated cases with biallelic NLRP1 variants reported with inflammatory skin conditions. Some of these variants are reported to be gain-of-function.

This gene has also been associated with relevant phenotypes in both OMIM and Gene2Phenotype.
Rare genetic inflammatory skin disorders v3.4 NLRP1 Achchuthan Shanmugasundram reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27662089, 27965258, 31873740; Phenotypes: Autoinflammation with arthritis and dyskeratosis, OMIM:617388, Palmoplantar carcinoma, multiple self-healing, OMIM:615225; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).; to: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 NLRP1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in this gene to this panel. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in this gene to this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 NLRP1 Achchuthan Shanmugasundram Classified gene: NLRP1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 NLRP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in this gene to this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.113 NLRP1 Achchuthan Shanmugasundram Gene: nlrp1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.112 NLRP1 Achchuthan Shanmugasundram Phenotypes for gene: NLRP1 were changed from Dyskeratosis, autoimmunity and arthritis; Palmoplantar carcinoma, corneal scarring; Autoinflammatory Disorders; Autoinflammation with arthritis and dyskeratosis, 617388 to Autoinflammation with arthritis and dyskeratosis, OMIM:617388; ?Respiratory papillomatosis, juvenile recurrent, congenital, OMIM:618803; Palmoplantar carcinoma, multiple self-healing, OMIM:615225; {Vitiligo-associated multiple autoimmune disease susceptibility 1}, OMIM:606579
Primary immunodeficiency or monogenic inflammatory bowel disease v4.111 NLRP1 Achchuthan Shanmugasundram Publications for gene: NLRP1 were set to 27965258; 31484767; 27662089; 29850521
Primary immunodeficiency or monogenic inflammatory bowel disease v4.110 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).; to: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in both OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.110 NLRP1 Achchuthan Shanmugasundram changed review comment from: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function variants.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).; to: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be of gain-of-function.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.110 NLRP1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: NLRP1 was changed from None to Other
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 NLRP1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NLRP1.
Tag Q4_23_NHS_review tag was added to gene: NLRP1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 NLRP1 Achchuthan Shanmugasundram commented on gene: NLRP1: There are five unrelated cases with monoallelic NLRP1 variants and three unrelated cases with biallelic NLRP1 variants. Some of these variants are reported to be gain-of-function variants.

This gene has been associated with multiple relevant phenotypes in OMIM and Gene2Phenotype (eye panel).
Intellectual disability v5.328 MAST4 Sarah Leigh Classified gene: MAST4 as Amber List (moderate evidence)
Intellectual disability v5.328 MAST4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.328 MAST4 Sarah Leigh Gene: mast4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 NLRP1 Achchuthan Shanmugasundram edited their review of gene: NLRP1: Changed mode of pathogenicity: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 NLRP1 Achchuthan Shanmugasundram edited their review of gene: NLRP1: Changed publications to: 27662089, 27965258, 31484767, 31873740
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 NLRP1 Achchuthan Shanmugasundram reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 27662089, 27965258, 31484767, 3187374; Phenotypes: Autoinflammation with arthritis and dyskeratosis, OMIM:617388, ?Respiratory papillomatosis, juvenile recurrent, congenital, OMIM:618803, Palmoplantar carcinoma, multiple self-healing, OMIM:615225, {Vitiligo-associated multiple autoimmune disease susceptibility 1}, OMIM:606579; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital fibrosis of the extraocular muscles v1.15 MYF5 Hannah Knight reviewed gene: MYF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 35186005; Phenotypes: Ophthalmoplegia, external, with rib and vertebral anomalies, 618155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.327 MAST4 Sarah Leigh Classified gene: MAST4 as Amber List (moderate evidence)
Intellectual disability v5.327 MAST4 Sarah Leigh Gene: mast4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.326 RBL2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: RBL2.
Tag Q4_23_NHS_review tag was added to gene: RBL2.
Intellectual disability v5.326 RBL2 Sarah Leigh Classified gene: RBL2 as Amber List (moderate evidence)
Intellectual disability v5.326 RBL2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.326 RBL2 Sarah Leigh Gene: rbl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.325 RBL2 Sarah Leigh edited their review of gene: RBL2: Added comment: RBL2 variants have been associated with Brunet-Wagner neurodevelopmental syndrome (OMIM:619690) but not with phenotype in Gen2Phen. To date six RBL2 variants have been reported in four unrelated cases of OMIM:619690 (PMIDs: 32105419; 33980986).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.325 RBL2 Sarah Leigh Phenotypes for gene: RBL2 were changed from intellectual diability to Brunet-Wagner neurodevelopmental syndrome, OMIM:619690
Intellectual disability v5.324 RBL2 Sarah Leigh Publications for gene: RBL2 were set to 32105419; 9806916
Intellectual disability v5.323 FAM111A Sarah Leigh Tag Q4_23_demote_red tag was added to gene: FAM111A.
Tag Q4_23_NHS_review tag was added to gene: FAM111A.
Severe Paediatric Disorders v1.176 FAM111A Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34382758 reports an autosomal recessive case of Kenny-Caffey Syndrome Type 2. The proband had inherited FAM111A variants from his healthy parents (paternal heterozygous missense
variant c.976T>A (p.L326I) and maternal heterozygous
in-frame deletion variant c.1714_1716del (p.Ile572del,
rs779963813)).
Severe Paediatric Disorders v1.176 FAM111A Sarah Leigh Mode of inheritance for gene: FAM111A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v3.115 FAM111A Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34382758 reports an autosomal recessive case of Kenny-Caffey Syndrome Type 2. The proband had inherited FAM111A variants from his healthy parents (paternal heterozygous missense
variant c.976T>A (p.L326I) and maternal heterozygous
in-frame deletion variant c.1714_1716del (p.Ile572del,
rs779963813)).
Fetal anomalies v3.115 FAM111A Sarah Leigh Mode of inheritance for gene: FAM111A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v3.114 FAM111A Sarah Leigh Publications for gene: FAM111A were set to
Skeletal dysplasia v4.30 FAM111A Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34382758 reports an autosomal recessive case of Kenny-Caffey Syndrome Type 2. The proband had inherited FAM111A variants from his healthy parents (paternal heterozygous missense
variant c.976T>A (p.L326I) and maternal heterozygous
in-frame deletion variant c.1714_1716del (p.Ile572del,
rs779963813)).
Skeletal dysplasia v4.30 FAM111A Sarah Leigh Mode of inheritance for gene: FAM111A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v4.29 FAM111A Sarah Leigh Publications for gene: FAM111A were set to
Intellectual disability v5.323 FAM111A Sarah Leigh Publications for gene: FAM111A were set to 23684011; 23996431; 25529582; 37023242; 34382758
Severe Paediatric Disorders v1.175 FAM111A Sarah Leigh Publications for gene: FAM111A were set to 30847515
Intellectual disability v5.322 FAM111A Sarah Leigh changed review comment from: Intellectual disability is not a feature of Gracile bone dysplasia (OMIM: 602361) or Kenny-Caffey syndrome, type 2 (OMIM: 127000)(PMID: 23684011;23996431;25529582).; to: Intellectual disability is not a feature of Gracile bone dysplasia (OMIM: 602361) or Kenny-Caffey syndrome, type 2 (OMIM: 127000)(PMID: 23684011;23996431;25529582).
PMID: 34382758 reports an autosomal recessive case of Kenny-Caffey Syndrome Type 2. The proband had inherited FAM111A variants from his healthy parents (paternal heterozygous missense
variant c.976T>A (p.L326I) and maternal heterozygous
in-frame deletion variant c.1714_1716del (p.Ile572del,
rs779963813)).
Intellectual disability v5.322 FAM111A Sarah Leigh Publications for gene: FAM111A were set to 23684011; 25529582; 37023242
Intellectual disability v5.321 FAM111A Sarah Leigh reviewed gene: FAM111A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v4.109 GIMAP5 Achchuthan Shanmugasundram Publications for gene: GIMAP5 were set to 33956074
Primary immunodeficiency or monogenic inflammatory bowel disease v4.108 GIMAP5 Achchuthan Shanmugasundram reviewed gene: GIMAP5: Rating: AMBER; Mode of pathogenicity: None; Publications: 29382851, 33956074; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.321 FAM111A Sarah Leigh Publications for gene: FAM111A were set to 23684011
Adult onset neurodegenerative disorder v4.39 DAO Hannah Knight reviewed gene: DAO: Rating: AMBER; Mode of pathogenicity: None; Publications: 28430856, 29895397; Phenotypes: Amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.51 HSPA9 Hannah Knight reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26598328, 32869452, 35779070, 36052765; Phenotypes: Even-plus syndrome 616854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.55 HSPA9 Hannah Knight reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26598328, 32869452, 35779070, 36052765; Phenotypes: Even-plus syndrome 616854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v4.7 MAN2B2 Achchuthan Shanmugasundram Classified gene: MAN2B2 as Amber List (moderate evidence)
Congenital disorders of glycosylation v4.7 MAN2B2 Achchuthan Shanmugasundram Gene: man2b2 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v4.6 MAN2B2 Achchuthan Shanmugasundram gene: MAN2B2 was added
gene: MAN2B2 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to 31775018; 35637269
Phenotypes for gene: MAN2B2 were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: MAN2B2 was set to AMBER
Added comment: There are two different cases reported with biallelic MAN2B2 variants and congenital disorders of glycosylation. The patient reported in PMID:31775018 with homozygous p.Asp38Asn variant presented with immune deficiency, dysmorphic facial features, coagulopathy, and severe developmental delay. Although the patient reported in PMID:35637269 with compound heterozygous variants (p.Ser147del and p.Glu790Lys) had severe developmental delay, dysmorphic facial features as in the previous case, this patient had new features including cleft palate and hypospadias with no immune deficiency.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.108 MAN2B2 Achchuthan Shanmugasundram Phenotypes for gene: MAN2B2 were changed from to congenital disorder of glycosylation, MONDO:0015286
Primary immunodeficiency or monogenic inflammatory bowel disease v4.107 MAN2B2 Achchuthan Shanmugasundram Publications for gene: MAN2B2 were set to PMID: 31775018
Primary immunodeficiency or monogenic inflammatory bowel disease v4.106 MAN2B2 Achchuthan Shanmugasundram Classified gene: MAN2B2 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.106 MAN2B2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case reported with immunodeficiency (PMID:31775018). The patient reported in PMID:35637269 presented with severe developmental delay and dysmorphic facial features as in the previous case, but do not present with immunodeficiency. Hence, this gene can only be rated red with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.106 MAN2B2 Achchuthan Shanmugasundram Gene: man2b2 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 MAN2B2 Achchuthan Shanmugasundram edited their review of gene: MAN2B2: Changed publications to: 31775018
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 MAN2B2 Achchuthan Shanmugasundram reviewed gene: MAN2B2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 SEC61A1 Achchuthan Shanmugasundram Classified gene: SEC61A1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 SEC61A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases in support of the association of this gene with this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.105 SEC61A1 Achchuthan Shanmugasundram Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.104 SEC61A1 Achchuthan Shanmugasundram Phenotypes for gene: SEC61A1 were changed from SEC61A1 deficiency; Severe recurrent respiratory tract infections; Hyperuricemic nephropathy, familial juvenile, 4, 617056; Predominantly Antibody Deficiencies; Severe congenital neutropenia to SEC61A1 deficiency; Severe recurrent respiratory tract infections; Hyperuricemic nephropathy, familial juvenile, 4, 617056; Predominantly Antibody Deficiencies; Hypogammaglobulinaemia; Severe congenital neutropenia
Primary immunodeficiency or monogenic inflammatory bowel disease v4.103 SEC61A1 Achchuthan Shanmugasundram Phenotypes for gene: SEC61A1 were changed from SEC61A1 deficiency; Severe recurrent respiratory tract infections; Hyperuricemic nephropathy, familial juvenile, 4, 617056; Predominantly Antibody Deficiencies to SEC61A1 deficiency; Severe recurrent respiratory tract infections; Hyperuricemic nephropathy, familial juvenile, 4, 617056; Predominantly Antibody Deficiencies; Severe congenital neutropenia
Primary immunodeficiency or monogenic inflammatory bowel disease v4.102 SEC61A1 Achchuthan Shanmugasundram Publications for gene: SEC61A1 were set to 28782633; 32086639; 32048120; 27392076
Primary immunodeficiency or monogenic inflammatory bowel disease v4.101 SEC61A1 Achchuthan Shanmugasundram Mode of inheritance for gene: SEC61A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.100 SEC61A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SEC61A1.
Tag Q4_23_NHS_review tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.100 SEC61A1 Achchuthan Shanmugasundram reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28782633, 32325141; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.100 CD81 Achchuthan Shanmugasundram Classified gene: CD81 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.100 CD81 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and functional evidence available in support of the association of this gene to common variable immunodeficiency (MIM #613496). Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.100 CD81 Achchuthan Shanmugasundram Gene: cd81 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.99 CD81 Achchuthan Shanmugasundram Phenotypes for gene: CD81 were changed from Common variable immunodeficiency disorders (CVID); Immunodeficiency, common variable 6, 613496; hypogammaglobulinaemia; CD81 deficiency; Isolated IgG subclass deficiency; Predominantly Antibody Deficiencies; Recurrent infections, may have glomerulonephritis to Immunodeficiency, common variable, 6, OMIM:613496
Primary immunodeficiency or monogenic inflammatory bowel disease v4.98 CD81 Achchuthan Shanmugasundram Publications for gene: CD81 were set to 27250108; 14530327; 20237408; 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v4.97 CD81 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CD81.
Tag Q4_23_NHS_review tag was added to gene: CD81.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.97 CD81 Achchuthan Shanmugasundram reviewed gene: CD81: Rating: GREEN; Mode of pathogenicity: None; Publications: 20237408, 25739915, 35849269; Phenotypes: Immunodeficiency, common variable, 6, OMIM:613496; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.97 CD4 Achchuthan Shanmugasundram Classified gene: CD4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.97 CD4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and functional evidence in support of the association of this gene with this panel. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.97 CD4 Achchuthan Shanmugasundram Gene: cd4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.96 CD4 Achchuthan Shanmugasundram Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts to Immunodeficiency 79, OMIM:619238; OKT4 epitope deficiency, OMIM:613949
Primary immunodeficiency or monogenic inflammatory bowel disease v4.95 CD4 Achchuthan Shanmugasundram edited their review of gene: CD4: Changed phenotypes to: Immunodeficiency 79, OMIM:619238, OKT4 epitope deficiency, OMIM:613949
Primary immunodeficiency or monogenic inflammatory bowel disease v4.95 CD4 Achchuthan Shanmugasundram Publications for gene: CD4 were set to 31781092
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 CD4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CD4.
Tag Q4_23_NHS_review tag was added to gene: CD4.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 CD4 Achchuthan Shanmugasundram reviewed gene: CD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31781092, 33471124; Phenotypes: Immunodeficiency 79, OMIM:619238; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 REL Achchuthan Shanmugasundram Classified gene: REL as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 REL Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.94 REL Achchuthan Shanmugasundram Gene: rel has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.93 REL Achchuthan Shanmugasundram Phenotypes for gene: REL were changed from Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic infections; c-Rel deficiency; Immunodeficiencies affecting cellular and humoral immunity to Immunodeficiency 92, OMIM:619652
Primary immunodeficiency or monogenic inflammatory bowel disease v4.92 REL Achchuthan Shanmugasundram Publications for gene: REL were set to 32086639; 31103457; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v4.91 REL Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: REL.
Tag Q4_23_NHS_review tag was added to gene: REL.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.91 REL Achchuthan Shanmugasundram reviewed gene: REL: Rating: GREEN; Mode of pathogenicity: None; Publications: 31103457, 34623332; Phenotypes: Immunodeficiency 92, OMIM:619652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.91 FCN3 Achchuthan Shanmugasundram Classified gene: FCN3 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.91 FCN3 Achchuthan Shanmugasundram Gene: fcn3 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.90 FCN3 Achchuthan Shanmugasundram Classified gene: FCN3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.90 FCN3 Achchuthan Shanmugasundram Gene: fcn3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.89 FCN3 Achchuthan Shanmugasundram Phenotypes for gene: FCN3 were changed from Respiratory infections, abscesses; Immunodeficiency due to ficolin 3 deficiency, 613860; Complement Deficiencies; Ficolin3 deficiency to Immunodeficiency due to ficolin 3 deficiency, OMIM:613860
Primary immunodeficiency or monogenic inflammatory bowel disease v4.88 FCN3 Achchuthan Shanmugasundram Publications for gene: FCN3 were set to 22226667; 32048120; 20971976; 19535802; 25662573; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v4.87 FCN3 Achchuthan Shanmugasundram reviewed gene: FCN3: Rating: AMBER; Mode of pathogenicity: None; Publications: 19535802, 20971976, 22226667, 25662573, 29907670, 31408713, 32634042; Phenotypes: Immunodeficiency due to ficolin 3 deficiency, OMIM:613860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.87 TRAF3IP2 Achchuthan Shanmugasundram Classified gene: TRAF3IP2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.87 TRAF3IP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.87 TRAF3IP2 Achchuthan Shanmugasundram Gene: traf3ip2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.86 TRAF3IP2 Achchuthan Shanmugasundram Phenotypes for gene: TRAF3IP2 were changed from Defects in Intrinsic and Innate Immunity; CMC, blepharitis, folliculitis and macroglossia; Chronic mucocutaneous candidiasis (CMC); Defects in intrinsic and innate immunity; ?Candidiasis, familial, 88 615527 to ?Candidiasis, familial, 8, OMIM:615527; Defects in Intrinsic and Innate Immunity; CMC, blepharitis, folliculitis and macroglossia; Chronic mucocutaneous candidiasis (CMC); Defects in intrinsic and innate immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v4.85 TRAF3IP2 Achchuthan Shanmugasundram Phenotypes for gene: TRAF3IP2 were changed from Defects in Intrinsic and Innate Immunity; CMC, blepharitis, folliculitis and macroglossia; Chronic mucocutaneous candidiasis (CMC); Defects in intrinsic and innate immunity; Candidiasis, familial, 8 615527 to Defects in Intrinsic and Innate Immunity; CMC, blepharitis, folliculitis and macroglossia; Chronic mucocutaneous candidiasis (CMC); Defects in intrinsic and innate immunity; ?Candidiasis, familial, 88 615527
Primary immunodeficiency or monogenic inflammatory bowel disease v4.84 TRAF3IP2 Achchuthan Shanmugasundram Publications for gene: TRAF3IP2 were set to 32048120; 24120361; 32086639; 31292894; 20660351
Primary immunodeficiency or monogenic inflammatory bowel disease v4.83 TRAF3IP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TRAF3IP2.
Tag Q4_23_NHS_review tag was added to gene: TRAF3IP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.83 TFRC Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is shared between two different families from different geographic regions reported in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.

The 'founder-effect' tag has also been added to highlight this.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.83 TFRC Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency, they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency (MIM #616740), they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.83 TFRC Achchuthan Shanmugasundram Phenotypes for gene: TFRC were changed from Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity; Immunodeficiency 46, 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia to Immunodeficiency 46, OMIM:616740
Primary immunodeficiency or monogenic inflammatory bowel disease v4.82 TFRC Achchuthan Shanmugasundram Publications for gene: TFRC were set to 32086639; 26642240; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v4.81 TFRC Achchuthan Shanmugasundram Classified gene: TFRC as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.81 TFRC Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there were eight unrelated families reported with immunodeficiency, they all harboured the same homozygous variant p.Tyr20His. Functional studies and mouse model provide supporting evidence in associating TFRC with green rating in this panel.

Although this variant is found in a homozygous region that is identified between two different families from different geographic regions in PMID:26642240, the segregation of this variant with the phenotype supports this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.81 TFRC Achchuthan Shanmugasundram Gene: tfrc has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 TFRC Achchuthan Shanmugasundram changed review comment from: PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the combined immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls.

The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor.

Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts.

In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype.


PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel).; to: PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls.

The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor.

Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts.

In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype.


PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 TFRC Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: TFRC.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 TFRC Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TFRC.
Tag Q4_23_NHS_review tag was added to gene: TFRC.
Mosaic skin disorders - deep sequencing v2.41 GNB2 Arina Puzriakova Classified gene: GNB2 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.41 GNB2 Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber in line with review by Tom Cullup (GOSH) to facilitate further gathering of data where appropriate which could potentially support future promotion to Green.
Mosaic skin disorders - deep sequencing v2.41 GNB2 Arina Puzriakova Gene: gnb2 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.40 EGFR Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Tom Cullup (GOSH). Rating Amber inline with his review. Single individual (PMID: 31745974) with nonepidermolytic keratinocytic epidermal naevi and a postzygotic variant in EGFR.; to: Comment on list classification: New gene added by Tom Cullup (GOSH). Rating Amber inline with this review to facilitate further gathering of data where appropriate which could potentially support future promotion to Green. Single individual (PMID: 31745974) with nonepidermolytic keratinocytic epidermal naevi and a postzygotic variant in EGFR.
Mosaic skin disorders - deep sequencing v2.40 EGFR Arina Puzriakova Classified gene: EGFR as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.40 EGFR Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Rating Amber inline with his review. Single individual (PMID: 31745974) with nonepidermolytic keratinocytic epidermal naevi and a postzygotic variant in EGFR.
Mosaic skin disorders - deep sequencing v2.40 EGFR Arina Puzriakova Gene: egfr has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v3.4 EGFR Arina Puzriakova Phenotypes for gene: EGFR were changed from INFLAMMATORY SKIN AND BOWEL DISEASE, NEONATAL, 2, MONDO:0014481 to ?Inflammatory skin and bowel disease, neonatal, 2, OMIM:616069
Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 TFRC Achchuthan Shanmugasundram reviewed gene: TFRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642240, 32851577; Phenotypes: Immunodeficiency 46, OMIM:616740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 SPI1 Achchuthan Shanmugasundram Phenotypes for gene: SPI1 were changed from Agammaglobulinemia to Agammaglobulinemia 10, autosomal dominant, OMIM:619707
Primary immunodeficiency or monogenic inflammatory bowel disease v4.79 SPI1 Achchuthan Shanmugasundram Mode of inheritance for gene: SPI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.78 SPI1 Achchuthan Shanmugasundram Tag watchlist was removed from gene: SPI1.
Tag Q4_23_promote_green tag was added to gene: SPI1.
Tag Q4_23_NHS_review tag was added to gene: SPI1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.78 SPI1 Achchuthan Shanmugasundram Classified gene: SPI1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.78 SPI1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, PMID:33951726 is now publicly available online and have six unrelated cases and some functional data in support of the disease association. Hence, this gene can be promoted to green rating in the next GMS review.

The 'watchlist' tag has now been removed as this gene is now recommended for promotion to green rating.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.78 SPI1 Achchuthan Shanmugasundram Gene: spi1 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.9 PROP1 Zornitza Stark reviewed gene: PROP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15941866, 11549703; Phenotypes: Pituitary hormone deficiency, combined, 2 (MIM#262600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism (GMS) v3.9 NDNF Zornitza Stark reviewed gene: NDNF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31883645; Phenotypes: Hypogonadotropic hypogonadism 25 with anosmia MIM#618841; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v3.9 CUL4B Zornitza Stark reviewed gene: CUL4B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25385192; Phenotypes: Mental retardation, X-linked, syndromic 15 (Cabezas type) 300354; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v3.18 FAM83G Arina Puzriakova Publications for gene: FAM83G were set to
Palmoplantar keratodermas v3.15 FAM83G Arina Puzriakova Publications for gene: FAM83G were set to 29138053
Palmoplantar keratodermas v3.14 FAM83G Arina Puzriakova Classified gene: FAM83G as Amber List (moderate evidence)
Palmoplantar keratodermas v3.14 FAM83G Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber inline with expert review by Tom Cullup (GOSH) to facilitate further gathering of data where appropriate which could potentially support future promotion to Green.
Palmoplantar keratodermas v3.14 FAM83G Arina Puzriakova Gene: fam83g has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.17 FAM83G Arina Puzriakova Classified gene: FAM83G as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.17 FAM83G Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber inline with expert review by Tom Cullup (GOSH) to facilitate further gathering of data where appropriate which could potentially support future promotion to Green.
Ichthyosis and erythrokeratoderma v3.17 FAM83G Arina Puzriakova Gene: fam83g has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: FLG2.
Tag Q4_23_NHS_review tag was added to gene: FLG2.
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Classified gene: FLG2 as Amber List (moderate evidence)
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review.
Palmoplantar keratodermas v3.13 FLG2 Arina Puzriakova Gene: flg2 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v3.12 FLG2 Arina Puzriakova Publications for gene: FLG2 were set to PubMed: 28884927; 29505760
Palmoplantar keratodermas v3.11 FLG2 Arina Puzriakova Phenotypes for gene: FLG2 were changed from peeling skin syndrome-6 (PSS6) (MIM 618084) to Peeling skin syndrome 6, OMIM: 618084
Ichthyosis and erythrokeratoderma v3.16 TGM5 Arina Puzriakova Publications for gene: TGM5 were set to PubMed: 16380904; 19440220; 20164844; 22036214
Palmoplantar keratodermas v3.10 TGM5 Arina Puzriakova Publications for gene: TGM5 were set to PubMed: 16380904; 19440220; 20164844; 22036214
Ichthyosis and erythrokeratoderma v3.15 TGM5 Arina Puzriakova Phenotypes for gene: TGM5 were changed from Peeling skin syndrome 2 to Peeling skin syndrome 2, OMIM:609796
Palmoplantar keratodermas v3.9 TGM5 Arina Puzriakova Phenotypes for gene: TGM5 were changed from Peeling skin syndrome 2 to Peeling skin syndrome 2, OMIM:609796
Palmoplantar keratodermas v3.8 TGM5 Arina Puzriakova Classified gene: TGM5 as Amber List (moderate evidence)
Palmoplantar keratodermas v3.8 TGM5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review.
Palmoplantar keratodermas v3.8 TGM5 Arina Puzriakova Gene: tgm5 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.14 TGM5 Arina Puzriakova Classified gene: TGM5 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.14 TGM5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review.
Ichthyosis and erythrokeratoderma v3.14 TGM5 Arina Puzriakova Gene: tgm5 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.13 TGM5 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: TGM5.
Tag Q4_23_NHS_review tag was added to gene: TGM5.
Palmoplantar keratodermas v3.7 TGM5 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: TGM5.
Tag Q4_23_NHS_review tag was added to gene: TGM5.
Palmoplantar keratodermas v3.7 SERPINB8 Arina Puzriakova Phenotypes for gene: SERPINB8 were changed from Peeling skin syndrome 5 to Peeling skin syndrome 5, OMIM:617115
Palmoplantar keratodermas v3.6 SERPINB8 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: SERPINB8.
Tag Q4_23_NHS_review tag was added to gene: SERPINB8.
Palmoplantar keratodermas v3.6 SERPINB8 Arina Puzriakova Classified gene: SERPINB8 as Amber List (moderate evidence)
Palmoplantar keratodermas v3.6 SERPINB8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review. Some patients exhibit diffuse yellowish hyperkeratotic palmoplantar plaques.
Palmoplantar keratodermas v3.6 SERPINB8 Arina Puzriakova Gene: serpinb8 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.13 SERPINB8 Arina Puzriakova Classified gene: SERPINB8 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.13 SERPINB8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review.
Ichthyosis and erythrokeratoderma v3.13 SERPINB8 Arina Puzriakova Gene: serpinb8 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.12 SERPINB8 Arina Puzriakova Phenotypes for gene: SERPINB8 were changed from Peeling skin syndrome 5 to Peeling skin syndrome 5, OMIM:617115
Ichthyosis and erythrokeratoderma v3.11 SERPINB8 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: SERPINB8.
Tag Q4_23_NHS_review tag was added to gene: SERPINB8.
Ichthyosis and erythrokeratoderma v3.11 CSTA Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: CSTA.
Tag Q4_23_NHS_review tag was added to gene: CSTA.
Ichthyosis and erythrokeratoderma v3.11 CSTA Arina Puzriakova Classified gene: CSTA as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.11 CSTA Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review.
Ichthyosis and erythrokeratoderma v3.11 CSTA Arina Puzriakova Gene: csta has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.10 CSTA Arina Puzriakova Phenotypes for gene: CSTA were changed from peeling skin syndrome-4 (PSS4) to Peeling skin syndrome 4, OMIM:607936
Ichthyosis and erythrokeratoderma v3.9 CDSN Arina Puzriakova Phenotypes for gene: CDSN were changed from Hypotrichosis 2; Peeling skin syndrome 1 to Peeling skin syndrome 1, OMIM:270300
Severe Paediatric Disorders v1.174 SLC12A3 Achchuthan Shanmugasundram Tag monogenic - polygenic was removed from gene: SLC12A3.
Tag monogenic-polygenic tag was added to gene: SLC12A3.
Childhood onset dystonia, chorea or related movement disorder v3.55 SLC12A3 Achchuthan Shanmugasundram Tag monogenic - polygenic was removed from gene: SLC12A3.
Tag monogenic-polygenic tag was added to gene: SLC12A3.
Ichthyosis and erythrokeratoderma v3.8 CDSN Arina Puzriakova Mode of inheritance for gene: CDSN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v3.7 CDSN Arina Puzriakova Classified gene: CDSN as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.7 CDSN Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Based on the recommendation by the specialist team that all genes causing peeling skin syndrome should be included on this panel, and that there is sufficient evidence of a gene:disease association, this gene should be promoted to Green at the next GMS review.

Changing MOI from 'BOTH mono- and biallelic' to 'BIALLELIC' as monoallelic variants are associated with hypotrichosis simplex of the scalp without other abnormalities (MIM# 146520).
Ichthyosis and erythrokeratoderma v3.7 CDSN Arina Puzriakova Gene: cdsn has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v4.17 SLC12A3 Achchuthan Shanmugasundram Tag monogenic - polygenic was removed from gene: SLC12A3.
Tag monogenic-polygenic tag was added to gene: SLC12A3.
Likely inborn error of metabolism - targeted testing not possible v4.55 SLC12A3 Achchuthan Shanmugasundram Tag monogenic - polygenic was removed from gene: SLC12A3.
Tag monogenic-polygenic tag was added to gene: SLC12A3.
Undiagnosed metabolic disorders v1.601 SLC12A3 Achchuthan Shanmugasundram Tag monogenic - polygenic was removed from gene: SLC12A3.
Tag monogenic-polygenic tag was added to gene: SLC12A3.
Ductal plate malformation v1.27 SLC12A3 Achchuthan Shanmugasundram Tag monogenic - polygenic was removed from gene: SLC12A3.
Tag monogenic-polygenic tag was added to gene: SLC12A3.
Ichthyosis and erythrokeratoderma v3.6 CDSN Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: CDSN.
Tag Q4_23_NHS_review tag was added to gene: CDSN.
Hypogonadotropic hypogonadism (GMS) v3.9 ARHGAP35 Achchuthan Shanmugasundram Classified gene: ARHGAP35 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v3.9 ARHGAP35 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for promoting this gene to green rating in the next GMS review.
Hypogonadotropic hypogonadism (GMS) v3.9 ARHGAP35 Achchuthan Shanmugasundram Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.8 ARHGAP35 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ARHGAP35.
Tag Q4_23_NHS_review tag was added to gene: ARHGAP35.
Hypogonadotropic hypogonadism (GMS) v3.8 ARHGAP35 Achchuthan Shanmugasundram gene: ARHGAP35 was added
gene: ARHGAP35 was added to Hypogonadotropic hypogonadism (GMS). Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 36178483
Phenotypes for gene: ARHGAP35 were set to hypogonadotropic hypogonadism, MONDO:0018555
Review for gene: ARHGAP35 was set to GREEN
Added comment: 16 patients from 13 different families were reported with idiopathic hypogonadotropic hypogonadism (9 with IHH and 7 with Kallmann syndrome (IHH + anosmia)) and with monoallelic ARHGAP35 variants. Rare protein-truncating variants and missense variants were found in the RhoGAP domain of ARHGAP35 gene.

Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a (predominant ARHGAP35 paralog in zebrafish brain), displayed decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant (Arg1284Trp) had decreased GAP activity.

This gene has not yet been associated with this phenotype either in OMIM or in Gene2Phenotype. However, this gene has been associated with ARHGAP35-related developmental disorder in DD panel of G2P (with 'definitive' rating).
Sources: Literature
Structural eye disease v3.56 RHOA Sarah Leigh Tag watchlist was removed from gene: RHOA.
Tag mosaicism tag was added to gene: RHOA.
Tag Q4_23_promote_green tag was added to gene: RHOA.
Tag Q4_23_NHS_review tag was added to gene: RHOA.
Structural eye disease v3.56 RHOA Sarah Leigh changed review comment from: RHOA variants have been associated with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic (OMIM:618727). Ocular involvement has been reported at least three unrelated cases carrying different RHOA variants (PMID: 31821646; 31570889; 35178721).; to: RHOA variants have been associated with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic (OMIM:618727). Ocular involvement has been reported at least three unrelated cases carrying different RHOA variants (PMID: 31821646; 31570889; 35178721).
Structural eye disease v3.56 RHOA Sarah Leigh edited their review of gene: RHOA: Added comment: RHOA variants have been associated with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic (OMIM:618727). Ocular involvement has been reported at least three unrelated cases carrying different RHOA variants (PMID: 31821646; 31570889; 35178721).; Changed rating: GREEN
Structural eye disease v3.56 RHOA Sarah Leigh Classified gene: RHOA as Amber List (moderate evidence)
Structural eye disease v3.56 RHOA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Structural eye disease v3.56 RHOA Sarah Leigh Gene: rhoa has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.55 RHOA Sarah Leigh Publications for gene: RHOA were set to 31821646; 31570889
Structural eye disease v3.54 PQBP1 Sarah Leigh reviewed gene: PQBP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Structural eye disease v3.54 PQBP1 Sarah Leigh Phenotypes for gene: PQBP1 were changed from Renpenning syndrome (can include microphthalmia/coloboma), 309500 to Renpenning syndrome, OMIM:309500; Renpenning syndrome, MONDO:0010653
Primary immunodeficiency or monogenic inflammatory bowel disease v4.77 SAMD9L Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SAMD9L.
Tag Q4_23_NHS_review tag was added to gene: SAMD9L.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.77 SAMD9L Achchuthan Shanmugasundram Classified gene: SAMD9L as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.77 SAMD9L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.77 SAMD9L Achchuthan Shanmugasundram Gene: samd9l has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.53 PQBP1 Sarah Leigh Publications for gene: PQBP1 were set to 17033686
Primary immunodeficiency or monogenic inflammatory bowel disease v4.76 SAMD9L Achchuthan Shanmugasundram Mode of inheritance for gene: SAMD9L was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.75 SAMD9L Achchuthan Shanmugasundram reviewed gene: SAMD9L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autoinflammatory syndrome, MONDO:0019751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.75 SAMD9L Achchuthan Shanmugasundram Publications for gene: SAMD9L were set to 32048120; 28202457; 32086639
Structural eye disease v3.52 NUP188 Sarah Leigh Tag watchlist was removed from gene: NUP188.
Tag Q4_23_promote_green tag was added to gene: NUP188.
Tag Q4_23_NHS_review tag was added to gene: NUP188.
Structural eye disease v3.52 NUP188 Sarah Leigh edited their review of gene: NUP188: Added comment: NUP188 biallelic terminating variants have been associated with Sandestig-Stefanova syndrome (OMIM:618804). PMID: 36158057 describes the first male case of Sandestig-Stefanova syndrome and presents a literature review, that shows that microphthalmia (8/8 cases) and bilateral congenital cataracts (6/8 cases) are commonly reported in patients with biallelic NUP188 variants.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v3.52 NUP188 Sarah Leigh Classified gene: NUP188 as Amber List (moderate evidence)
Structural eye disease v3.52 NUP188 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Structural eye disease v3.52 NUP188 Sarah Leigh Gene: nup188 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.51 NUP188 Sarah Leigh Publications for gene: NUP188 were set to 32021605; 32275884
Structural eye disease v3.50 KDM6A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: KDM6A.
Tag Q4_23_promote_green tag was added to gene: KDM6A.
Tag Q4_23_NHS_review tag was added to gene: KDM6A.
Structural eye disease v3.50 KDM6A Sarah Leigh Publications for gene: KDM6A were set to 22197486; 29617172; 29300383; 23076834; 24664873; 36672956
Structural eye disease v3.49 KDM6A Sarah Leigh changed review comment from: PMID: 36672956, 29300383, 24664873, 23076834 together report four KDM6A variants in four cases (3 male, 1 female), where the subject manifests ocular phenotypes, including: long palpebral fissures, nystagmus, bilateral coloboma, unilateral microphthalmia, nystagmus, sparse eyebrows, long eyelashes, ectropion of the lower eyelids, myopia, strabismus, arched eyebrows. PMID: 22197486 reports ocular features in three cases with microdeletions that included KDM6A, together with other genes.; to: PMID: 36672956, 29300383, 24664873, 23076834 together report four KDM6A variants in four cases (3 male, 1 female), where the subject manifests ocular phenotypes, including: long palpebral fissures, nystagmus, bilateral coloboma, unilateral microphthalmia, nystagmus, sparse eyebrows, long eyelashes, ectropion of the lower eyelids, myopia, strabismus, arched eyebrows. PMID: 22197486 reports ocular features in three cases with microdeletions that included KDM6A, together with other genes.
Skewed X-inactivation has also been reported at this locus (PMID: 22197486, 23913813).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.74 JAK1 Achchuthan Shanmugasundram Classified gene: JAK1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.74 JAK1 Achchuthan Shanmugasundram Gene: jak1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.73 JAK1 Achchuthan Shanmugasundram Phenotypes for gene: JAK1 were changed from Susceptibility to mycobacteria and viruses, urothelial carcinoma; Hypereosinophilic syndrome; Defects in Intrinsic and Innate Immunity; Diseases of Immune Dysregulation; HSM, eosinophilic enteritis, thyroid disease, poor growth, viral infections; HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections to Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999
Primary immunodeficiency or monogenic inflammatory bowel disease v4.72 JAK1 Achchuthan Shanmugasundram Publications for gene: JAK1 were set to 32086639; 28111307; 32048120; 28008925; 30671064; 32750333; 34496019; 35046931
Primary immunodeficiency or monogenic inflammatory bowel disease v4.71 JAK1 Achchuthan Shanmugasundram Publications for gene: JAK1 were set to 32086639; 28111307; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v4.70 JAK1 Achchuthan Shanmugasundram changed review comment from: Comment on mode of pathogenicity: Two of monoallelic variants were shown to be gain-of-function, one is mosaic and the other is somatic. Hence, MOP is set as 'Other'. In addition, 'mosaicsm' and 'somatic' tags were added.; to: Comment on mode of pathogenicity: Two of monoallelic variants were shown to be gain-of-function, one is mosaic and the other is somatic. Hence, MOP is set as 'Other'. In addition, 'mosaicism' and 'somatic' tags were added.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.70 JAK1 Achchuthan Shanmugasundram Tag mosaicism tag was added to gene: JAK1.
Tag somatic tag was added to gene: JAK1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.70 JAK1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: JAK1 was changed from None to Other
Primary immunodeficiency or monogenic inflammatory bowel disease v4.69 JAK1 Achchuthan Shanmugasundram Added comment: Comment on mode of pathogenicity: Two of monoallelic variants were shown to be gain-of-function, one is mosaic and the other is somatic. Hence, MOP is set as 'Other'. In addition, 'mosaicsm' and 'somatic' tags were added.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.69 JAK1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: JAK1 was changed from Other - please provide details in the comments to None
Primary immunodeficiency or monogenic inflammatory bowel disease v4.68 JAK1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of monoallelic variants in this gene to Autoinflammation, immune dysregulation, and eosinophilia (MIM #618999). However, the evidence for the association of biallelic variants is not sufficient for green rating. Hence, the MOI is set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.68 JAK1 Achchuthan Shanmugasundram Mode of inheritance for gene: JAK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.67 JAK1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: JAK1.
Tag Q4_23_NHS_review tag was added to gene: JAK1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.67 JAK1 Achchuthan Shanmugasundram reviewed gene: JAK1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28008925, 28111307, 30671064, 32750333, 34496019, 35046931; Phenotypes: Autoinflammation, immune dysregulation, and eosinophilia, OMIM:618999; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.67 PSMB10 Achchuthan Shanmugasundram Classified gene: PSMB10 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.67 PSMB10 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence for the promotion of this gene to green rating in this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.67 PSMB10 Achchuthan Shanmugasundram Gene: psmb10 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.66 PSMB10 Achchuthan Shanmugasundram Phenotypes for gene: PSMB10 were changed from Proteasome-associated autoinflammatory syndrome (PRAAS) to Proteasome-associated autoinflammatory syndrome 5, OMIM:619175
Primary immunodeficiency or monogenic inflammatory bowel disease v4.65 PSMB10 Achchuthan Shanmugasundram Publications for gene: PSMB10 were set to 31783057
Primary immunodeficiency or monogenic inflammatory bowel disease v4.64 PSMB10 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PSMB10.
Tag Q4_23_NHS_review tag was added to gene: PSMB10.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.64 PSMB10 Achchuthan Shanmugasundram reviewed gene: PSMB10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Proteasome-associated autoinflammatory syndrome 5, OMIM:619175; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.64 NFAT5 Achchuthan Shanmugasundram Tag watchlist was removed from gene: NFAT5.
Tag Q4_23_promote_green tag was added to gene: NFAT5.
Tag Q4_23_NHS_review tag was added to gene: NFAT5.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.64 NFAT5 Achchuthan Shanmugasundram Classified gene: NFAT5 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.64 NFAT5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.64 NFAT5 Achchuthan Shanmugasundram Gene: nfat5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.63 NFAT5 Achchuthan Shanmugasundram Publications for gene: NFAT5 were set to 32086639; 25667416; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v4.62 NFAT5 Achchuthan Shanmugasundram Mode of inheritance for gene: NFAT5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.61 NFAT5 Achchuthan Shanmugasundram reviewed gene: NFAT5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25667416, 36238298; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.61 IRF4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IRF4.
Tag Q4_23_NHS_review tag was added to gene: IRF4.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.61 IRF4 Achchuthan Shanmugasundram Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724 to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v4.60 IRF4 Achchuthan Shanmugasundram Publications for gene: IRF4 were set to 29537367; 31953710
Primary immunodeficiency or monogenic inflammatory bowel disease v4.59 IRF4 Achchuthan Shanmugasundram Classified gene: IRF4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.59 IRF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two different heterozygous missense variants identified from seven unrelated cases reported with hypogammaglobulinemia/ combined immunodeficiency. In addition, there is supporting functional evidence for these variants. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.59 IRF4 Achchuthan Shanmugasundram Gene: irf4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.58 IRF4 Achchuthan Shanmugasundram reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.41 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Severe microcephaly v4.41 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with severe microcephaly. Hence, this gene can be promoted to green rating in this panel in the next GMS review.
Severe microcephaly v4.41 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.40 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499
Severe microcephaly v4.39 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ARF3.
Severe microcephaly v4.39 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, microcephaly, MONDO:0001149; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>3 unrelated cases and supporting functional evidence) for the promotion of this gene to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>3 unrelated cases and supporting functional evidence) for the promotion of this gene to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>3 unrelated cases and supporting functional evidence) for the promotion of this gene to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.125 ARF3 Achchuthan Shanmugasundram Tag watchlist was removed from gene: ARF3.
Tag Q4_23_promote_green tag was added to gene: ARF3.
Early onset or syndromic epilepsy v4.125 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499
Early onset or syndromic epilepsy v4.124 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34346499, 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Tag watchlist was removed from gene: ARF3.
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability v5.320 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.319 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ARF3.
Intellectual disability v5.319 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499; 36369169
Intellectual disability v5.319 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499
Intellectual disability v5.318 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia with onset in adulthood v4.26 FGF14_GAA Eleanor Williams Tag Q1_23_promote_green was removed from STR: FGF14_GAA.
Tag Q1_23_expert_review was removed from STR: FGF14_GAA.
Tag Q1_23_NHS_review was removed from STR: FGF14_GAA.
Tag watchlist tag was added to STR: FGF14_GAA.
Hereditary ataxia with onset in adulthood v4.26 FGF14_GAA Eleanor Williams commented on STR: FGF14_GAA: After NHS Genomic Medicine Service consideration, the rating of this STR has not been changed and remains Amber.

Comments from review:
Agree that the expansion is likely disease causing. However only a small number of cases have been used to define the number of repeats that could be considered pathogenic. Would recommend that more cases should be identified to better define the pathogenic repeat lengths of this STR. Perhaps study in 100,000 Genomes and GMS data would provide additional cases.

Agree that alleles >250 rpts are of interest and those >300 likely to be diagnostic but concerned that Expansion Hunter will not be able to provide accurate sizing beyond a threshold well below this (~100 repeats). See Supplementary figure S2 of PMID 36493768 for an illustration of this. Can ExpansionHunterDeNovo do better using paired IRRs (PMID PMID: 32345345), or can Expansion Hunter be adapted to factor-in paired IRRs to give a better prediction of expansion size? PCR based assays will also be essential for confirmation and sizing of any repeats detected, not currently available diagnostically to our knowledge.
Likely inborn error of metabolism - targeted testing not possible v4.55 SLC6A20 Eleanor Williams commented on gene: SLC6A20: Added the gene-checked tag as this is the right gene on the panel, even though it probably should be demoted.
Likely inborn error of metabolism - targeted testing not possible v4.55 SLC6A20 Eleanor Williams Tag gene-checked tag was added to gene: SLC6A20.
Structural eye disease v3.49 KDM6A Sarah Leigh edited their review of gene: KDM6A: Added comment: PMID: 36672956, 29300383, 24664873, 23076834 together report four KDM6A variants in four cases (3 male, 1 female), where the subject manifests ocular phenotypes, including: long palpebral fissures, nystagmus, bilateral coloboma, unilateral microphthalmia, nystagmus, sparse eyebrows, long eyelashes, ectropion of the lower eyelids, myopia, strabismus, arched eyebrows. PMID: 22197486 reports ocular features in three cases with microdeletions that included KDM6A, together with other genes.; Changed rating: GREEN; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Structural eye disease v3.49 KDM6A Sarah Leigh Classified gene: KDM6A as Amber List (moderate evidence)
Structural eye disease v3.49 KDM6A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Structural eye disease v3.49 KDM6A Sarah Leigh Gene: kdm6a has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.2 MDH2 Terri McVeigh reviewed gene: MDH2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.2 DLST Terri McVeigh reviewed gene: DLST: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inherited phaeochromocytoma and paraganglioma excluding NF1 v2.2 SLC25A11 Terri McVeigh reviewed gene: SLC25A11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.318 RBL2 Mike Spiller reviewed gene: RBL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32105419, PMID: 33980986; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v3.76 KCNH5 Eleanor Williams Phenotypes for gene: KCNH5 were changed from INFANTILE EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 112, OMIM:620537
Arthrogryposis v5.19 ADAMTS15 Arina Puzriakova Phenotypes for gene: ADAMTS15 were changed from distal arthrogryposis to Arthrogryposis, distal, type 12, OMIM:620545
Arthrogryposis v5.18 ADAMTS15 Arina Puzriakova Tag gene-checked was removed from gene: ADAMTS15.
Intellectual disability v5.317 KCNH5 Arina Puzriakova Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to Developmental and epileptic encephalopathy 112, OMIM:620537
Early onset or syndromic epilepsy v4.122 KCNH5 Arina Puzriakova Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027 to Developmental and epileptic encephalopathy 112, OMIM:620537
DDG2P v3.74 KCNH5 Arina Puzriakova Tag gene-checked was removed from gene: KCNH5.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.57 MCTS1 Boaz Palterer gene: MCTS1 was added
gene: MCTS1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: MCTS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: MCTS1 were set to MSMD; non tubercular mycobacteria infection; BCGtis; BCG infection
Penetrance for gene: MCTS1 were set to Complete
Review for gene: MCTS1 was set to GREEN
Added comment: Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria
https://doi.org/10.1016/j.cell.2023.09.024

Bohlen et al. identified 6 male subjects from 5 kindreds with LOF MCTS-1 variants with MSMD.
Extensive ex-vivo functional validation and mouse model.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.57 CBLB Boaz Palterer gene: CBLB was added
gene: CBLB was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CBLB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBLB were set to 36006710
Phenotypes for gene: CBLB were set to immunedysregulation; autoimmunity; hypothyroidism; diabetes mellitus type I; vitiligo; urticaria; HLH; ITP; autoimmune hemolytic anemia
Penetrance for gene: CBLB were set to unknown
Review for gene: CBLB was set to RED
Added comment: Janssen et al. described 3 unrelated children with early-onset autoimmunity with homozygous CBLB variants. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking.

Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient’s p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.57 FGL2 Boaz Palterer gene: FGL2 was added
gene: FGL2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: FGL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGL2 were set to 36243222
Phenotypes for gene: FGL2 were set to immunedysregulation; autoimmunity; arthritis; Treg dysfunction; leukocytoclastic vasculitis
Penetrance for gene: FGL2 were set to unknown
Review for gene: FGL2 was set to RED
Added comment: One subject from one kindred with homozygous truncating FGL2 variant. Some in vitro phenotype rescue and mouse model.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.56 RELA Achchuthan Shanmugasundram Classified gene: RELA as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.56 RELA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are at least eight unrelated cases identified with monoallelic RELA variants and reported with chronic mucocutaneous ulceration (MIM #618287). Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.56 RELA Achchuthan Shanmugasundram Gene: rela has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.55 RELA Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RELA.
Tag Q4_23_NHS_review tag was added to gene: RELA.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.55 RELA Achchuthan Shanmugasundram Publications for gene: RELA were set to 28600438; 32086639; 32048120; 29305315
Primary immunodeficiency or monogenic inflammatory bowel disease v4.54 RELA Achchuthan Shanmugasundram Mode of inheritance for gene: RELA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.315 DOCK8 Dmitrijs Rots reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.46 KDM6A Sarah Leigh Publications for gene: KDM6A were set to 29617172; 29300383; 36672956
Structural eye disease v3.45 KDM6A Sarah Leigh Phenotypes for gene: KDM6A were changed from Kabuki Syndrome 2, KABUK2, 300867 to Kabuki syndrome 2, OMIM:300867; Kabuki syndrome 2, MONDO:0010465
Structural eye disease v3.44 KDM6A Sarah Leigh Publications for gene: KDM6A were set to 29617172; 29300383
Structural eye disease v3.43 GDF3 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: GDF3.
Tag Q4_23_NHS_review tag was added to gene: GDF3.
Structural eye disease v3.43 GDF3 Sarah Leigh Classified gene: GDF3 as Amber List (moderate evidence)
Structural eye disease v3.43 GDF3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Structural eye disease v3.43 GDF3 Sarah Leigh Gene: gdf3 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.42 GDF3 Sarah Leigh reviewed gene: GDF3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Structural eye disease v3.42 GDF3 Sarah Leigh Phenotypes for gene: GDF3 were changed from Klippel-Feil Syndrome3, 613702; Klippel-Feil syndrome 3, autosomal dominant, 613702; Microphthalmia with coloboma 6, 613703; Microphthalmia, isolated 7, 613704 to Klippel-Feil syndrome 3, autosomal dominant, OMIM:613702; Klippel-Feil syndrome 3, autosomal dominant, MONDO:0013375; Microphthalmia with coloboma 6, OMIM:613703; microphthalmia, isolated, with coloboma 6, MONDO:0013376; Microphthalmia, isolated 7, OMIM:613704; isolated microphthalmia 7, MONDO:0013377
Structural eye disease v3.41 GDF3 Sarah Leigh Publications for gene: GDF3 were set to 19864492
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ARX.
Early onset dystonia v1.146 ARX Sarah Leigh Classified gene: ARX as Green List (high evidence)
Early onset dystonia v1.146 ARX Sarah Leigh Gene: arx has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.16 ARX Sarah Leigh commented on gene: ARX: A review by Eldar Dedic (Independent Clinical Genetics Consultant):
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh changed review comment from: A review by Eldar Dedic (Independent Clinical Genetics Consultant)
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021; to: A review by Eldar Dedic (Independent Clinical Genetics Consultant):
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh commented on gene: ARX: A review by Eldar Dedic (Independent Clinical Genetics Consultant)
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: None; Publications: 31324350, 29778428, 23657928, 29343471; Phenotypes: ; Mode of inheritance: None
Adult onset dystonia, chorea or related movement disorder v3.16 ARX Sarah Leigh reviewed gene: ARX: Rating: AMBER; Mode of pathogenicity: None; Publications: 31324350, 29778428, 23657928, 29343471; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Adult onset dystonia, chorea or related movement disorder v3.16 ARX Sarah Leigh Mode of inheritance for gene: ARX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset dystonia v1.145 ARX Sarah Leigh Phenotypes for gene: ARX were changed from Dystonia to Developmental and epileptic encephalopathy 1, OMIM:308350; X-linked spasticity-intellectual disability-epilepsy syndromeMONDO:0017856; Partington syndrome, OMIM:309510; Partington syndrome, MONDO:0010654
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh Phenotypes for gene: ARX were changed from Partington Syndrome, 300382 to Developmental and epileptic encephalopathy 1, OMIM:308350; X-linked spasticity-intellectual disability-epilepsy syndromeMONDO:0017856; Partington syndrome, OMIM:309510; Partington syndrome, MONDO:0010654
Adult onset dystonia, chorea or related movement disorder v3.15 ARX Sarah Leigh Phenotypes for gene: ARX were changed from Partington Syndrome, OMIM:309510 to Developmental and epileptic encephalopathy 1, OMIM:308350; X-linked spasticity-intellectual disability-epilepsy syndromeMONDO:0017856; Partington syndrome, OMIM:309510; Partington syndrome, MONDO:0010654
Childhood onset dystonia, chorea or related movement disorder v3.52 ARX Sarah Leigh Publications for gene: ARX were set to
Adult onset dystonia, chorea or related movement disorder v3.14 ARX Sarah Leigh Publications for gene: ARX were set to 29343471; 17664398; 26029707
Early onset dystonia v1.144 ARX Sarah Leigh Publications for gene: ARX were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.53 FMNL2 Hannah Knight gene: FMNL2 was added
gene: FMNL2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: FMNL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FMNL2 were set to 34043722
Phenotypes for gene: FMNL2 were set to Severe very early onset inflammatory bowel disease
Review for gene: FMNL2 was set to AMBER
Added comment: PMID: 34043722 reported a patient who presented with severe very early onset inflammatory bowel disease, with a de novo heterozygous FMNL2 variant (p.Leu136Pro)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.53 NFAT5 Hannah Knight reviewed gene: NFAT5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36238298; Phenotypes: NFAT5 haploinsufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset dystonia v1.143 FOXG1 Arina Puzriakova Phenotypes for gene: FOXG1 were changed from Dystonia to Rett Syndrome, congenital variant OMIM:613454
Early onset dystonia v1.142 FOXG1 Arina Puzriakova Publications for gene: FOXG1 were set to
Childhood onset dystonia, chorea or related movement disorder v3.51 FOXG1 Arina Puzriakova Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037; 27029630
Early onset dystonia v1.141 FOXG1 Arina Puzriakova Classified gene: FOXG1 as Green List (high evidence)
Early onset dystonia v1.141 FOXG1 Arina Puzriakova Gene: foxg1 has been classified as Green List (High Evidence).
Early onset dystonia v1.140 FOXG1 Arina Puzriakova Classified gene: FOXG1 as Red List (low evidence)
Early onset dystonia v1.140 FOXG1 Arina Puzriakova Added comment: Comment on list classification: Upgrading the rating from red to green as there is enough evidence to support the gene-disease association. Also green on the childhood dystonia GMS panel (R57).
Early onset dystonia v1.140 FOXG1 Arina Puzriakova Gene: foxg1 has been classified as Red List (Low Evidence).
Early onset dystonia v1.139 FOXG1 Arina Puzriakova Mode of inheritance for gene: FOXG1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset dystonia v1.138 AFG3L2 Arina Puzriakova Classified gene: AFG3L2 as Green List (high evidence)
Early onset dystonia v1.138 AFG3L2 Arina Puzriakova Added comment: Comment on list classification: Associated with AR and AD ataxia. Dystonia can be a feature but is not typically prominent. Mean age of onset is adulthood, but has been reported in juveniles. More appropriate on ataxia panels.
However, is rated as green on equivalent GMS panels and therefore upgrading the rating from red to green on this 100K panel.
Early onset dystonia v1.138 AFG3L2 Arina Puzriakova Gene: afg3l2 has been classified as Green List (High Evidence).
Early onset dystonia v1.137 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Dystonia to Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Early onset dystonia v1.136 AFG3L2 Arina Puzriakova Mode of inheritance for gene: AFG3L2 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v5.315 MYCN Zornitza Stark edited their review of gene: MYCN: Added comment: PMID 37710961: Three individuals now reported with gain-of-function missense variants (identical variant in two individuals) and somewhat opposing phenotype cf Feingold. Clinical presentation includes megalencephaly, hypoplastic corpus callosum, postaxial polydactyly, intellectual disability and motor delay. Knock-in mouse model showed morphological manifestations in multiple tissues including digits, female reproductive system and kidney.; Changed publications to: 21224895, 8470948, 37710961; Changed phenotypes to: Feingold syndrome 1, Megalencephaly, intellectual disability, Neurodevelopmental disorder (MONDO:0700092), MYCN-related
Retinal disorders v4.36 CFAP20 Zornitza Stark gene: CFAP20 was added
gene: CFAP20 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP20 were set to 36329026
Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200)
Review for gene: CFAP20 was set to GREEN
Added comment: Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin.

Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate.
Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5)
Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly).
Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys)

For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old).

Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues.

CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development.
Sources: Literature
Intellectual disability v5.315 MAST4 Zornitza Stark gene: MAST4 was added
gene: MAST4 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Review for gene: MAST4 was set to GREEN
Added comment: 9 individuals with de novo missense variants and ID reported altogether.

PMID: 36910266 - 4 affecteds from unrelated families, all de novo missense

2x borderline microcephaly (-2SD)
2x gross motor delay
2x dysmorphism
4x ID + seizures
3x abnormal brain MRI findings

PMID: 33057194 - 5x de novos, 4x missense + 1x PTC
Cohort of individuals with severe developmental disorder
individual phenotypic information not provided


Recurrent variants are Thr1471Ile (3x) and Ser1181Phe)
Sources: Literature
Intellectual disability v5.315 ZBTB47 Zornitza Stark gene: ZBTB47 was added
gene: ZBTB47 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Review for gene: ZBTB47 was set to GREEN
Added comment: PMID 37743782:
- 5 individuals with de novo missense variants, 4/5 have a recurring p.Gly477Lys. Probands have intellectual disability (5/5), seizures (5/5), hypotonia (5/5), gait abnormalities, and variable movement abnormalities (5/5).
- Missense variants are positioned close to His and Cys residues involved in forming C2H2 zinc fingers.
- No functional studies performed
Sources: Literature
Congenital disorders of glycosylation v4.3 COG3 Zornitza Stark gene: COG3 was added
gene: COG3 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, MIM# 620546
Review for gene: COG3 was set to AMBER
Added comment: Two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings.
Sources: Literature
Hereditary neuropathy or pain disorder v3.60 MT-ND6 Dmitrijs Rots gene: MT-ND6 was added
gene: MT-ND6 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene gene: MT-ND6 was set to MITOCHONDRIAL
Publications for gene: MT-ND6 were set to PMID: 20301353
Phenotypes for gene: MT-ND6 were set to LHON; peripheral neuropathy
Penetrance for gene: MT-ND6 were set to unknown
Mode of pathogenicity for gene: MT-ND6 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MT-ND6 was set to GREEN
Added comment: Gene is associated with LHON, but GeneReviews states: "Neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in the general population. ".
Identified in our lab in a young patient with peripheral neuropathy phenotype only.
Sources: Literature
Structural eye disease v3.40 EPHA2 Sarah Leigh changed review comment from: EPHA2 variants are associated with Cataract 6, multiple types (OMIM:116600) and as definitive Gen2Phen gene for the same condition. PMID: 35918037 presents a review numerous EPHA2 variants and their associated phenotypes, together with a report of a syndromic complex microphthalmia with iris hypoplasia caused compound heterozygous EPHA2 variants. Various ocular features are reported, including microphthalmia, congenital cataracts, nystagmus, microcornea (PMID: 35918037, table 1). This article also highlights that both monoallelic and biallelic EPHA2 variants are responsible for the phenotypes reported in table 1.; to: EPHA2 variants are associated with Cataract 6, multiple types (OMIM:116600) and as definitive Gen2Phen gene for the same condition. PMID: 35918037 presents a review numerous EPHA2 variants and their associated phenotypes, together with a report of a syndromic complex microphthalmia with iris hypoplasia caused compound heterozygous EPHA2 variants. Various ocular features are reported, including microphthalmia, congenital cataracts, nystagmus, microcornea (PMID: 35918037, table 1).
Bilateral congenital or childhood onset cataracts v4.6 EPHA2 Sarah Leigh Tag Q4_23_MOI tag was added to gene: EPHA2.
Bilateral congenital or childhood onset cataracts v4.6 EPHA2 Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 35918037 highlights that both monoallelic and biallelic EPHA2 variants are responsible for the phenotypes reported in table 1, therefore, the mode of inheritance for EPHA2 should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review.
Bilateral congenital or childhood onset cataracts v4.6 EPHA2 Sarah Leigh Mode of inheritance for gene: EPHA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v3.40 EPHA2 Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 35918037 highlights that both monoallelic and biallelic EPHA2 variants are responsible for the phenotypes reported in table 1, therefore, the mode of inheritance for EPHA2 should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review.
Structural eye disease v3.40 EPHA2 Sarah Leigh Mode of inheritance for gene: EPHA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v3.39 EPHA2 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: EPHA2.
Tag Q4_23_MOI tag was added to gene: EPHA2.
Tag Q4_23_NHS_review tag was added to gene: EPHA2.
Structural eye disease v3.39 EPHA2 Sarah Leigh reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v4.5 EPHA2 Sarah Leigh Phenotypes for gene: EPHA2 were changed from Age-Related Cortical Cataract; Cataract 6, multiple types, 116600 to Cataract 6, multiple types, OMIM:116600
Bilateral congenital or childhood onset cataracts v4.4 EPHA2 Sarah Leigh Publications for gene: EPHA2 were set to
Structural eye disease v3.39 EPHA2 Sarah Leigh Publications for gene: EPHA2 were set to
Structural eye disease v3.38 EPHA2 Sarah Leigh Phenotypes for gene: EPHA2 were changed from Cataract 6, multiple types, 116600 to Cataract 6, multiple types, OMIM:116600
Structural eye disease v3.37 SMG8 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: SMG8.
Tag Q4_23_NHS_review tag was added to gene: SMG8.
Structural eye disease v3.37 SMG8 Sarah Leigh commented on gene: SMG8: SMG8 variants are associated with Alzahrani-Kuwahara syndrome (OMIM:619268) and as strong Gen2Phen gene for the same condition. So far four validated variants have been reported (PMID: 33242396& 34761517) in unrelated cases of OMIM:619268. An ocular phenotype was observed in three of these cases (strabismus, cataract & microphthalmia).
Structural eye disease v3.37 SMG8 Sarah Leigh Classified gene: SMG8 as Amber List (moderate evidence)
Structural eye disease v3.37 SMG8 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Structural eye disease v3.37 SMG8 Sarah Leigh Gene: smg8 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.36 SMG8 Sarah Leigh Classified gene: SMG8 as Amber List (moderate evidence)
Structural eye disease v3.36 SMG8 Sarah Leigh Gene: smg8 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.35 SMG8 Sarah Leigh Phenotypes for gene: SMG8 were changed from Alzahrani-Kuwahara syndrome to Alzahrani-Kuwahara syndrome, OMIM:619268
Structural eye disease v3.34 SMG8 Sarah Leigh Publications for gene: SMG8 were set to 34761517
Structural eye disease v3.33 SMG9 Sarah Leigh Publications for gene: SMG9 were set to 27018474; 33242396
Structural eye disease v3.32 SMG9 Sarah Leigh Publications for gene: SMG9 were set to 27018474
Structural eye disease v3.31 PDGFRA Sarah Leigh reviewed gene: PDGFRA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Structural eye disease v3.31 CDH4 Sarah Leigh changed review comment from: CDH4 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35034853 identified a monoallelic CDH4 variant in a case with unilateral right iris coloboma and intellectual disability, postnatal
and microcephaly. In situ hybridization showed that cdh4 was expressed in the ciliary marginal zone and
periocular mesenchyme cells in zebrafish embryos at 48 & 56 hpf (PMID: 35034853, Fig S1) and cdh4 morphants displayed
microphthalmia (FigS3), together with pleiotropic developmental defects. PMID: 15918170 had previously reported evidence of brain disorganization in a cdh4 knockdown zebrafish.; to: CDH4 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35034853 identified a monoallelic CDH4 variant in a case with unilateral right iris coloboma and intellectual disability, postnatal
and microcephaly. In situ hybridization showed that cdh4 was expressed in the ciliary marginal zone and
periocular mesenchyme cells in zebrafish embryos at 48 & 56 hpf (PMID: 35034853, Fig S1) and knockdown of cdh4 morphants displayed microphthalmia (FigS3), together with pleiotropic developmental defects. PMID: 15918170 had previously reported evidence of brain disorganization in a cdh4 knockdown zebrafish.
Structural eye disease v3.31 PDGFRA Sarah Leigh Classified gene: PDGFRA as Amber List (moderate evidence)
Structural eye disease v3.31 PDGFRA Sarah Leigh Gene: pdgfra has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v4.17 NEK8 Dmitrijs Rots reviewed gene: NEK8: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37598857; Phenotypes: polycystic kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v1.1 UBA1 Dorota Rowczenio reviewed gene: UBA1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33108101, 36823397, 34048852, 34213531, 34340250, 33930131, 34802547, 37501758, 37223371, 36692560, 33789873, 33779074; Phenotypes: ever, chondritis, vasculitis, neutrophilic dermatosis, sterile alveolitis, progressive bone marrow failure, cytopenia; Mode of inheritance: Other; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v4.53 RELA Achchuthan Shanmugasundram Phenotypes for gene: RELA were changed from Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287 to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
Primary immunodeficiency or monogenic inflammatory bowel disease v4.52 RELA Achchuthan Shanmugasundram Phenotypes for gene: RELA were changed from Mucocutaneous ulceration, chronic, 618287; RelA haplosufficiency; Mucosal ulceration, impaired NFkB activation; Immunodeficiencies affecting cellular and humoral immunity to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
Primary immunodeficiency or monogenic inflammatory bowel disease v4.51 RELA Achchuthan Shanmugasundram reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.51 POLD1 Achchuthan Shanmugasundram Classified gene: POLD1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.51 POLD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases and functional data in support of the association of biallelic POL1D variants with immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.51 POLD1 Achchuthan Shanmugasundram Gene: pold1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 POLD1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: POLD1.
Tag Q4_23_NHS_review tag was added to gene: POLD1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 POLD1 Achchuthan Shanmugasundram reviewed gene: POLD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 IRF4 Hannah Knight reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36917008, PMID: 36662884; Phenotypes: ?Whipple's disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 MAN2B2 Hannah Knight reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35637269; Phenotypes: Severe developmental delay, dysmorphic facial features, immune dysregulation, developmental delay, stroke; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 PSMB10 Hannah Knight reviewed gene: PSMB10: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37600812; Phenotypes: Proteasome-associated autoinflammatory syndrome 5; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 NLRP1 Hannah Knight reviewed gene: NLRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31873740; Phenotypes: Autoinflammatory disease with corneal and mucosal dyskeratosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 GIMAP5 Hannah Knight reviewed gene: GIMAP5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33956074; Phenotypes: Portal hypertension, noncirrhotic, 2, MIM# 619463; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
NARP syndrome or maternally inherited Leigh syndrome v1.1 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Severe Paediatric Disorders v1.174 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Adult onset dystonia, chorea or related movement disorder v3.13 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Retinal disorders v4.36 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Mitochondrial disorders v4.99 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Undiagnosed metabolic disorders v1.601 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Adult onset neurodegenerative disorder v4.37 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Optic neuropathy v4.11 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Structural basal ganglia disorders v1.38 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Albinism or congenital nystagmus v3.1 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Early onset dystonia v1.135 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Leber hereditary optic neuropathy v2.6 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Infantile nystagmus v1.10 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND6.
Severe Paediatric Disorders v1.174 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND5.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND5.
Mitochondrial disorders v4.99 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND5.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND5.
Undiagnosed metabolic disorders v1.601 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND5.
Severe Paediatric Disorders v1.174 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4L.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4L.
Mitochondrial disorders v4.99 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4L.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4L.
Undiagnosed metabolic disorders v1.601 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4L.
Severe Paediatric Disorders v1.174 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Retinal disorders v4.36 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Mitochondrial disorders v4.99 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Intellectual disability v5.315 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Undiagnosed metabolic disorders v1.601 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Optic neuropathy v4.11 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Leber hereditary optic neuropathy v2.6 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND4.
Severe Paediatric Disorders v1.174 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND3.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND3.
Mitochondrial disorders v4.99 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND3.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND3.
Undiagnosed metabolic disorders v1.601 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND3.
Severe Paediatric Disorders v1.174 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Mitochondrial disorders v4.99 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Undiagnosed metabolic disorders v1.601 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Albinism or congenital nystagmus v3.1 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Infantile nystagmus v1.10 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND2.
Severe Paediatric Disorders v1.174 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Adult onset dystonia, chorea or related movement disorder v3.13 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Retinal disorders v4.36 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Mitochondrial disorders v4.99 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Intellectual disability v5.315 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Undiagnosed metabolic disorders v1.601 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Optic neuropathy v4.11 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Structural basal ganglia disorders v1.38 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Sudden death in young people v1.15 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Leber hereditary optic neuropathy v2.6 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ND1.
Severe Paediatric Disorders v1.174 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Mitochondrial disorders v4.99 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Undiagnosed metabolic disorders v1.601 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Albinism or congenital nystagmus v3.1 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Sudden death in young people v1.15 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Infantile nystagmus v1.10 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CYB.
Severe Paediatric Disorders v1.174 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Mitochondrial disorders v4.99 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Early onset or syndromic epilepsy v4.120 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Undiagnosed metabolic disorders v1.601 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Albinism or congenital nystagmus v3.1 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Infantile nystagmus v1.10 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Acute rhabdomyolysis v1.16 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Severe Paediatric Disorders v1.174 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Mitochondrial disorders v4.99 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 CD8A Hannah Knight changed review comment from: PMID: 26563160 reported a third patient with this disorder. From consanguineous Portuguese family, with same homozygous variant as previously reported. Not sure whether this is enough to push gene into green category (as same variant, and Portuguese vs Spanish Gypsy heritage); to: PMID: 26563160 reported a third patient with this disorder. From consanguineous Portuguese family, with same homozygous variant as previously reported. Not sure whether this is enough to push gene into green category (as same variant, and Portuguese vs Spanish Gypsy heritage)
PMID mentioned below, but not sure if taken into account as no reference to contents of paper
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Undiagnosed metabolic disorders v1.601 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.50 CD8A Hannah Knight reviewed gene: CD8A: Rating: AMBER; Mode of pathogenicity: None; Publications: 26563160; Phenotypes: CD8 deficiency familial, 608957; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.37 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO2.
Acute rhabdomyolysis v1.16 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Severe Paediatric Disorders v1.174 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Mitochondrial disorders v4.99 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Undiagnosed metabolic disorders v1.601 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Albinism or congenital nystagmus v3.1 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Rhabdomyolysis and metabolic muscle disorders v3.37 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Infantile nystagmus v1.10 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO1.
Severe Paediatric Disorders v1.174 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Mitochondrial disorders v4.99 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Undiagnosed metabolic disorders v1.601 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Skeletal muscle channelopathy v3.1 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Paroxysmal central nervous system disorders v3.8 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
Skeletal Muscle Channelopathies v1.45 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP8.
NARP syndrome or maternally inherited Leigh syndrome v1.1 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Severe Paediatric Disorders v1.174 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Childhood onset dystonia, chorea or related movement disorder v3.50 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Hereditary neuropathy or pain disorder v3.60 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Adult onset dystonia, chorea or related movement disorder v3.13 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Retinal disorders v4.36 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Hereditary ataxia with onset in adulthood v4.24 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Mitochondrial disorders v4.99 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Intellectual disability v5.315 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Hereditary neuropathy v1.472 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Likely inborn error of metabolism - targeted testing not possible v4.52 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Undiagnosed metabolic disorders v1.601 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Adult onset neurodegenerative disorder v4.37 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Skeletal muscle channelopathy v3.1 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Optic neuropathy v4.11 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Paroxysmal central nervous system disorders v3.8 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Structural basal ganglia disorders v1.38 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Albinism or congenital nystagmus v3.1 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Hereditary ataxia v1.331 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Ataxia and cerebellar anomalies - narrow panel v4.38 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Skeletal Muscle Channelopathies v1.45 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Infantile nystagmus v1.10 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-ATP6.
Structural eye disease v3.30 CDH4 Sarah Leigh Publications for gene: CDH4 were set to 35034853
Structural eye disease v3.29 CDH4 Sarah Leigh reviewed gene: CDH4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.315 ERI1 Achchuthan Shanmugasundram Classified gene: ERI1 as Amber List (moderate evidence)
Intellectual disability v5.315 ERI1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases with biallelic null ERI1 variants and mild intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.315 ERI1 Achchuthan Shanmugasundram Gene: eri1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.314 ERI1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ERI1.
Intellectual disability v5.314 ERI1 Achchuthan Shanmugasundram gene: ERI1 was added
gene: ERI1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 36208065; 37352860
Phenotypes for gene: ERI1 were set to intellectual disability, MONDO:0001071
Review for gene: ERI1 was set to GREEN
Added comment: PMID:36208065 reported a female patient with a homozygous nonsense variant in ERI1 gene and with mild intellectual disability (ID), eyelid ptosis, and anomalies in her hands and feet (brachydactyly, clinodactyly, dysplastic/short nail of halluces, brachytelephalangy, short metacarpals, and toe syndactyly).

PMID:37352860 reported eight patients from seven unrelated families with compound heterozygous variants in ERI1 gene, of which four patients had missense variants, three had null variants and one had missense and PTC variants. The patients with missense variants had a more severe severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly. The patients with null variants had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly. The patient with both missense and PTC variants had phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, and delayed motor milestones and speech and generalised hypotonia.

This gene has not yet been reported with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Structural eye disease v3.29 CDH4 Sarah Leigh Classified gene: CDH4 as Amber List (moderate evidence)
Structural eye disease v3.29 CDH4 Sarah Leigh Gene: cdh4 has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.28 BMPR1B Sarah Leigh Tag Q4_23_promote_green tag was added to gene: BMPR1B.
Tag Q4_23_NHS_review tag was added to gene: BMPR1B.
Structural eye disease v3.28 BMPR1B Sarah Leigh Classified gene: BMPR1B as Amber List (moderate evidence)
Structural eye disease v3.28 BMPR1B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Structural eye disease v3.28 BMPR1B Sarah Leigh Gene: bmpr1b has been classified as Amber List (Moderate Evidence).
Structural eye disease v3.27 BMPR1B Sarah Leigh Added comment: Comment on phenotypes: Ocular coloboma has yet to be associated with OMIM:609441, OMIM:616849 or OMIM:112600.
Structural eye disease v3.27 BMPR1B Sarah Leigh Phenotypes for gene: BMPR1B were changed from Ocular coloboma to Ocular coloboma
Structural eye disease v3.26 BMPR1B Sarah Leigh commented on gene: BMPR1B
Skeletal dysplasia v4.25 ERI1 Achchuthan Shanmugasundram Classified gene: ERI1 as Amber List (moderate evidence)
Skeletal dysplasia v4.25 ERI1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for promotion of this gene to green rating in the next GMS review.
Skeletal dysplasia v4.25 ERI1 Achchuthan Shanmugasundram Gene: eri1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.24 ERI1 Achchuthan Shanmugasundram Tag Q4_23_NHS_review tag was added to gene: ERI1.
Skeletal dysplasia v4.24 ERI1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Tracy Lester, four patients from three different families were identified with compound heterozygous missense variants in ERI1 gene and were reported with spondyloepimetaphyseal dysplasia. In addition, another unrelated patient with a missense and a null variant was reported with spondyloepimetaphyseal dysplasia, and delayed motor milestones and speech and generalised hypotonia.; to: As reviewed by Tracy Lester, four patients from three different families were identified with compound heterozygous missense variants in ERI1 gene and were reported with spondyloepimetaphyseal dysplasia. In addition, another unrelated patient with a missense and a null variant was reported with spondyloepimetaphyseal dysplasia, and delayed motor milestones and speech and generalised hypotonia (PMID:37352860).


This gene has not yet been associated with relevantly phenotypes either in OMIM or in Gene2Phenotype.