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Severe insulin resistance and lipodystrophy syndromes v2.8 VIM Eleanor Williams gene: VIM was added
gene: VIM was added to Lipodystrophy - childhood onset. Sources: Literature
Mode of inheritance for gene: VIM was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VIM were set to 32066935
Phenotypes for gene: VIM were set to lipodystrophy HP:0009125
Review for gene: VIM was set to RED
Added comment: Previously variants in this gene have been associated with cataracts (PMID: 26694549, 19126778). Cogne et al 2020 (PMID: 32066935) - report a de novo heterozygous variant in VIM (c.1160 T > C; p.(Leu387Pro)) causing a syndromic disorder affecting craniofacial development, peripheral nervous system, and adipose and ectodermal tissues in a 39 year old male. The variant was identified by WES. Both parents lacked the variant. Expression of human vimentin p.(Leu387Pro) in zebrafish resulted in a phenotype of perturbed body fat distribution, and craniofacial and peripheral nervous system development. Functional studies using patient-derived and transfected cells showed that the variant affects vimentin turnover and its ability to form filaments in the absence of wild-type vimentin.
Sources: Literature
Hereditary neuropathy v1.381 PNKP Dmitrijs Rots changed review comment from: In PMID: 30039206 reported a homozygous nonsense variant in a large Costa Rican family segregating with CMT2 phenotype. Additional 5 cases with compound heterozygous nonsense variants and CMT2 phenotype also reported. Some patients have Ataxia, but not oculomotor apraxia or Microcephaly, seizures, and developmental delay.; to: In PMID: 30039206 reported a homozygous nonsense variant in a large Costa Rican family segregating with CMT2 phenotype. Additional 5 cases with compound heterozygous nonsense variants and CMT2 phenotype also reported. Some patients have Ataxia, but not oculomotor apraxia or Microcephaly, seizures, and developmental delay.
Hereditary neuropathy or pain disorder v1.19 PNKP Dmitrijs Rots reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30039206; Phenotypes: Polyneuropathy, ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary neuropathy v1.381 PNKP Dmitrijs Rots reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30039206; Phenotypes: Polyneuropathy, ataxia; Mode of inheritance: None; Current diagnostic: yes
Likely inborn error of metabolism v2.44 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.44 NUS1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber on advice from Genomics England clinical team. 1 case plus some functional data.
Likely inborn error of metabolism v2.44 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.43 NUS1 Eleanor Williams Publications for gene: NUS1 were set to 25066056
Likely inborn error of metabolism v2.42 NUS1 Eleanor Williams Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa 617082 to ?Congenital disorder of glycosylation, type 1aa OMIM:617082; congenital disorder of glycosylation, type IAA MONDO:0014904
Likely inborn error of metabolism v2.42 NUS1 Eleanor Williams Publications for gene: NUS1 were set to
Likely inborn error of metabolism v2.41 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: Provisionally associated with ?Congenital disorder of glycosylation, type 1aa #617082 (AR) in OMIM based on family reported in Park et al 2014 (PMID: 25066056). They describe a family of Roma origin in which 2 out of 4 siblings presented with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit and visual impairment with discrete bilateral macular lesions. A homozgyous missense mutation, R290H, was found in NUS1 (called NGBR in the paper) by exome sequencing. It segregated with the disease in the family. Patient fibroblasts showed reduced dolichol profiles and enhanced accumulation of free cholesterol as do fibroblasts from mice lacking NgBR.; Changed publications: 25066056; Changed phenotypes: ?Congenital disorder of glycosylation, type 1aa OMIM:617082, congenital disorder of glycosylation, type IAA MONDO:0014904
Likely inborn error of metabolism v2.41 NUS1 Eleanor Williams reviewed gene: NUS1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Congenital disorder of glycosylation, type 1aa 617082 AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.702 NUS1 Eleanor Williams edited their review of gene: NUS1: Changed rating: GREEN
Intellectual disability v3.702 NUS1 Eleanor Williams Added comment: Comment on mode of inheritance: The mode of inheritance should be considered for change to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal in line with its classification on the Genetic Epilepsy Syndromes panel.
Intellectual disability v3.702 NUS1 Eleanor Williams Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.701 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.701 NUS1 Eleanor Williams Added comment: Comment on list classification: Due to further reported cases, and review on the Genetic epilepsy syndromes by Helen Lord this gene should be considered for a green rating as GMS review.
Intellectual disability v3.701 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v1.29 LRIF1 Eleanor Williams Classified gene: LRIF1 as Amber List (moderate evidence)
Distal myopathies v1.29 LRIF1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, and there is one case plus some functional data.
Distal myopathies v1.29 LRIF1 Eleanor Williams Gene: lrif1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v1.28 LRIF1 Eleanor Williams gene: LRIF1 was added
gene: LRIF1 was added to Distal myopathies. Sources: Literature
Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIF1 were set to 32467133
Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy
Review for gene: LRIF1 was set to AMBER
Added comment: Review from Bryony Thompson (Royal Melbourne Hospital) on gene in PanelApp Australia.
https://panelapp.agha.umccr.org/panels/328/gene/LRIF1/:
A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 LRIF1 Eleanor Williams Classified gene: LRIF1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 LRIF1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, and there is one case plus some functional data.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.15 LRIF1 Eleanor Williams Gene: lrif1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.14 LRIF1 Eleanor Williams gene: LRIF1 was added
gene: LRIF1 was added to Limb girdle muscular dystrophy. Sources: Literature
Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIF1 were set to 32467133
Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy
Review for gene: LRIF1 was set to AMBER
Added comment: Review from Bryony Thompson (Royal Melbourne Hospital) on gene in PanelApp Australia.
https://panelapp.agha.umccr.org/panels/328/gene/LRIF1/:
A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Monogenic hearing loss v2.145 GJB3 Eleanor Williams Classified gene: GJB3 as Green List (high evidence)
Monogenic hearing loss v2.145 GJB3 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green for now, but with recommendation of review at the next GMS update.
Monogenic hearing loss v2.145 GJB3 Eleanor Williams Gene: gjb3 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.144 GJB3 Eleanor Williams Tag for-review tag was added to gene: GJB3.
Monogenic hearing loss v2.144 GJB3 Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in to the cell surface in a similar way to wild type protein.

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WT Cx31.
Monogenic hearing loss v2.144 GJB3 Eleanor Williams changed review comment from: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in many cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535) . 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.; to: GJB3 - nonsyndromic genetic deafness association DISPUTED in ClinGen.

A large number of early studies have looked at GJB3 variants in HL patients. In all cases targeted screening of hearing loss genes was performed, with only a few genes looked at in most cases. At least 17 protein altering variants have been reported, but with no or limited segregation data. Two variants (NM_001005752.1:c.94C>T, Arg32Trp and c.598G>A, Val200Ile) are found at high allele frequency in the general population (both >0.02 gnomad v3.1) and c.529T>G, Tyr177Asp at a fairly high frequency (0.005535). 14 other variants are either not present in gnomad, or found at low frequency (< 0.0005). There is some data to support a functional change in proteins with 5 of the variants but no animal knockout model has been reported. One variant ((Ile141Val) found in a compound het case (Lui et al 2000) was found to migrate in cell

Monoallelic cases:
PMID:9843210 - Xia et al. 1998 - report monallelic variants found in GJB3 in 2 families with sensorineural deafness. Only the GJB3 gene was sequenced. In both families some carriers were unaffected. The two variants are ENST00000373362.3:c.547G>A GLU183LYS, ENST00000373362.3:c.538C>T (ARG180TER).

PMID:12630965 - Mhatre et al. 2003 - assessed 63 individuals with non-syndromic sporadic hearing impairment for CX31 (GJB3) mutations. 15 out of 63 patients (24%) had variants but only one variant was protein altering (C94T, R32W). This was found in two unrelated individuals with late onset hearing loss.

PMID: 10790215 - López-Bigas et al 2000 - report the molecular analysis of GJB3 in 153 patients with deafness and 110 with peripheral neuropathy. Identified two amino acid changes in patients; R32W and V200I. However, the R32W change was also detected in 18% of control subjects.

PMID:12791041 - Uyguner et al. 2003; Screened 60 Turkish patients with autosomal‐recessive NSSHL for variants in GJB2, GJB3, GJA1, DeltaGJB6-D13S1830 and CLDN14. A novel heterozygous variant, C667A;P223T, in GJB3 was found in a family with two affected children. However, the non-affected father also carried this variant. The authors suggest they may carry a second non-identified variant in a functionally related gene.

PMID:15131355 - Alexandrino et al. 2004 - analysed the GJB3 gene in 67 families with sporadic nonsyndromic hearing impairment. They found three amino acid changes: Y177D (c.529T > G), 49delK (c.144-146delGAA), and R32W (c.1227C > T). Abstract only accessed.

PMID:17259707 - Yang et al. 2007 - screened 260 Taiwanese individuals with nonsyndromic deafness and 120 with normal hearing. 8 genes were looked at GJB2, GJE1, GJB6, GJB4, GJB3, GJB1, GJA1 and pseudogene rho GJA1. A novel variant was identified GJB3 in 3 patients with nonsyndromic deafness. Abstract only accessed.

PMID:19744334 - Yuan et al. 2009 - screened 284 unrelated school children with hearing loss, and 200 control patients for variants in GJB2, GJB3, GJB6, SLC26A4, 12S rRNA, and tRNAser(UCN) genes. 2 patients were found with heterozygous protein altering variants that were not found in controls; c.24_49ins26bp (results in frameshift), c.497A>G, N166S. However, the patient carrying N166S mutation in one allele was verified to carry GJB2 235delC mutation in the other. Parental DNA was not available for the patient with the c.24_49ins26bp variant.

PMID:22617145 - Oh et al. 2013 - looked at GJB3 and GJB6 in 215 unrelated Korean nonsyndromic sensorineural HL patients. 7 variants were identified in GJB3. 2 variants (c.79G>A,p.V27M and c.250G>A,p.V84I) were not observed in normal Korean controls. Functional tests showed that these two variants did not functional normally when each was expressed as a heterozygote with the wild-type Cx31.

PMID: 23638949 - Yao et al 2013 - screened 227 segregating deaf students and 200 individuals with normal hearing for variants in GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Four patients carried three unclassified mutations in GJB3 genes. Abstract only accessed.

PMID:25214170 - Beck et al. 2015; screened 188 HL probands in a 3 step process with GJB2 first, then GJB1, GJB3 and GJB6 and then if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK. 3 amino acid changes, c.166A>C, Lys56Gln (2/188), c.302G>A, Arg101Gln (1/188) and c.317G>A, Arg106His (1/188) were detected in the patient cohort but not in controls. The authors report that the role of these sequence variations remains unclear as no second mutation was found to establish a causative connection between genotype and phenotype.

PMID: 27610647 - Chen et al 2016 - using NGS they screened GJB2, SLC26A4, and GJB3, as well as exons of 57 additional candidate genes in 116 Chinese Han individuals suffering from hearing loss. 2 heterozygous variants were detected in GJB3 - c.131G>C, p.Trp44Ser; c.580G>A, p.Ala194Thr.

Biallelic cases:
PMID: 10587579 - Liu et al. (2000) - screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. Both families had an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A>G transversion in the other allele, which creates an Ile>Val substitution (I141V) (later found to function as wild type by He et al 2005). Note: I think coords should be NM_001005752.1:c.421A>G and NM_001005752.1:c.421_423del.

Functional studies:
PMID: 16077902 - He et al 2005 - functional analysis of 11 disease-associated Cx31 (GJB3) variants, 2 which are associated with dominant HL (R180X, E183K) and 2 recessive HL (I141V, 141delI). R180X, E183K and 141delI were characterised by cytoplasmic accumulation of Cx31 and the absence of cell surface expression. I141V migrates mainly to the cell surface, which resembles that of WTCx31.
Ectodermal dysplasia v1.15 LSS Eleanor Williams Classified gene: LSS as Amber List (moderate evidence)
Ectodermal dysplasia v1.15 LSS Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber for now, but with a recommendation for consideration for a green rating following GMS review, if appropriate for the panel.
Ectodermal dysplasia v1.15 LSS Eleanor Williams Gene: lss has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.14 LSS Eleanor Williams gene: LSS was added
gene: LSS was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 32101538; 30401459; 30723320; 29016354
Phenotypes for gene: LSS were set to Hypotrichosis 14 OMIM:618275; hypotrichosis 14 MONDO:0032649
Review for gene: LSS was set to GREEN
Added comment: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.

PMID: 29016354 - Chen and Lui 2017 - report a pediatric patient with congenital cataract, small penis, baldness and absence of eyebrows and compound heterozygous variants in LSS.
Sources: Literature
Non-syndromic hypotrichosis v1.7 LSS Eleanor Williams Publications for gene: LSS were set to 32101538; 30401459
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams edited their review of gene: LSS: Changed publications: 32101538, 30401459, 30723320, 29016354
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams Classified gene: LSS as Green List (high evidence)
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams Added comment: Comment on list classification: After consultation with Genomics England clinicians, promoting this gene from red to green as there are > 3 cases (some syndromic, some non-syndromic).
Non-syndromic hypotrichosis v1.6 LSS Eleanor Williams Gene: lss has been classified as Green List (High Evidence).
Holoprosencephaly v2.14 STAG2 Sarah Leigh Tag for-review tag was added to gene: STAG2.
Holoprosencephaly v2.14 STAG2 Sarah Leigh edited their review of gene: STAG2: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 6 variants reported in unrelated cases, together with supporting in situ and functional evidence (PMID 31334757).; Changed rating: GREEN; Changed publications: 31334757
Holoprosencephaly v2.14 STAG2 Sarah Leigh Classified gene: STAG2 as Amber List (moderate evidence)
Holoprosencephaly v2.14 STAG2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Holoprosencephaly v2.14 STAG2 Sarah Leigh Gene: stag2 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.13 STAG2 Sarah Leigh Phenotypes for gene: STAG2 were changed from holoprosencephaly to Holoprosencephaly 13, X-linked OMIM:301043
Congenital myopathy v2.18 KY Sarah Leigh Classified gene: KY as Amber List (moderate evidence)
Congenital myopathy v2.18 KY 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 myopathy v2.18 KY Sarah Leigh Gene: ky has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.17 KY Sarah Leigh Tag for-review tag was added to gene: KY.
Congenital myopathy v2.17 KY Sarah Leigh reviewed gene: KY: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.17 KY Sarah Leigh Phenotypes for gene: KY were changed from congenital myopathy to Myopathy, myofibrillar 7 OMIM:617114
Congenital myopathy v2.16 KY Sarah Leigh Publications for gene: KY were set to 27484770
Congenital myopathy v2.15 HNRNPA2B1 Sarah Leigh Tag watchlist tag was added to gene: HNRNPA2B1.
Tag for-review tag was added to gene: HNRNPA2B1.
Congenital myopathy v2.15 HNRNPA2B1 Sarah Leigh Publications for gene: HNRNPA2B1 were set to
Congenital myopathy v2.14 HNRNPA2B1 Sarah Leigh Mode of inheritance for gene: HNRNPA2B1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.13 HNRNPA2B1 Sarah Leigh Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Congenital myopathy v2.13 HNRNPA2B1 Sarah Leigh Added comment: Comment on list classification: De novo terminating variants clustered in the C-terminus of the protein have been reported in six unrelated families all with a distinct class of dominantly-acting heterozygous variants in hnRNPA2B1 with a unique clinical phenotype of early childhood-onset progressive muscle weakness, ophthalmoplegia, ptosis, dysphagia, and variable degrees of respiratory insufficiency but no dementia (https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext). This source is a meeting abstract an there is no peer reviewed source at this time.
Congenital myopathy v2.13 HNRNPA2B1 Sarah Leigh Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Tag watchlist tag was added to gene: HNRNPA2B1.
Tag for-review tag was added to gene: HNRNPA2B1.
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Publications for gene: HNRNPA2B1 were set to
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Added comment: Comment on list classification: De novo terminating variants clustered in the C-terminus of the protein have been reported in six unrelated families all with a distinct class of dominantly-acting heterozygous variants in hnRNPA2B1 with a unique clinical phenotype of early childhood-onset progressive muscle weakness, ophthalmoplegia, ptosis, dysphagia, and variable degrees of respiratory insufficiency but no dementia (https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext).
This source is a meeting abstract an there is no peer reviewed source at this time.
Congenital muscular dystrophy v2.5 HNRNPA2B1 Sarah Leigh Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.27 NF2 Eleanor Williams Classified gene: NF2 as Red List (low evidence)
Structural eye disease v1.27 NF2 Eleanor Williams Added comment: Comment on list classification: Leaving this gene for red now, but flagging for review by the GMS as ocular manifestations other than cataracts are seen in some patients.
Structural eye disease v1.27 NF2 Eleanor Williams Gene: nf2 has been classified as Red List (Low Evidence).
Structural eye disease v1.26 NF2 Eleanor Williams Phenotypes for gene: NF2 were changed from Neurofibromatosis, Type II, 101000 to Neurofibromatosis, type 2 OMIM:101000; neurofibromatosis type 2 MONDO:0007039
Structural eye disease v1.25 NF2 Eleanor Williams Publications for gene: NF2 were set to
Structural eye disease v1.24 NF2 Eleanor Williams edited their review of gene: NF2: Changed rating: AMBER; Changed publications: 33075808, 31089872, 29923868, 9246269, 12210058; Changed phenotypes: Neurofibromatosis, type 2 OMIM:101000, neurofibromatosis type 2 MONDO:0007039; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.24 NF2 Eleanor Williams Tag for review tag was added to gene: NF2.
Structural eye disease v1.24 NF2 Eleanor Williams changed review comment from: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose cause defects resulting in persistent coloboma.; to: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose cause defects resulting in persistent coloboma.

Additional papers supporting association of variants in NF2 and eye abnormalities

PMID: 31089872 - Waisberg et al 2019 - report on the eye examination of 8 unrelated NF2 patients from Brazil. 6 had germline variants (nonsense, frameshift, or splice site) in NF2. Ophthalmological features were present in all patients and varied from subtle retinal changes to a severe ocular phenotype preset at birth. Of those 6 with NF2 variants: cataracts 4/6, Hamartoma 4/6, Flame-shaped ERM 5/6, Strabismus 3/6, Retinal Tuft 2/6 and Choroidal nodules 3/6.

PMID: 29923868 - Painter et al 2019 - reviewed longitudinal ophthalmological data of 83 patients with NF2 who had a mutation present on blood testing, or identical mutations found in 2 or more tissue samples, or they met the updated Manchester modified criteria for a clinical diagnosis of NF2. Mutations in NF2 associated with severe systemic disease were found to result in greater visual morbidity at an earlier age.

PMID: 12210058 - Chan et al 2002 - looked at 40 ocular lesions from four NF2 patients, from three unrelated families. All had germline nonsense mutations in NF2. Cataracts were evident by pseudophakia in seven eyes, iris naevoid hyperplasia at the anterior surface in two eyes of two patients, and retinal lesions in all eyes.

PMID: 9246269 - Ragge et al 1997 - report 5 unrelated cases of patients with Neurofibromatosis 2 to illustrate the diverse ocular phenotypes seen in patients. Molecular analysis not given. The authors note that ocular manifestations are often the first sign of disease.
Retinal disorders v2.120 HK1 Ivone Leong commented on gene: HK1
Retinal disorders v2.120 HK1 Ivone Leong Tag for-review tag was added to gene: HK1.
Retinal disorders v2.120 HK1 Ivone Leong Publications for gene: HK1 were set to 25190649; 25316723
Retinal disorders v2.119 HK1 Ivone Leong Phenotypes for gene: HK1 were changed from Retinitis pigmentosa 79 617460 to Retinitis pigmentosa 79, OMIM:617460, MONDO:0044320
Differences in sex development v2.14 TSPYL1 Eleanor Williams Classified gene: TSPYL1 as Amber List (moderate evidence)
Differences in sex development v2.14 TSPYL1 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber, but there are 3 cases now reported and so this gene should be reviewed at the next GMS update.
Differences in sex development v2.14 TSPYL1 Eleanor Williams Gene: tspyl1 has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.13 TSPYL1 Eleanor Williams Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome 608800 to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Differences in sex development v2.12 TSPYL1 Eleanor Williams Publications for gene: TSPYL1 were set to 15273283; 22137496; 19463995
Differences in sex development v2.11 TSPYL1 Eleanor Williams Tag for-review tag was added to gene: TSPYL1.
Differences in sex development v2.11 TSPYL1 Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial non syndromic congenital heart disease v1.54 MYH6 Sarah Leigh Publications for gene: MYH6 were set to 15735645, 20656787
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.102 EZH2 Sarah Leigh Tag for-review tag was added to gene: EZH2.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.102 EZH2 Sarah Leigh Added comment: Comment on mode of inheritance: EZH2 is a epigene, where LOF or GOF variants result in a characteristic genome-wide, multilocus DNA methylation signature in the carrier. There does not appear to be evidence for allele specificity of this effect and so this gene should not be regarded as imprinted (PMID 32243864).
Therefore, the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.102 EZH2 Sarah Leigh Mode of inheritance for gene: EZH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Sudden death in young people v1.15 TSPYL1 Eleanor Williams Classified gene: TSPYL1 as Green List (high evidence)
Sudden death in young people v1.15 TSPYL1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as there are now 3 independent cases of patients with plausible disease cause variants in this gene with SIDDT
Sudden death in young people v1.15 TSPYL1 Eleanor Williams Gene: tspyl1 has been classified as Green List (High Evidence).
Sudden death in young people v1.14 TSPYL1 Eleanor Williams Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome,608800; SIDDT to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Sudden death in young people v1.13 TSPYL1 Eleanor Williams Publications for gene: TSPYL1 were set to
Sudden death in young people v1.12 TSPYL1 Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815, 15273283, 25449952, 16418600, 19463995, 22137496; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.118 NEUROD1 Ivone Leong Mode of inheritance for gene: NEUROD1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.117 HARS Ivone Leong commented on gene: HARS
Retinal disorders v2.117 HARS Ivone Leong Tag for-review tag was added to gene: HARS.
Retinal disorders v2.117 HARS Ivone Leong Publications for gene: HARS were set to
Retinal disorders v2.116 CTSF Ivone Leong changed review comment from: Comment on list classification: This gene is associated with Ceroid lipofuscinosis, neuronal, 13, Kufs type (also known as Kufs disease or Adult neuronal ceroid lipofuscinosis) in OMIM but not in Gene2Phenotype.

While neuronal ceroid lipofuscinosis are characterized by lysosomal lipopigment storage in neurons, and usually the eye, and cause progressive neurological impairment, motor and intellectual deterioration, seizures, visual failure, and early death, Kufs disease is different. For Kufs disease the retina is not involvolved and the onset is in adulthood (PMID: 21549341). Because of this CTSF has been given a Red rating.; to: Comment on list classification: This gene is associated with Ceroid lipofuscinosis, neuronal, 13, Kufs type (also known as Kufs disease or Adult neuronal ceroid lipofuscinosis) in OMIM but not in Gene2Phenotype.

While neuronal ceroid lipofuscinosis are characterized by lysosomal lipopigment storage in neurons, and usually the eye, and cause progressive neurological impairment, motor and intellectual deterioration, seizures, visual failure, and early death, Kufs disease is different. For Kufs disease the retina is not involvolved and the onset is in adulthood (PMID: 21549341). Based on the phenotype, this gene has been given a Red rating as the phenotype does not fit this panel.
Retinal disorders v2.116 CTSF Ivone Leong Classified gene: CTSF as Red List (low evidence)
Retinal disorders v2.116 CTSF Ivone Leong Added comment: Comment on list classification: This gene is associated with Ceroid lipofuscinosis, neuronal, 13, Kufs type (also known as Kufs disease or Adult neuronal ceroid lipofuscinosis) in OMIM but not in Gene2Phenotype.

While neuronal ceroid lipofuscinosis are characterized by lysosomal lipopigment storage in neurons, and usually the eye, and cause progressive neurological impairment, motor and intellectual deterioration, seizures, visual failure, and early death, Kufs disease is different. For Kufs disease the retina is not involvolved and the onset is in adulthood (PMID: 21549341). Because of this CTSF has been given a Red rating.
Retinal disorders v2.116 CTSF Ivone Leong Gene: ctsf has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from AD MR type 57 - 618050 to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Intellectual disability v3.700 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but may be promoted to Green at the next GMS panel update (added for-review' tag).

Sufficient number of unrelated cases (3) with microcephaly of relevant severity to this panel (more than -3 SD). Truncating variants appear to be associated with a more severe disease presentation (PMID: 33397746).
Severe microcephaly v2.67 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.66 ZNF526 Arina Puzriakova gene: ZNF526 was added
gene: ZNF526 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: ZNF526.
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last updated on 09/12/2011), but has a 'possible' disease confidence rating for 'Autosomal Recessive Mental Retardation' in Gene2Phenotype.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.56 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.56 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added for-review' tag).

At least 5 individuals from 4 unrelated families all presenting bilateral ocular cataracts, among other features (PMID: 33397746)
Bilateral congenital or childhood onset cataracts v2.56 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.55 ZNF526 Arina Puzriakova gene: ZNF526 was added
gene: ZNF526 was added to Cataracts. Sources: Literature
for-review tags were added to gene: ZNF526.
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last updated on 09/12/2011), but has a 'possible' disease confidence rating for 'Autosomal Recessive Mental Retardation' in Gene2Phenotype.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Retinal disorders v2.115 CIB2 Ivone Leong commented on gene: CIB2
Intellectual disability v3.699 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
Intellectual disability v3.699 ZNF526 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but can be rated Green at the next GMS panel update (added 'for-review' tag).

Truncating variants associated with a more severe disease presentation; however, ID is the universal feature among individuals with biallelic variants in this gene.
Intellectual disability v3.699 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.115 CIB2 Ivone Leong Tag for-review tag was added to gene: CIB2.
Intellectual disability v3.698 ZNF526 Arina Puzriakova Phenotypes for gene: ZNF526 were changed from Non-syndromic autosomal recessive intellectual disability to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Intellectual disability v3.697 ZNF526 Arina Puzriakova Publications for gene: ZNF526 were set to 21937992; 27012031
Intellectual disability v3.696 ZNF526 Arina Puzriakova Tag for-review tag was added to gene: ZNF526.
Retinal disorders v2.115 ROM1 Ivone Leong Phenotypes for gene: ROM1 were changed from Retinitis pigmentosa 7, digenic; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa; Retinitis pigmentosa 7, digenic, 608133 to Retinitis pigmentosa 7, digenic, OMIM:608133
Retinal disorders v2.114 ROM1 Ivone Leong Publications for gene: ROM1 were set to 8595413; 32716032
Intellectual disability v3.696 ZNF526 Arina Puzriakova reviewed gene: ZNF526: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 25558065, 33397746; Phenotypes: Intellectual disability, Microcephaly, Cataracts, Epilepsy, Hypertonia, Dystonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.113 PNPLA6 Ivone Leong commented on gene: PNPLA6: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.
Retinal disorders v2.113 PNPLA6 Ivone Leong Mode of inheritance for gene: PNPLA6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.112 PNPLA6 Ivone Leong Tag for-review tag was added to gene: PNPLA6.
Retinal disorders v2.112 PNPLA6 Ivone Leong Phenotypes for gene: PNPLA6 were changed from to Boucher-Neuhauser syndrome, OMIM:215470; Oliver-McFarlane syndrome, OMIM:275400; ?Laurence-Moon syndrome, OMIM:245800
Retinal disorders v2.111 PNPLA6 Ivone Leong Publications for gene: PNPLA6 were set to
Retinal disorders v2.110 TUBGCP6 Ivone Leong commented on gene: TUBGCP6: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Retinal disorders v2.110 TUBGCP6 Ivone Leong Added comment: Comment on publications: PMID: 31077665 extra case
Retinal disorders v2.110 TUBGCP6 Ivone Leong Publications for gene: TUBGCP6 were set to 22279524; 25344692
Retinal disorders v2.109 TUBGCP6 Ivone Leong Mode of inheritance for gene: TUBGCP6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.108 TUBGCP6 Ivone Leong Tag for-review tag was added to gene: TUBGCP6.
Retinal disorders v2.108 TUBGCP6 Ivone Leong Phenotypes for gene: TUBGCP6 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 1, OMIM:251270; microcephaly and chorioretinopathy 1, MONDO:0009624
Retinal disorders v2.107 TUBGCP6 Ivone Leong Publications for gene: TUBGCP6 were set to
Anophthalmia or microphthalmia v1.35 PLK4 Ivone Leong Classified gene: PLK4 as Amber List (moderate evidence)
Anophthalmia or microphthalmia v1.35 PLK4 Ivone Leong Gene: plk4 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.34 PLK4 Ivone Leong gene: PLK4 was added
gene: PLK4 was added to Anophthalmia or microphthalmia. Sources: Literature
watchlist tags were added to gene: PLK4.
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 25344692; 25320347; 27650967
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516
Review for gene: PLK4 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25344692 describes 3 unrelated families with affected individuals who have biallelic variants in PLK4. All affected individuals have impaired growth/short stature. In one family 3 out of 7 affected individuals have an eye phenotype (ranging from microcornea, microphthalmia and cataract). Family 2 had retinopathy and family 3 did not have an eye exam performed.

PMID: 27650967 describes a case where the affected individual has bilateral microphthalmia and persistant hyperplastic primary vitreous of the left eye. The affected individual also has growth impairment.

PMID: 25320347 describes a case where the affected individuals have retinopathy and impaired growth.

As there are 2 unrelated cases there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Sources: Literature
Structural eye disease v1.24 PLK4 Ivone Leong Classified gene: PLK4 as Amber List (moderate evidence)
Structural eye disease v1.24 PLK4 Ivone Leong Gene: plk4 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.23 PLK4 Ivone Leong gene: PLK4 was added
gene: PLK4 was added to Structural eye disease. Sources: Literature
watchlist tags were added to gene: PLK4.
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 25344692; 25320347; 27650967
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516
Review for gene: PLK4 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25344692 describes 3 unrelated families with affected individuals who have biallelic variants in PLK4. All affected individuals have impaired growth/short stature. In one family 3 out of 7 affected individuals have an eye phenotype (ranging from microcornea, microphthalmia and cataract). Family 2 had retinopathy and family 3 did not have an eye exam performed.

PMID: 27650967 describes a case where the affected individual has bilateral microphthalmia and persistant hyperplastic primary vitreous of the left eye. The affected individual also has growth impairment.

PMID: 25320347 describes a case where the affected individuals have retinopathy and impaired growth.

As there are 2 unrelated cases there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Sources: Literature
Retinal disorders v2.106 PLK4 Ivone Leong commented on gene: PLK4: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Retinal disorders v2.106 PLK4 Ivone Leong Tag for-review tag was added to gene: PLK4.
Retinal disorders v2.106 TMEM216 Ivone Leong Publications for gene: TMEM216 were set to
Retinal disorders v2.105 TMEM216 Ivone Leong Mode of inheritance for gene: TMEM216 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.104 PLK4 Ivone Leong Mode of inheritance for gene: PLK4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.103 PLK4 Ivone Leong Phenotypes for gene: PLK4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516
Retinal disorders v2.102 PLK4 Ivone Leong Publications for gene: PLK4 were set to
Retinal disorders v2.101 PEX6 Ivone Leong Phenotypes for gene: PEX6 were changed from Heimler syndrome 2, MIM# 616617 to Heimler syndrome 2, OMIM:616617, MONDO:0014709
Retinal disorders v2.100 P3H2 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.; to: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. The GMS specialist group should review whether the phenotype for this gene is relevant for inclusion in this panel.
Retinal disorders v2.100 P3H2 Ivone Leong Classified gene: P3H2 as Amber List (moderate evidence)
Retinal disorders v2.100 P3H2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.
Retinal disorders v2.100 P3H2 Ivone Leong Gene: p3h2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.99 P3H2 Ivone Leong Tag for-review tag was added to gene: P3H2.
Retinal disorders v2.99 P3H2 Ivone Leong Mode of inheritance for gene: P3H2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.98 P3H2 Ivone Leong Phenotypes for gene: P3H2 were changed from Myopia, high, with cataract and vitreoretinal degeneration, 614292 -3 to Myopia, high, with cataract and vitreoretinal degeneration, OMIM:614292, MONDO:0013670
Retinal disorders v2.97 P3H2 Ivone Leong Publications for gene: P3H2 were set to
Intellectual disability v3.696 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957
Early onset or syndromic epilepsy v2.255 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957; 25326637
Hereditary ataxia, adult onset v2.20 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Complex cortical dysplasia with other brain malformations 5, 615763 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Early onset or syndromic epilepsy v2.254 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cortical dysplasia, complex, with other brain malformations 5, 615763; infantile-onset epilepsy to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Retinal disorders v2.96 NEUROD1 Ivone Leong Phenotypes for gene: NEUROD1 were changed from to Retinitis pigmentosa; Retinopathy; Permanent neonatal diabetes
Intellectual disability v3.695 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Retinal disorders v2.95 NEUROD1 Ivone Leong Publications for gene: NEUROD1 were set to
Fetal anomalies v1.136 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 5 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Cerebral vascular malformations v2.8 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cerebral Malformation Disorders to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Malformations of cortical development v2.24 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cortical dysplasia, complex, with other brain malformations 5 615763 to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Retinal disorders v2.94 MTTP Ivone Leong Classified gene: MTTP as Amber List (moderate evidence)
Retinal disorders v2.94 MTTP Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases listed in OMIM. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.94 MTTP Ivone Leong Gene: mttp has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.23 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957
Retinal disorders v2.93 MTTP Ivone Leong Tag for-review tag was added to gene: MTTP.
Retinal disorders v2.93 MTTP Ivone Leong Mode of inheritance for gene: MTTP was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.92 MTTP Ivone Leong Phenotypes for gene: MTTP were changed from Eye Disorders to Abetalipoproteinemia, OMIM:200100, MONDO:0008692
Retinal disorders v2.91 MSTO1 Ivone Leong Classified gene: MSTO1 as Amber List (moderate evidence)
Retinal disorders v2.91 MSTO1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not in Gene2Phenotype. There are at least 7 unrelated cases who are biallelic for variants in this gene and 1 family of patients (4 affected) who are monoallelic for variants in this gene.

For patients who are biallelic, there are 3 cases that reported pigmentary retinopathy. 5 out of 7 cases had growth impairments. For patients who are monoallelic there are no ophthalmological findings and growth impairment was only reported for 1 affected individual.

As not all affected individuals with biallelic variants showed a retinal disorder this gene has been given an Amber rating. Whether there is enough evidence to support a gene-disease association and for this gene to be rated Green should be reviewed by the GMS specialist group.
Retinal disorders v2.91 MSTO1 Ivone Leong Gene: msto1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.90 MSTO1 Ivone Leong Tag for-review tag was added to gene: MSTO1.
Retinal disorders v2.90 MSTO1 Ivone Leong Publications for gene: MSTO1 were set to 29339779; 28544275
Retinal disorders v2.89 MSTO1 Ivone Leong Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia MIM#617675 to Myopathy, mitochondrial, and ataxia, OMIM:617675
Retinal disorders v2.88 MMACHC Ivone Leong Classified gene: MMACHC as Amber List (moderate evidence)
Retinal disorders v2.88 MMACHC Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 cases in the literature; therefore, there is enough evidence to support a gene-disease association. This gene has been rated Amber and should be given Green status at the next review.
Retinal disorders v2.88 MMACHC Ivone Leong Gene: mmachc has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.87 MMACHC Ivone Leong Tag for-review tag was added to gene: MMACHC.
Retinal disorders v2.87 MMACHC Ivone Leong Phenotypes for gene: MMACHC were changed from Methylmalonic aciduria and homocystinuria, cblC type MIM#277400 to Methylmalonic aciduria and homocystinuria, cblC type, OMIM:277400, MONDO:0010184
Retinal disorders v2.86 MMACHC Ivone Leong Publications for gene: MMACHC were set to 28481040
Albinism or congenital nystagmus v1.10 LAMA1 Ivone Leong Classified gene: LAMA1 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.10 LAMA1 Ivone Leong Gene: lama1 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v1.9 LAMA1 Ivone Leong gene: LAMA1 was added
gene: LAMA1 was added to Albinism or congenital nystagmus. Sources: Literature
for-review tags were added to gene: LAMA1.
Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA1 were set to 25105227; 28283601; 33251915; 29167897; 328840387; 32195884
Phenotypes for gene: LAMA1 were set to Poretti-Boltshauser syndrome, OMIM:615960
Review for gene: LAMA1 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases of this affected gene in patients who have an eye phenotype, 6 out of 11 cases have nystagmus. There is enough evidence to support a gene-disease association and this gene should be considered for Green status at the next review.
Sources: Literature
Retinal disorders v2.85 LAMA1 Ivone Leong changed review comment from: This gene is associated with an relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore enough evidence to support a gene-disease association. This gene should be given a Green status at the next review.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore enough evidence to support a gene-disease association. This gene should be given a Green status at the next review.
Retinal disorders v2.85 LAMA1 Ivone Leong commented on gene: LAMA1: This gene is associated with an relevant phenotype in OMIM and Gene2Phenotype. There are >3 unrelated cases and therefore enough evidence to support a gene-disease association. This gene should be given a Green status at the next review.
Retinal disorders v2.85 LAMA1 Ivone Leong Tag for-review tag was added to gene: LAMA1.
Retinal disorders v2.85 LAMA1 Ivone Leong Publications for gene: LAMA1 were set to 25105227
Retinal disorders v2.84 LAMA1 Ivone Leong Publications for gene: LAMA1 were set to
Retinal disorders v2.83 LAMA1 Ivone Leong Mode of inheritance for gene: LAMA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.82 LAMA1 Ivone Leong Phenotypes for gene: LAMA1 were changed from to Poretti-Boltshauser syndrome, OMIM:615960
Retinal disorders v2.81 IFT81 Ivone Leong Phenotypes for gene: IFT81 were changed from to Short-rib thoracic dysplasia 19 with or without polydactyly, OMIM:617895,MONDO:0033485
Retinal disorders v2.80 IFT81 Ivone Leong Mode of inheritance for gene: IFT81 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.79 IFT81 Ivone Leong Publications for gene: IFT81 were set to
Ophthalmological ciliopathies v1.15 IFT74 Ivone Leong Publications for gene: IFT74 were set to 27486776
Ophthalmological ciliopathies v1.14 IFT74 Ivone Leong Classified gene: IFT74 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.14 IFT74 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 32144365 is the second case for this gene. Taken together there are 2 cases and an animal model. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Ophthalmological ciliopathies v1.14 IFT74 Ivone Leong Gene: ift74 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v1.9 IFT74 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.; to: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 32144365 is the second case for this gene. Taken together there are 2 cases and an animal model. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Ophthalmological ciliopathies v1.13 IFT74 Ivone Leong Tag for-review tag was added to gene: IFT74.
Rare multisystem ciliopathy disorders v1.132 IFT74 Ivone Leong Publications for gene: IFT74 were set to 27486776
Rare multisystem ciliopathy disorders v1.131 IFT74 Ivone Leong Classified gene: IFT74 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.131 IFT74 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 32144365 is the second case for this gene. Taken together there are 2 cases and an animal model. There is enough evidence to support a gene-disease association.
Rare multisystem ciliopathy disorders v1.131 IFT74 Ivone Leong Gene: ift74 has been classified as Green List (High Evidence).
Bardet Biedl syndrome v1.9 IFT74 Ivone Leong Publications for gene: IFT74 were set to 27486776
Bardet Biedl syndrome v1.8 IFT74 Ivone Leong Classified gene: IFT74 as Amber List (moderate evidence)
Bardet Biedl syndrome v1.8 IFT74 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Bardet Biedl syndrome v1.8 IFT74 Ivone Leong Gene: ift74 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v1.7 IFT74 Ivone Leong Tag for-review tag was added to gene: IFT74.
Retinal disorders v2.78 IFT74 Ivone Leong Classified gene: IFT74 as Amber List (moderate evidence)
Retinal disorders v2.78 IFT74 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and should be made Green at the next review.
Retinal disorders v2.78 IFT74 Ivone Leong Gene: ift74 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.77 IFT74 Ivone Leong Tag for-review tag was added to gene: IFT74.
Retinal disorders v2.77 IFT74 Ivone Leong Phenotypes for gene: IFT74 were changed from Bardet-Biedl syndrome 20, MIM# 617119 to ?Bardet-Biedl syndrome 20, OMIM:617119
Retinal disorders v2.76 IFT27 Ivone Leong Phenotypes for gene: IFT27 were changed from to ?Bardet-Biedl syndrome 19, OMIM:615996
Retinal disorders v2.75 IFT27 Ivone Leong Publications for gene: IFT27 were set to
Retinal disorders v2.74 IFT172 Ivone Leong commented on gene: IFT172: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough data to support a gene-disease association. This gene should be made Green at the next review (tagged with "for-review").

This gene is also Green on the following panels:
- Ophthalmological ciliopathies (Version 1.13)
- Skeletal ciliopathies (Version 1.4)
- Rare multisystem ciliopathy disorders (Version 1.130)
Retinal disorders v2.74 IFT172 Ivone Leong Tag for-review tag was added to gene: IFT172.
Retinal disorders v2.74 IFT172 Ivone Leong Mode of inheritance for gene: IFT172 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.73 IFT172 Ivone Leong Phenotypes for gene: IFT172 were changed from to Retinitis pigmentosa 71, OMIM:616394, MONDO:0014618
Retinal disorders v2.72 IFT172 Ivone Leong Publications for gene: IFT172 were set to
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Classified gene: GRN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Gene: grn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.252 GRN Ivone Leong gene: GRN was added
gene: GRN was added to Genetic epilepsy syndromes. Sources: Literature
for-review 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 31855245; 28404863; 30922528
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; neuronal ceroid lipofuscinosis 1, MONDO:0013866
Review for gene: GRN was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Biallic variants in GRN cause Ceroid lipofuscinosis, neuronal, 11, which is characterised by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be considered for Green status at the next review.

This gene is also on the Retinal disorders panel (Version 2.71), with the following review:
"Multiple individuals reported with bi-allelic variants and CLN phenotype. Please also note literature regarding retinal abnormalities in those with mono-allelic variants.
Zornitza Stark (Australian Genomics), 11 Oct 2020"
Sources: Literature
Retinal disorders v2.71 GRN Ivone Leong Classified gene: GRN as Amber List (moderate evidence)
Retinal disorders v2.71 GRN Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be made Green at the next review.
Retinal disorders v2.71 GRN Ivone Leong Gene: grn has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.70 GRN Ivone Leong Tag for-review tag was added to gene: GRN.
Hereditary neuropathy or pain disorder v1.19 NUDT2 Zornitza Stark reviewed gene: NUDT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33058507, 27431290, 30059600, 33058507; Phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Neurodegenerative disorders, adult onset v2.37 UQCRC1 Zornitza Stark gene: UQCRC1 was added
gene: UQCRC1 was added to Neurodegenerative disorders - adult onset. Sources: Literature
Mode of inheritance for gene: UQCRC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UQCRC1 were set to 33141179; 33248804
Phenotypes for gene: UQCRC1 were set to 33141179; 33248804
Review for gene: UQCRC1 was set to AMBER
Added comment: Three unrelated families reported in PMID 33141179 with some functional data, however PMID 33248804 failed to identify significant variants in this gene in a large PD cohort.
Sources: Literature
Early onset or syndromic epilepsy v2.251 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Intellectual disability v3.694 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
gene: FGF13 was marked as current diagnostic
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Skeletal dysplasia v2.42 SCUBE3 Zornitza Stark reviewed gene: SCUBE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33308444; Phenotypes: Short stature, skeletal abnormalities, craniofacial abnormalities, dental anomalies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.694 UBR7 Zornitza Stark reviewed gene: UBR7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33340455; Phenotypes: Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.251 RALGAPB Zornitza Stark gene: RALGAPB was added
gene: RALGAPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RALGAPB were set to 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to AMBER
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense, epilepsy only present in 2/10 and ID in 1/10.

Variants in this gene cause a neurodevelopmental disorder, but autism seems to be the most prominent feature.
Sources: Literature
Intellectual disability v3.694 RNU7-1 Zornitza Stark gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.18 RPL3L Zornitza Stark gene: RPL3L was added
gene: RPL3L was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy
Review for gene: RPL3L was set to GREEN
gene: RPL3L was marked as current diagnostic
Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype.
Sources: Literature
Intellectual disability v3.694 DPH2 Zornitza Stark gene: DPH2 was added
gene: DPH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
Added comment: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

Another family (sibs) was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative. Patients had ID and microcephaly (in contrast to the 19 month old above).

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Intellectual disability v3.694 FBRSL1 Zornitza Stark gene: FBRSL1 was added
gene: FBRSL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBRSL1 were set to 32424618
Phenotypes for gene: FBRSL1 were set to Intellectual disability; congenital anomalies
Review for gene: FBRSL1 was set to GREEN
gene: FBRSL1 was marked as current diagnostic
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement.
Supported by Xenopus oocyte functional studies
Sources: Literature
Severe microcephaly v2.65 CAMK2B Zornitza Stark gene: CAMK2B was added
gene: CAMK2B was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CAMK2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2B were set to 32875707
Phenotypes for gene: CAMK2B were set to microcephaly; intellectual disability; behavioural problems
Review for gene: CAMK2B was set to GREEN
Added comment: 5 individuals in review of literature with same de novo monoallelic variant reported with microcephaly
Sources: Literature
Structural eye disease v1.22 CRYAA Zornitza Stark reviewed gene: CRYAA: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32791987; Phenotypes: Anterior segment dysgenesis, microphthalmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v2.54 COL6A3 Zornitza Stark gene: COL6A3 was added
gene: COL6A3 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: COL6A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL6A3 were set to 33304895
Phenotypes for gene: COL6A3 were set to Peters anomaly
Review for gene: COL6A3 was set to AMBER
Added comment: Not sure if this is the right panel for Peters anomaly.

Variants in this gene are associated with neurological phenotypes (myopathy, dystonia). Two families reported with bi-allelic missense variants in this gene and Peters anomaly, limited functional data.
Sources: Literature
Ocular coloboma v1.41 FZD5 Zornitza Stark gene: FZD5 was added
gene: FZD5 was added to Ocular coloboma. Sources: Literature
Mode of inheritance for gene: FZD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZD5 were set to 32737437; 26908622
Phenotypes for gene: FZD5 were set to Coloboma
Review for gene: FZD5 was set to GREEN
gene: FZD5 was marked as current diagnostic
Added comment: Four unrelated families reported.
Sources: Literature
Primary ovarian insufficiency v1.19 NANOS3 Zornitza Stark reviewed gene: NANOS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25054146, 24091668; Phenotypes: Primary ovarian insufficiency; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.19 MSH5 Zornitza Stark reviewed gene: MSH5: Rating: AMBER; Mode of pathogenicity: None; Publications: 28175301, 9916805, 24970489; Phenotypes: Premature ovarian failure 13 MIM#617442; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.19 FANCM Zornitza Stark gene: FANCM was added
gene: FANCM was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: FANCM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCM were set to 30075111; 29895858; 28837162
Phenotypes for gene: FANCM were set to Premature ovarian failure
Review for gene: FANCM was set to GREEN
Added comment: 2 Finnish sisters with non-syndromic POI with a homozygous mutation (p.Gln1701*), and supporting functional assays. 1 case with 2 truncating variants (phase unknown) and non-syndromic POI and MMC chromosome-induced breakage. 3/5 women with homozygous truncating variants and breast cancer also reported early menopause or ovarian insufficiency. Null mouse model demonstrates significant reduction in ovarian follicles.
Sources: Literature
Primary ovarian insufficiency v1.19 EIF4ENIF1 Zornitza Stark reviewed gene: EIF4ENIF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31810472, 23902945, 33095795; Phenotypes: 31810472, 23902945, 33095795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary ovarian insufficiency v1.19 DIAPH2 Zornitza Stark reviewed gene: DIAPH2: Rating: RED; Mode of pathogenicity: None; Publications: 9497258, 30689869, 26175800, 11129329; Phenotypes: Premature ovarian failure 2A MIM#300511; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hypogonadotropic hypogonadism (GMS) v1.11 CCDC141 Zornitza Stark gene: CCDC141 was added
gene: CCDC141 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Literature
Mode of inheritance for gene: CCDC141 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CCDC141 were set to 27014940; 28324054; 25192046
Phenotypes for gene: CCDC141 were set to Anosmic hypogonadotropic hypogonadism
Review for gene: CCDC141 was set to AMBER
Added comment: A consanguineous family had a homozygous nonsense variant, but also had a homozygous missense in FEZF1. 3 other families reported with heterozygous variants, but other variants in other genes present. In an olfactory mouse model, Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration.
Sources: Literature
Intellectual disability v3.694 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disability
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.

Gene referred to as PRP17 in paper.
Sources: Literature
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark commented on gene: CCDC40: PMID 33220177, provided in error, refers to CDC40.
Intellectual disability v3.694 CCDC40 Zornitza Stark Deleted their comment
Intellectual disability v3.694 CCDC40 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: ID is not part of the phenotype.
Intellectual disability v3.694 CCDC40 Zornitza Stark edited their review of gene: CCDC40: Added comment: New publication: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association.; Changed publications: 33220177
Intellectual disability v3.694 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures; intellectual disbility
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Neurological ciliopathies v1.11 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to neural tube defects
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Skeletal ciliopathies v1.4 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to polydactyly; growth retardation
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Structural eye disease v1.22 NF2 Eleanor Williams changed review comment from: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose result defects leading to persistent coloboma.; to: PMID: 33075808 - Sun et al 2020 - mouse model of Nf2 inactivation in embryonic eyes shows increased retinal pigmented epithelium proliferation which they propose cause defects resulting in persistent coloboma.
Retinal disorders v2.70 GRN Ivone Leong Mode of inheritance for gene: GRN was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.69 GRN Ivone Leong Phenotypes for gene: GRN were changed from Eye Disorders to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; neuronal ceroid lipofuscinosis 1, MONDO:0013866
Retinal disorders v2.68 GRN Ivone Leong Publications for gene: GRN were set to
Structural eye disease v1.22 NF2 Eleanor Williams reviewed gene: NF2: Rating: ; Mode of pathogenicity: None; Publications: 33075808; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.67 GNB3 Ivone Leong commented on gene: GNB3: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be given Green status at the next review.
Retinal disorders v2.67 GNB3 Ivone Leong Tag for-review tag was added to gene: GNB3.
Neurological segmental overgrowth v1.7 AKT1 Eleanor Williams Publications for gene: AKT1 were set to
Neurological segmental overgrowth v1.6 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.135 AKT1 Eleanor Williams Publications for gene: AKT1 were set to
Fetal anomalies v1.134 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Mosaic skin disorders - Deep sequencing v1.5 AKT1 Eleanor Williams Publications for gene: AKT1 were set to 21793738
Mosaic skin disorders - Deep sequencing v1.4 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Segmental overgrowth disorders - Deep sequencing v2.9 AKT1 Eleanor Williams Publications for gene: AKT1 were set to
Segmental overgrowth disorders - Deep sequencing v2.8 AKT1 Eleanor Williams reviewed gene: AKT1: Rating: ; Mode of pathogenicity: None; Publications: 33030203; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.67 GNB3 Ivone Leong Mode of inheritance for gene: GNB3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.66 GNB3 Ivone Leong Publications for gene: GNB3 were set to
Retinal disorders v2.65 GNB3 Ivone Leong Phenotypes for gene: GNB3 were changed from to Night blindness, congenital stationary, type 1H, OMIM:617024, MONDO:0014872
Retinal disorders v2.64 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Ceroid lipofuscinosis, neuronal, 13, Kufs type OMIM #615362 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362
Retinal disorders v2.63 CTNNA1 Ivone Leong commented on gene: CTNNA1: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 26691986a also describes a mouse model that mimics the human phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.63 CTNNA1 Ivone Leong Tag for-review tag was added to gene: CTNNA1.
Retinal disorders v2.63 CTNNA1 Ivone Leong Mode of inheritance for gene: CTNNA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.62 CTNNA1 Ivone Leong Phenotypes for gene: CTNNA1 were changed from to Macular dystrophy, patterned, 2, OMIM:608970
Retinal disorders v2.61 CTNNA1 Ivone Leong Publications for gene: CTNNA1 were set to
Retinal disorders v2.60 CTC1 Ivone Leong Classified gene: CTC1 as Amber List (moderate evidence)
Retinal disorders v2.60 CTC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.60 CTC1 Ivone Leong Gene: ctc1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.59 CTC1 Ivone Leong Tag for-review tag was added to gene: CTC1.
Retinal disorders v2.59 CTC1 Ivone Leong Phenotypes for gene: CTC1 were changed from Cerebroretinal microangiopathy with calcifications and cysts MIM#612199 to Cerebroretinal microangiopathy with calcifications and cysts, OMIM:612199
Monogenic hearing loss v2.144 CEP250 Ivone Leong Classified gene: CEP250 as Amber List (moderate evidence)
Monogenic hearing loss v2.144 CEP250 Ivone Leong Gene: cep250 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.143 CEP250 Ivone Leong gene: CEP250 was added
gene: CEP250 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: CEP250.
Mode of inheritance for gene: CEP250 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP250 were set to 24780881; 29718797; 30459346
Phenotypes for gene: CEP250 were set to Cone-rod dystrophy and hearing loss 2, OMIM:618358, MONDO:0020780
Review for gene: CEP250 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made considered for Green status at the next review.

This gene is also on the Retinal disorders panel (v2.58) with the following review from Zornitza Stark:
"Cone-rod dystrophy and hearing loss-2 (CRDHL2) is characterized by retinal dystrophy, with photophobia and progressive reduction in visual acuity, associated with sensorineural hearing loss. Three unrelated families reported.
Zornitza Stark (Australian Genomics), 10 Oct 2020"
Sources: Literature
Retinal disorders v2.58 CEP250 Ivone Leong commented on gene: CEP250: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made Green at the next review.
Retinal disorders v2.58 CEP250 Ivone Leong Tag for-review tag was added to gene: CEP250.
Retinal disorders v2.58 CEP250 Ivone Leong Mode of inheritance for gene: CEP250 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.57 CEP250 Ivone Leong Phenotypes for gene: CEP250 were changed from to Cone-rod dystrophy and hearing loss 2, OMIM:618358, MONDO:0020780
Retinal disorders v2.56 CEP250 Ivone Leong Publications for gene: CEP250 were set to
Retinal disorders v2.55 ARL13B Ivone Leong Classified gene: ARL13B as Amber List (moderate evidence)
Retinal disorders v2.55 ARL13B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be promoted to Green at the next review.
Retinal disorders v2.55 ARL13B Ivone Leong Gene: arl13b has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.54 ARL13B Ivone Leong Tag for-review tag was added to gene: ARL13B.
Retinal disorders v2.54 ARL13B Ivone Leong Phenotypes for gene: ARL13B were changed from Eye Disorders to Joubert syndrome 8, OMIM:612291, MONDO:0012855
Retinal disorders v2.53 ARL13B Ivone Leong Publications for gene: ARL13B were set to
Retinal disorders v2.52 AP3B2 Ivone Leong Classified gene: AP3B2 as Red List (low evidence)
Retinal disorders v2.52 AP3B2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with an eye phenotype in Gene2Phenotype but not in OMIM. PMID:27889060 describes 1 out of 8 families where individuals who have variants in this gene had retinitis pigmentosa and mild optic disc pallor. This gene is also Amber on the Optic neuropathy panel (Version 2.29).

Therefore, there is currently not enough evidence to support a gene-disease association, this gene has been given a Red rating.
Retinal disorders v2.52 AP3B2 Ivone Leong Gene: ap3b2 has been classified as Red List (Low Evidence).
Retinal disorders v2.51 AP3B2 Ivone Leong Phenotypes for gene: AP3B2 were changed from Early-onset epileptic encephalopathy with optic atrophy to Developmental and epileptic encephalopathy 48, OMIM:617276, MONDO:0015000
Optic neuropathy v2.29 AP3B2 Ivone Leong Phenotypes for gene: AP3B2 were changed from Epileptic encephalopathy, early infantile, 48, 617276 to Developmental and epileptic encephalopathy 48, OMIM:617276, MONDO:0015000
Optic neuropathy v2.28 AP3B2 Ivone Leong Tag for-review was removed from gene: AP3B2.
Tag watchlist tag was added to gene: AP3B2.
Optic neuropathy v2.28 AP3B2 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark. AP3B2 is associated with a relevant disease in OMIM and probably associated with a relevant disease in Gene2Phenotype. There is enough evidence for this gene to be Green; however, until the next major review this gene will be rated as Amber for now.; to: Comment on list classification: New gene added by Zornitza Stark. AP3B2 is associated with a relevant disease in OMIM and probably associated with a relevant disease in Gene2Phenotype. PMID:27889060 describes 2 out of 8 families where individuals who have variants in this gene had optic disc/nerve pallor. Therefore, there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Retinal disorders v2.50 ALPK1 Ivone Leong Classified gene: ALPK1 as Amber List (moderate evidence)
Retinal disorders v2.50 ALPK1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association; therefore, this gene has been given an Amber rating and should be promoted to Green at the next review.
Retinal disorders v2.50 ALPK1 Ivone Leong Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.49 ALPK1 Ivone Leong Tag for-review tag was added to gene: ALPK1.
Retinal disorders v2.49 ALPK1 Ivone Leong Phenotypes for gene: ALPK1 were changed from ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache to ROSAH syndrome, OMIM:614979
Retinal disorders v2.48 CIB2 Ivone Leong Publications for gene: CIB2 were set to
Retinal disorders v2.47 CA4 Ivone Leong commented on gene: CA4: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the external reviews and available evidence the rating of this gene should be re-reviewed by the GMS specialist group at the next review. Have tagged with "for-review".
Retinal disorders v2.47 CA4 Ivone Leong Tag for-review tag was added to gene: CA4.
Retinal disorders v2.47 CA4 Ivone Leong Publications for gene: CA4 were set to 15563508; 17652713; 15090652
Retinal disorders v2.46 CA4 Ivone Leong Phenotypes for gene: CA4 were changed from Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa; Retinitis pigmentosa 17, 600852 to Retinitis pigmentosa 17, OMIM:600852, MONDO:0010945
Retinal disorders v2.45 AFG3L2 Ivone Leong commented on gene: AFG3L2: This gene is associated with a relevant phenotype in OMIM, but it is not associated with an eye phenotype in Gene2Phenotype. Based on the available information there is enough evidence to support a gene-disease association. This gene has been tagged with "for-review" and should be promoted to Green at the next review.
Retinal disorders v2.45 AFG3L2 Ivone Leong Tag for-review tag was added to gene: AFG3L2.
Retinal disorders v2.45 AFG3L2 Ivone Leong Mode of inheritance for gene: AFG3L2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.44 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to
Retinal disorders v2.43 AFG3L2 Ivone Leong Phenotypes for gene: AFG3L2 were changed from to Optic atrophy 12, OMIM:618977, MONDO:0033549
Retinal disorders v2.42 ACBD5 Ivone Leong Tag watchlist tag was added to gene: ACBD5.
Retinal disorders v2.42 ACBD5 Ivone Leong Classified gene: ACBD5 as Amber List (moderate evidence)
Retinal disorders v2.42 ACBD5 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. As there are only 2 reported cases there is not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Retinal disorders v2.42 ACBD5 Ivone Leong Gene: acbd5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.41 ACBD5 Ivone Leong Added comment: Comment on publications: Previous Publications comment:
Abu-Safieh et al Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013 Feb;23(2):236-47 PMID: 23105016
Retinal disorders v2.41 ACBD5 Ivone Leong Publications for gene: ACBD5 were set to Abu-Safieh et al Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013 Feb; 23(2):236-47 PMID: 23105016
Retinal disorders v2.40 ACBD5 Ivone Leong Added comment: Comment on phenotypes: Previous Phenotypes comment: No OMIM disease ID; novel variant reported in PMID: 23105016 in family with cone-rod dystrophyand psychomotor delay associated with significant white matter involvement
Retinal disorders v2.40 ACBD5 Ivone Leong Phenotypes for gene: ACBD5 were changed from No OMIM disease ID; novel variant reported in PMID: 23105016 in family with cone-rod dystrophyand psychomotor delay associated with significant white matter involvement to Retinal dystrophy with leukodystrophy, OMIM:618863, MONDO:0030026
Retinal disorders v2.39 ACBD5 Ivone Leong Mode of inheritance for gene: ACBD5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary ciliary disorders v1.27 MCIDAS Ivone Leong Phenotypes for gene: MCIDAS were changed from Too new - not yet linked to the PCD mutations publication to Ciliary dyskinesia, primary, 42, OMIM:618695,MONDO:0032872
Respiratory ciliopathies including non-CF bronchiectasis v1.42 MCIDAS Ivone Leong Phenotypes for gene: MCIDAS were changed from to Ciliary dyskinesia, primary, 42, OMIM:618695,MONDO:0032872
Retinal disorders v2.38 GDF6 Mehdi Montazer reviewed gene: GDF6: 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: https://doi.org/10.1038/s41431-020-0678-9; Phenotypes: kidney hypodysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.42 NPR2 Mehdi Montazer reviewed gene: NPR2: 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: https://doi.org/10.1038/s10038-020-00871-0; Phenotypes: Acromesomelic dysplasia, Maroteaux type (OMIM: # 602875); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v1.16 AP4E1 Arina Puzriakova Tag for-review tag was added to gene: AP4E1.
Hereditary spastic paraplegia, adult onset v1.16 AP4E1 Arina Puzriakova Publications for gene: AP4E1 were set to 21620353; 23472171
Hereditary spastic paraplegia, adult onset v1.15 AP4E1 Arina Puzriakova commented on gene: AP4E1
Hereditary spastic paraplegia, adult onset v1.15 AP4B1 Arina Puzriakova changed review comment from: Review of literature did not reveal any adult onset published cases.

Tagged 'for-review' to highlight that this is a childhood onset condition and therefore AP4B1 should be downgraded to Red on this panel at the next GMS panel update. This gene is already Green on the 'Hereditary spastic paraplegia - childhood onset v.1.12' panel.; to: Review of literature did not reveal any adult onset published cases.

Tagged 'for-review' to highlight that this is a childhood onset condition and therefore AP4B1 should be downgraded to Red on this panel at the next GMS panel update. This gene is already Green on the 'Hereditary spastic paraplegia - childhood onset v.2.18' panel.
Severe microcephaly v2.65 AP4E1 Arina Puzriakova Publications for gene: AP4E1 were set to 20972249; 21620353; 21937992
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Tag for-review tag was added to gene: AP4E1.
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Classified gene: AP4E1 as Amber List (moderate evidence)
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but details regarding head circumference were mostly unavailable. At least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).
Severe microcephaly v2.64 AP4E1 Arina Puzriakova Gene: ap4e1 has been classified as Amber List (Moderate Evidence).
Ocular coloboma v1.41 SIX3 Sarah Leigh changed review comment from: Comment on mode of inheritance: The gene was previously listed as an imprinted gene, with maternal expression. It would appear that this is not the case, although there is variable penetrance of the Holoprosencephaly 2 157170 phenotype in at least three unrelated families (PMID 17001667;19353631;19346217).; to: Comment on mode of inheritance: SIX3 was previously listed as an imprinted gene, with maternal expression. It would appear that this is not the case, although there is variable penetrance of the Holoprosencephaly 2 157170 phenotype in at least three unrelated families (PMID 17001667;19353631;19346217).
Ocular coloboma v1.41 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 21976454; 28670735
Ocular coloboma v1.40 SIX3 Sarah Leigh Added comment: Comment on mode of inheritance: The gene was previously listed as an imprinted gene, with maternal expression. It would appear that this is not the case, although there is variable penetrance of the Holoprosencephaly 2 157170 phenotype in at least three unrelated families (PMID 17001667;19353631;19346217).
Ocular coloboma v1.40 SIX3 Sarah Leigh Mode of inheritance for gene: SIX3 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.63 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, MIM# 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.694 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Fetal anomalies v1.134 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Neurodegenerative disorders, adult onset v2.37 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Hereditary spastic paraplegia, adult onset v1.15 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Hereditary spastic paraplegia, childhood onset v2.23 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Hereditary spastic paraplegia v1.219 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.693 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Fetal anomalies v1.133 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Neurodegenerative disorders, adult onset v2.36 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Hereditary spastic paraplegia, childhood onset v2.22 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Hereditary spastic paraplegia v1.218 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Hereditary spastic paraplegia, adult onset v1.14 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Hereditary spastic paraplegia, adult onset v1.13 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
Hereditary spastic paraplegia, adult onset v1.13 AP4B1 Arina Puzriakova commented on gene: AP4B1
White matter disorders and cerebral calcification - childhood onset v1.30 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
White matter disorders and cerebral calcification - childhood onset v1.30 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive MIM#614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
White matter disorders and cerebral calcification - childhood onset v1.29 AP4B1 Arina Puzriakova Publications for gene: AP4B1 were set to 29193663
White matter disorders and cerebral calcification - childhood onset v1.28 AP4B1 Arina Puzriakova Classified gene: AP4B1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.28 AP4B1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag).

Literature search revealed at least 24 unrelated published families with biallelic variants in this gene. Disorder mainly characterised by HSP but white matter loss is reported in over half of patients (see Publications list)
White matter disorders and cerebral calcification - childhood onset v1.28 AP4B1 Arina Puzriakova Gene: ap4b1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.62 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, MIM# 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Severe microcephaly v2.61 AP4B1 Arina Puzriakova Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Classified gene: AP4B1 as Amber List (moderate evidence)
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but will be flagged for review at the next GMS panel update to assess whether clinical utility is sufficient for inclusion as Green (added 'for-review' tag).

Literature search revealed at least 24 unrelated published cases with biallelic variants in this gene. Microcephaly is commonly reported but often mild, and particularly in the context of other more prominent/universal features (ID, HSP, etc) this disorder may be better represented by other panels.

Nonetheless, microcephaly of relevant severity to this panel (OFC ≤ -3 SD) has been recorded in at least 8 unrelated families which reaches the threshold for inclusion (PMIDs: 21620353; 29193663; 30337681; 32166732)
Severe microcephaly v2.60 AP4B1 Arina Puzriakova Gene: ap4b1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.59 AP4B1 Arina Puzriakova Tag for-review tag was added to gene: AP4B1.
Severe microcephaly v2.59 C7orf43 Arina Puzriakova Phenotypes for gene: C7orf43 were changed from Microcephaly 25, primary, autosomal recessive, MIM# 618351 to Microcephaly 25, primary, autosomal recessive, OMIM:618351; Microcephaly 25, primary, autosomal recessive, MONDO:0032694
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Tag new-gene-name tag was added to gene: C7orf43.
Severe microcephaly v2.58 C7orf43 Arina Puzriakova commented on gene: C7orf43: Added new-gene-name tag, new approved HGNC gene symbol for C7orf43 is MAP11
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Classified gene: C7orf43 as Amber List (moderate evidence)
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM (MIM# 618351) but not yet in Gene2Phenotype.

Three individuals from one family with severe ID and primary microcephaly of relevant severity (-5 SD to -6 SD). Zebrafish model recapitulates human microcephaly phenotype.

Rating Amber as additional cases required prior to inclusion on a diagnostic panel.
Severe microcephaly v2.58 C7orf43 Arina Puzriakova Gene: c7orf43 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.5 PLVAP Zornitza Stark gene: PLVAP was added
gene: PLVAP was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, MIM# 618183
Review for gene: PLVAP was set to GREEN
gene: PLVAP was marked as current diagnostic
Added comment: Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients.

Four unrelated families reported.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 NEUROG3 Zornitza Stark gene: NEUROG3 was added
gene: NEUROG3 was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: NEUROG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG3 were set to 16855267; 32574610; 28724572; 21490072
Phenotypes for gene: NEUROG3 were set to Diarrhoea 4, malabsorptive, congenital, MIM# 610370
Review for gene: NEUROG3 was set to GREEN
Added comment: Multiple families reported with malabsorptive diarrhoea +/- neonatal diabetes.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 TMPRSS15 Zornitza Stark gene: TMPRSS15 was added
gene: TMPRSS15 was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: TMPRSS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS15 were set to 11719902; 33061943
Phenotypes for gene: TMPRSS15 were set to Enterokinase deficiency, MIM# 226200
Review for gene: TMPRSS15 was set to GREEN
gene: TMPRSS15 was marked as current diagnostic
Added comment: Deficiency of enterokinase, a sequence-specific protease that activates trypsinogen and has a major role in protein digestion, is an autosomal recessive disorder characterised by severe protein malabsorption in early infancy, with failure to thrive, chronic diarrhoea, and generalized oedema. In adulthood, patients have normal body weight and no gastrointestinal symptoms, even when pancreatic enzyme supplements are discontinued. Three unrelated families reported with molecularly confirmed diagnosis.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 WNT2B Zornitza Stark gene: WNT2B was added
gene: WNT2B was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: WNT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT2B were set to 29909964
Phenotypes for gene: WNT2B were set to Diarrhoea 9, MIM# 618168
Review for gene: WNT2B was set to GREEN
gene: WNT2B was marked as current diagnostic
Added comment: Diarrhoea-9 is a form of neonatal-onset chronic diarrhoea characterized by an osmotic diarrhoea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption. Three probands from two unrelated families and functional data suggesting severe intestinal dysregulation due to decreased intestinal stem cell number and function.

Borderline Green/Amber.
Sources: Expert Review
Ocular coloboma v1.39 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 21976454
Paediatric or syndromic cardiomyopathy v1.18 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Dilated Cardiomyopathy and conduction defects v1.67 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Dilated and arrhythmogenic cardiomyopathy v1.11 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from arrythmogenic cardiomyopathy; Cardiomyopathy, familial hypertrophic, 26; Cardiomyopathy, familial restrictive 5; Myopathy, myofibrillar, 5 to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.13 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Myopathy, myofibrillar, 5 609524 to Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Congenital myopathy v2.12 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Myopathy, myofibrillar, 5, 609524; early-onset restrictive cardiomyopathy and congenital myopathy to Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Arrhythmogenic right ventricular cardiomyopathy v2.13 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Arrhythmogenic cardiomyopathy; Cardiomyopathy, familial restrictive 5 (617047); Myopathy, distal, 4 (614065); Myopathy, myofibrillar, 5 (609524) to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883
Hypertrophic cardiomyopathy v2.16 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883
Distal myopathies v1.27 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from myofibrillar myopathy 5, 609524; Distal myopathy 4, 614065 to Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Arthrogryposis v3.42 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Myopathy, myofibrillar, 5, 609524 to Cardiomyopathy, familial hypertrophic, 26, OMIM:617047; Cardiomyopathy, familial restrictive 5, OMIM:617047; Hypertrophic cardiomyopathy 26, MONDO:0014883; Myopathy, distal, 4, OMIM:614065; Distal myopathy with posterior leg and anterior hand involvement, MONDO:0013550; Myopathy, myofibrillar, 5, OMIM:609524; Myopathy, myofibrillar, 5, MONDO:0012289
Arthrogryposis v3.41 FLNC Arina Puzriakova Classified gene: FLNC as Amber List (moderate evidence)
Arthrogryposis v3.41 FLNC Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag). PMID: 29858533 reports on 3 unrelated individuals who presented at birth with arthrogryposis. This was evident prior to other FLNC-related features such as muscle weakness and cardiomyopathy, and so it is plausible that these cases may be tested in the context of this clinical indication.
Arthrogryposis v3.41 FLNC Arina Puzriakova Gene: flnc has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.40 FLNC Arina Puzriakova Publications for gene: FLNC were set to
Arthrogryposis v3.39 FLNC Arina Puzriakova Mode of inheritance for gene: FLNC was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.692 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum 617193 to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Early onset or syndromic epilepsy v2.251 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, 617193; seizures; West syndrome to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Fetal anomalies v1.132 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Early-Onset Neurodegenerative Encephalopathy to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Arthrogryposis v3.38 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Arthrogryposis v3.37 TBCD Arina Puzriakova Publications for gene: TBCD were set to
Arthrogryposis v3.36 TBCD Arina Puzriakova Classified gene: TBCD as Red List (low evidence)
Arthrogryposis v3.36 TBCD Arina Puzriakova Added comment: Comment on list classification: Maintaining the Red rating on this panel as curation of published literature revealed only a single report of an individual with multiple arthrogryposis (individual II-2 from PMID:27666374). This disorder is better represented by other panels for which this gene is already Green (Genetic epilepsy syndromes, Intellectual disability, etc).
Arthrogryposis v3.36 TBCD Arina Puzriakova Gene: tbcd has been classified as Red List (Low Evidence).
Arthrogryposis v3.35 TBCD Arina Puzriakova Mode of inheritance for gene: TBCD was changed from to BIALLELIC, autosomal or pseudoautosomal
Paediatric motor neuronopathies v1.35 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from Spinal muscular atrophy with congenital bone fractures 1 616866 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806
Fetal anomalies v1.131 TRIP4 Arina Puzriakova Publications for gene: TRIP4 were set to
Fetal anomalies v1.130 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806; ?Muscular dystrophy, congenital, Davignon-Chauveau type, OMIM:617066; Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, MONDO:0014896
Congenital myopathy v2.11 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from severe congenital myopathy with congenital bone fractures, 616866; Spinal muscular atrophy with congenital bone fractures 1, 616866 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806; ?Muscular dystrophy, congenital, Davignon-Chauveau type, OMIM:617066; Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, MONDO:0014896
Arthrogryposis v3.34 TRIP4 Arina Puzriakova Phenotypes for gene: TRIP4 were changed from Spinal muscular atrophy with congenital bone fractures 1, 616866 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806
Arthrogryposis v3.33 TRIP4 Arina Puzriakova Classified gene: TRIP4 as Amber List (moderate evidence)
Arthrogryposis v3.33 TRIP4 Arina Puzriakova Added comment: Comment on list classification: Three families with multiple congenital contractures among other features associated with variants in this gene (PMID: 26924529). However, a founder effect was suspected in the two Kosovo families and therefore this can only be considered as 2 cases total. Maintaining Amber rating, awaiting further cases/clinical evidence.
Arthrogryposis v3.33 TRIP4 Arina Puzriakova Gene: trip4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Boaz Palterer. Biallelic variant identified in a patient with lymphopenia and recurrent infections. The same variant was detected in an asymptomatic older sibling and although authors state that GIMAP6 was the best candidate to explain the clinical phenotype in the affected individual, homozygous variants were also identified in 8 other genes. Therefore, there is only enough evidence for a Red rating at present.; to: Comment on list classification: New gene added by Boaz Palterer. Biallelic variant identified in a patient with lymphopenia and recurrent infections. The same variant was detected in an asymptomatic older sibling and although authors state that GIMAP6 was the best candidate to explain the clinical phenotype in the affected individual, homozygous variants were also identified in 8 other genes (PMID: 33328581). Therefore, there is only enough evidence for a Red rating at present.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova Classified gene: GIMAP6 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Biallelic variant identified in a patient with lymphopenia and recurrent infections. The same variant was detected in an asymptomatic older sibling and although authors state that GIMAP6 was the best candidate to explain the clinical phenotype in the affected individual, homozygous variants were also identified in 8 other genes. Therefore, there is only enough evidence for a Red rating at present.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.388 GIMAP6 Arina Puzriakova Gene: gimap6 has been classified as Red List (Low Evidence).
Rare anaemia v1.9 ADH5 Arina Puzriakova Phenotypes for gene: ADH5 were changed from Aplastic anaemia; myelodysplasia; short stature to Aplastic anaemia; Mental retardation; Skin hyperpigmentation, Short stature; Microcephaly
Rare anaemia v1.8 ADH5 Arina Puzriakova Publications for gene: ADH5 were set to 33147438
Rare anaemia v1.7 ADH5 Arina Puzriakova Classified gene: ADH5 as Amber List (moderate evidence)
Rare anaemia v1.7 ADH5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient unrelated cases (>3) with relevant phenotype for this panel; however, as inheritance is digenic, this gene has been made Amber rather than Green and tagged 'digenic'.
Rare anaemia v1.7 ADH5 Arina Puzriakova Gene: adh5 has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.6 ADH5 Arina Puzriakova Tag digenic tag was added to gene: ADH5.
Rare anaemia v1.6 ADH5 Arina Puzriakova reviewed gene: ADH5: Rating: ; Mode of pathogenicity: None; Publications: 33147438, 33355142; Phenotypes: Aplastic anaemia, Mental retardation, Skin hyperpigmentation, Short stature, Microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.250 CPA6 Zornitza Stark reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: 25875328, 21922598, 23105115; Phenotypes: Epilepsy, familial temporal lobe, 5 MIM#614417, Febrile seizures, familial, 11 MIM#614418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.387 TLR8 Boaz Palterer gene: TLR8 was added
gene: TLR8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR8 was set to Other
Publications for gene: TLR8 were set to 10.1182/blood.2020009620
Phenotypes for gene: TLR8 were set to neutropenia; lymphoproliferation; hypogammaglobulinemia; bone marrow failure
Penetrance for gene: TLR8 were set to unknown
Mode of pathogenicity for gene: TLR8 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: TLR8 was set to AMBER
Added comment: Aluri et al. (Blood 2020, 10.1182/blood.2020009620) identified six unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and bone marrow failure associated with three different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8).
The variants are functionally gain-of-function and all patients are males, it's unclear if heterozygous females are affected. Both germline and somatic variants have been identified, but somatic mutations appear to be prominent.
Sources: Literature
Intellectual disability v3.691 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME TYPE 2 (CDLS2) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Early onset or syndromic epilepsy v2.250 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY; Rett-like phenotype to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Clefting v2.13 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME 2; CDLS2 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Skeletal dysplasia v2.42 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2 300590 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
Fetal anomalies v1.129 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from CORNELIA DE LANGE SYNDROME TYPE 2; EPILEPTIC ENCEPHALOPATHY to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Severe microcephaly v2.57 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590 (includes microcephaly) to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Limb disorders v2.19 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; Cornelia de Lange syndrome 2 300590 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
IUGR and IGF abnormalities v1.35 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia De Lange to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
Radial dysplasia v1.13 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590 to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370
Holoprosencephaly v2.12 SMC1A Arina Puzriakova Tag for-review tag was added to gene: SMC1A.
Holoprosencephaly v2.12 SMC1A Arina Puzriakova Classified gene: SMC1A as Amber List (moderate evidence)
Holoprosencephaly v2.12 SMC1A Arina Puzriakova Added comment: Comment on list classification: New gene added by external reviewer. At least 6 unrelated females with holoprosencephaly, mostly commonly semi-lobar type, associated with de novo variants in this gene (PMIDs: 28166369 and 31334757). Likely represents the severe end of the spectrum of SMC1A-related disorders.

Sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)
Holoprosencephaly v2.12 SMC1A Arina Puzriakova Gene: smc1a has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.11 SMC1A Arina Puzriakova Publications for gene: SMC1A were set to PMID: 31334757
Holoprosencephaly v2.10 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from holoprosencephaly; single central incisor to Developmental and epileptic encephalopathy 85, with midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Clefting v2.12 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS; Cleft palate to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Fetal anomalies v1.128 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome 170390 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Skeletal muscle channelopathy v1.7 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome, 170390 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Paroxysmal central nervous system disorders v1.10 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome, 170390; Andersen cardiodysrhythmic periodic paralysis; Episodic weakness; Periodic paralysis; Hypokalemic Periodic Paralysis, Type 2 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Catecholaminergic polymorphic VT v2.7 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from catecholaminergic polymorphic ventricular tachycardia; Atrial fibrillation, familial, 9 (613980); Andersen syndrome (170390); Short QT syndrome 3 (609622) to Short QT syndrome 3, OMIM:609622; Short QT syndrome type 3, MONDO:0012314; Atrial fibrillation, familial, 9, OMIM:613980; Atrial fibrillation, familial, 9, MONDO:0013513; Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Long QT syndrome v2.22 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome (170390); Atrial fibrillation, familial, 9 (613980); ANDERSEN SYNDROME (170390); LONG QT SYNDROME 7 (170390); Short QT syndrome 3 (609622) to Short QT syndrome 3, OMIM:609622; Short QT syndrome type 3, MONDO:0012314; Atrial fibrillation, familial, 9, OMIM:613980; Atrial fibrillation, familial, 9, MONDO:0013513; Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Short QT syndrome v2.7 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Atrial fibrillation, familial, 9 (613980); Short QT syndrome 3 609622; Short QT syndrome 3 (609622); Andersen syndrome (170390); ventricular tacyarrhythmia; short qt; atrial fibrillation to Short QT syndrome 3, OMIM:609622; Short QT syndrome type 3, MONDO:0012314; Atrial fibrillation, familial, 9, OMIM:613980; Atrial fibrillation, familial, 9, MONDO:0013513; Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222
Skeletal Muscle Channelopathies v1.27 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Hypokalemic Periodic Paralysis, Type 2; Episodic weakness; Periodic paralysis; ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS; Andersen syndrome to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Brain channelopathy v1.59 KCNJ2 Arina Puzriakova Phenotypes for gene: KCNJ2 were changed from Andersen syndrome, MIM# 170390 to Andersen syndrome, OMIM:170390; Andersen-Tawil syndrome, MONDO:0008222; Episodic weakness; Periodic paralysis
Brain channelopathy v1.58 KCNJ2 Arina Puzriakova Classified gene: KCNJ2 as Green List (high evidence)
Brain channelopathy v1.58 KCNJ2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Green as there are sufficient unrelated cases (>3) with monoallelic variants in this potassium channel gene. KCNJ2 is also Green on the 'Skeletal muscle channelopathy v1.6' GMS panel.
Brain channelopathy v1.58 KCNJ2 Arina Puzriakova Gene: kcnj2 has been classified as Green List (High Evidence).
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Tag watchlist tag was added to gene: SLC9A7.
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Classified gene: SLC9A7 as Amber List (moderate evidence)
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Associated with relevant phenotype in OMIM and Gene2Phenotype. However, only 2 unrelated families reported at present (PMID: 30335141) and therefore only sufficient for an Amber rating, awaiting further publications/clinical evidence (added 'watchlist' tag)
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Gene: slc9a7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.689 SLC9A7 Arina Puzriakova Phenotypes for gene: SLC9A7 were changed from Intellectual developmental disorder, X-linked 108; OMIM #301024 to Intellectual developmental disorder, X-linked 108, OMIM:301024; Intellectual developmental disorder, X-linked 108, MONDO:0026723
Dystonia, chorea or related movement disorder, childhood onset v1.70 MPI Arina Puzriakova Mode of inheritance for gene: MPI was changed from to BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.69 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Primary lymphoedema v2.7 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Fetal anomalies v1.127 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Likely inborn error of metabolism v2.41 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation); Congenital disorder of glycosylation, type Ib 602579 to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation)
Likely inborn error of metabolism v2.40 MPI Arina Puzriakova Publications for gene: MPI were set to 10980531
Undiagnosed metabolic disorders v1.436 MPI Arina Puzriakova Publications for gene: MPI were set to 27604308
Undiagnosed metabolic disorders v1.435 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation); Congenital disorder of glycosylation, type Ib 602579; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation) to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.387 MPI Arina Puzriakova Mode of inheritance for gene: MPI was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.386 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Congenital disorders of glycosylation v2.20 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Congenital disorder of glycosylation, type Ib 602579; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation) to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257; Phosphomannose isomerase deficiency (Disorders of protein N-glycosylation)
Congenital disorders of glycosylation v2.19 MPI Arina Puzriakova Publications for gene: MPI were set to 10980531
Cholestasis v1.76 MPI Arina Puzriakova Publications for gene: MPI were set to 12414827; 10980531; 9585601; 28108845
Cholestasis v1.75 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Congenital disorder of glycosylation, type Ib, OMIM:602579 to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
COVID-19 research v1.71 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Neonatal cholestasis v1.17 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from Congenital disorder of glycosylation, type Ib 602579 to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Intellectual disability v3.688 MPI Arina Puzriakova Publications for gene: MPI were set to 9525984; 3080572; 9585601
Intellectual disability v3.687 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
Intellectual disability v3.686 MPI Arina Puzriakova reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.686 MPI Arina Puzriakova Tag for-review tag was added to gene: MPI.
Intellectual disability v3.686 HDAC4 Arina Puzriakova commented on gene: HDAC4
Intellectual disability v3.686 HDAC4 Arina Puzriakova Tag for-review was removed from gene: HDAC4.
Intellectual disability v3.686 AGO2 Arina Puzriakova Classified gene: AGO2 as Amber List (moderate evidence)
Intellectual disability v3.686 AGO2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. All patients reported in PMID: 33199684 presented GDD/ID, while other features were relatively heterogenous. However, cognitive impairment was perhaps too mild in majority of cases. Tagged 'for-review' to assess whether there is sufficient evidence for a Green rating in light of the scope of the ID panel.
Intellectual disability v3.686 AGO2 Arina Puzriakova Gene: ago2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.685 AGO2 Arina Puzriakova Tag for-review tag was added to gene: AGO2.
Intellectual disability v3.685 AGO2 Arina Puzriakova reviewed gene: AGO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33199684; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.685 ZNF407 Arina Puzriakova Classified gene: ZNF407 as Amber List (moderate evidence)
Intellectual disability v3.685 ZNF407 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Some evidence linking both mono- and biallelic variants with disease but currently not sufficient for a Green rating. Further cases would help validate this gene-disease association (added 'watchlist' tag)
Intellectual disability v3.685 ZNF407 Arina Puzriakova Gene: znf407 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit
Bilateral congenital or childhood onset cataracts v2.54 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.54 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as although number of unrelated cases reaches threshold for inclusion (3), the phenotype is not fully penetrant and the disorder is better represented by other panels (e.g. ID, microcephaly etc). This may however we revised if further cases arise.
Bilateral congenital or childhood onset cataracts v2.54 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.53 SMG8 Arina Puzriakova gene: SMG8 was added
gene: SMG8 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to 31130284; 33242396
Phenotypes for gene: SMG8 were set to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism; Cataract
Review for gene: SMG8 was set to AMBER
Added comment: Currently not associated with any phenotype in OMIM or G2P.
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- PMID: 31130284 (2019) - One individual with cataract and a homozygous variant in this gene identified as part of a large candidate gene discovery study. Other features include microcephaly, ID, and neck hyperpigmentation. No further details were provided.

- PMID: 33242396 (2020) - Different biallelic variants in the SMG8 gene identified in 4 consanguineous families, of which 2 kindreds had 3 individuals with cataract. Authors reported congenital bilateral cataract in the two sibs, while the third patient had cataract operated at age 12yrs although the age of onset or any further information was not available. Other clinical features include GDD/ID, dysmorphic features, microcephaly, short stature, brain imaging anomalies and congenital heart disease. Some supportive functional data also provided.
Sources: Literature
Severe microcephaly v2.56 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Severe microcephaly v2.56 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but can be promoted to Green at the next GMS panel update (added 'for-review' tag).

At least 5 unrelated families with microcephaly and different homozygous variants in the SMG8 gene. OFC recorded for only 3 families, but each includes at least one microcephalic individual with severity relevant to this panel (more than -3 SD)
Severe microcephaly v2.56 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.55 SMG8 Arina Puzriakova gene: SMG8 was added
gene: SMG8 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: SMG8.
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to 31130284; 33242396
Phenotypes for gene: SMG8 were set to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Review for gene: SMG8 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM or G2P.
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- PMID: 31130284 (2019) - Two individuals with distinct homozygous variants in this gene identified as part of a large candidate gene discovery study. Phenotype in one patient included microcephaly, ID, cataract, and neck hyperpigmentation; while the other presented short stature, microcephaly, fine motor delay, ventricular septal defect, failure to thrive, and facial dysmorphism.

- PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD/ID (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Some supportive functional data also provided. Microcephaly was recorded in 3/4 families, ranging in severity from -2.5 SD to -4.1 SD.
Sources: Literature
Intellectual disability v3.683 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
Intellectual disability v3.683 SMG8 Arina Puzriakova Added comment: Comment on list classification: Additional cases reported in recent publication (PMID: 33242396) extend the total to at least 5 unrelated families with GDD/ID and different homozygous variants in the SMG8 gene. Also some supporting functional data provided.

Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.683 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.682 SMG8 Arina Puzriakova Publications for gene: SMG8 were set to 31130284
Intellectual disability v3.681 SMG8 Arina Puzriakova edited their review of gene: SMG8: Added comment: PMID: 33242396 (2020) - 9 affected individuals from 4 consanguineous families with different biallelic variants in the SMG8 gene. Clinical features include GDD (8/8), dysmorphic features (9/9) microcephaly (6/9), short stature (4/9), brain imaging anomalies (4/5), congenital heart disease (3/9) and cataract (3/8). Only two sibs from Family 2 had a formal ID diagnosis, but this can be inferred from the clinical reports of the other cases demonstrating severe language delays, difficulties to follow simple instructions or perform daily activities.
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Several features described here overlap with those in the previously reported cases from PMID: 31130284 (e.g. microcephaly, ID, cataract, VSD); Changed rating: GREEN; Changed publications: 31130284, 33242396
Rare anaemia v1.6 NHLRC2 Eleanor Williams changed review comment from: Comment on list classification: Changing rating from red to amber with recommendation of review by the GMS with regards to phenotypic fit for this panel. Sufficient cases to make green if appropriate.; to: Comment on list classification: On recommendation of Genomics England clinical team, changing rating from red to amber with recommendation of review by the GMS with regards to phenotypic fit for this panel. Sufficient cases to make green if appropriate.
Rare anaemia v1.6 NHLRC2 Eleanor Williams Classified gene: NHLRC2 as Amber List (moderate evidence)
Rare anaemia v1.6 NHLRC2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber with recommendation of review by the GMS with regards to phenotypic fit for this panel. Sufficient cases to make green if appropriate.
Rare anaemia v1.6 NHLRC2 Eleanor Williams Gene: nhlrc2 has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.5 NHLRC2 Eleanor Williams Tag for-review tag was added to gene: NHLRC2.
Rare anaemia v1.5 NHLRC2 Eleanor Williams gene: NHLRC2 was added
gene: NHLRC2 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 29423877; 32435055
Phenotypes for gene: NHLRC2 were set to FINCA syndrome OMIM:618278
Review for gene: NHLRC2 was set to GREEN
Added comment: PMID: 29423877 Uusimaa et al 2018 - report 3 patients from 2 unrelated non-consanguineous Finnish families in which the children were born asymptomatic but by 2 months of age they had developed a progressive multi-organ disorder. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. All three patients were found using WES to be compound heterozygous for NM_198514:c.442G>T, p.Asp148Tyr and c.601_602delAG, p.Arg201GlyfsTer6. Segregation data for both families is provided. The family history of the two families, traced back 7–9 generations, showed that they did not have common ancestors. Both variants are rare in both Finnish (Sequencing Initiative Suomi - 0.003 and 0.0001 respectively) and non-Finnish populations (Exac). Patient fibroblasts expressed only mRNA with the c.442G>T missense variant, and at low levels. Development of Nhlrc2 null mice stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos showed that nhlrc2 has a role in cellular integrity of the central nervous system during development.

PMID: 32435055 - Brodsky et al 2020 - report a 2 year old Ukranian patient with FINCA syndrome who was found by WES to have compound heterozygous variants in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P). The c.428C>A variant is not found in the gnomAD database. Each parent was a carrier for one of the variants.
Sources: Literature
Paediatric disorders - additional genes v1.70 NHLRC2 Eleanor Williams Classified gene: NHLRC2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.70 NHLRC2 Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene from red to amber, but with a green rating recommendation for GMS review. 3 cases reported, plus mouse and zebrafish models and functional data from patient fibroblasts.
Paediatric disorders - additional genes v1.70 NHLRC2 Eleanor Williams Gene: nhlrc2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.69 NHLRC2 Eleanor Williams gene: NHLRC2 was added
gene: NHLRC2 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 29423877; 32435055
Phenotypes for gene: NHLRC2 were set to FINCA syndrome OMIM:618278
Review for gene: NHLRC2 was set to GREEN
Added comment: PMID: 29423877 Uusimaa et al 2018 - report 3 patients from 2 unrelated non-consanguineous Finnish families in which the children were born asymptomatic but by 2 months of age they had developed a progressive multi-organ disorder. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. All three patients were found using WES to be compound heterozygous for NM_198514:c.442G>T, p.Asp148Tyr and c.601_602delAG, p.Arg201GlyfsTer6. Segregation data for both families is provided. The family history of the two families, traced back 7–9 generations, showed that they did not have common ancestors. Both variants are rare in both Finnish (Sequencing Initiative Suomi - 0.003 and 0.0001 respectively) and non-Finnish populations (Exac). Patient fibroblasts expressed only mRNA with the c.442G>T missense variant, and at low levels. Development of Nhlrc2 null mice stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos showed that nhlrc2 has a role in cellular integrity of the central nervous system during development.

PMID: 32435055 - Brodsky et al 2020 - report a 2 year old Ukranian patient with FINCA syndrome who was found by WES to have compound heterozygous variants in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P). The c.428C>A variant is not found in the gnomAD database. Each parent was a carrier for one of the variants.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.68 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.67 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886
Early onset or syndromic epilepsy v2.249 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Early onset or syndromic epilepsy v2.248 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911; 29545233; 27567911
Monogenic hearing loss v2.142 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Red List (low evidence)
Monogenic hearing loss v2.142 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: Multiple individuals with KCNMA1-related channelopathy characterised by a variety of neurologic symptoms, with both mono- and biallelic cases reported. Only a single patient described by Liang et al., 2019 (PMID: 31152168) with hearing impairment and therefore a Red rating on this panel is appropriate.
Monogenic hearing loss v2.142 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.141 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to
Monogenic hearing loss v2.140 KCNMA1 Arina Puzriakova Mode of inheritance for gene: KCNMA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.681 LSS Eleanor Williams changed review comment from: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; to: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS, as agreed with Genomics England clinicians. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.
Intellectual disability v3.681 LSS Eleanor Williams Tag for-review tag was added to gene: LSS.
Intellectual disability v3.681 LSS Eleanor Williams edited their review of gene: LSS: Added comment: In light of the recent expert review green by Zornitza Stark, this gene should be considered for a green rating by the GMS. The phenotype is variable with the ID phenotype being part of the presentation in approx half the families.; Changed rating: GREEN
Paroxysmal central nervous system disorders v1.9 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to
Paroxysmal central nervous system disorders v1.8 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276
Brain channelopathy v1.57 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446 to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276
Brain channelopathy v1.56 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Green List (high evidence)
Brain channelopathy v1.56 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Green as there are sufficient unrelated cases (3) with early-onset paroxysmal nonkinesigenic dyskinesia associated with monoallelic variants in this potassium channel gene. KCNMA1 is also Green on the 'Paroxysmal central nervous system disorders v1.7' GMS panel.
Brain channelopathy v1.56 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Green List (High Evidence).
Intellectual disability v3.681 KCNMA1 Arina Puzriakova changed review comment from: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity to this panel has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.; to: Multiple individuals reported with either mono- or biallelic variants. Developmental delay and intellectual disability of relevant severity has been reported in a sufficient number of cases for inclusion on this panel. Although in most cases the phenotypes are primarily characterised by seizures or dyskinesia, it is plausible that these individuals may still be tested under the ID panel in context of the severe intellectual impairment that may be observed.

Furthermore, several individuals have been reported with severe GDD/ID and other variable feature such as craniofacial dysmorphism, ataxia, bone dysplasia, visceral malformations, and brain imaging anomalies, but without epilepsy or paroxysmal dyskinesia (namely Liang-Wang syndrome, PMID: 31152168). In less severely affected cases DD with significant speech delay has been noted as the main clinical indication of the presenting phenotypes, further indicating benefit of inclusion on a diagnostic ID panel.
Intellectual disability v3.681 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Intellectual disability v3.680 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911; 29545233; 26195193
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Amber List (moderate evidence)
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.678 KCNMA1 Arina Puzriakova Tag for-review tag was added to gene: KCNMA1.
Intellectual disability v3.678 KCNMA1 Arina Puzriakova reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26195193, 27567911, 29330545, 29545233, 31152168, 31427379; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643, Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551, Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446, Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276, Liang-Wang syndrome, OMIM:618729, Liang-Wang syndrome, MONDO:0032886, {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596, Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.678 LIAS Eleanor Williams commented on gene: LIAS
Intellectual disability v3.678 LIAS Eleanor Williams Tag for-review tag was added to gene: LIAS.
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams changed review comment from: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature; to: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.

PMID: 29016354 - Chen and Lui 2017 - report a pediatric patient with congenital cataract, small penis, baldness and absence of eyebrows and compound heterozygous variants in LSS.

Sources: Literature
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams changed review comment from: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature; to: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30723320 - Besnard et al 2019 - report 7 unrelated families (11 individuals) with variants in LSS who present with alopecia (11/11), intellectual disability (10 mod/severe, 1 mild) and epilepsy (7/11). Segregation data shown for 6 families.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams changed review comment from: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental.
Sources: Literature; to: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental. No other phenotypes such as cataracts were reported.
Sources: Literature
Non-syndromic hypotrichosis v1.5 LSS Eleanor Williams gene: LSS was added
gene: LSS was added to Non-syndromic hypotrichosis. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 32101538; 30401459
Phenotypes for gene: LSS were set to Hypotrichosis 14 OMIM:618275; hypotrichosis 14 MONDO:0032649
Review for gene: LSS was set to GREEN
Added comment: Associated with Hypotrichosis 14 618275 (AR) in OMIM.

PMID: 32101538 - Wada et al 2020 - report two siblings from a nonconsanguineous Japanese family with novel biallelic LSS mutations (compound het) who presented congenital hypotrichosis, midline anomalies, such as cleft palate and agenesis of the corpus callosum, and no cataracts. The motor and mental development of the patients were normal. They also created tissue specific knock-out mice as Lss constitutive knockout mice are embryonically lethal, and found epidermis-specific knockout of Lss caused hypotrichosis, lens-specific Lss knockout mice had cataracts.

PMID: 30401459 - Romano et al 2018 - report 3 unrelated (Arabic, Swiss, Afgan origin) families with potentially autosomal-recessive Hypotrichosis simplex in which they identify by WES 5 five different missense and nonsense mutations in LSS. Variants were shown to segregate with the disorder in 2 families (DNA not available for the third). In one family the siblings also presented with intellectual disability but the authors consider this coincidental.
Sources: Literature
Intellectual disability v3.678 GRIA1 Arina Puzriakova Classified gene: GRIA1 as Amber List (moderate evidence)
Intellectual disability v3.678 GRIA1 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as no new evidence has been published since previous review. Most commonly reported as a candidate gene in large screening studies with limited segregation/phenotype/functional data. Also variable penetrance of the ID phenotype. Therefore, there is currently not enough evidence to classify as Green.
Intellectual disability v3.678 GRIA1 Arina Puzriakova Gene: gria1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.139 GJB3 Eleanor Williams edited their review of gene: GJB3: Changed publications: 9843210, 12630965, 10790215, 12791041, 15131355, 17259707, 19744334, 22617145, 23638949, 25214170, 27610647, 10587579, 16077902
Monogenic hearing loss v2.139 GJB3 Eleanor Williams edited their review of gene: GJB3: Changed publications: 9843210, 12630965, 10790215, 12791041, 15131355, 17259707, 19744334, 22617145, 23638949, 25214170, 27610647, 10587579, 1607790279
Monogenic hearing loss v2.139 GJB3 Eleanor Williams reviewed gene: GJB3: Rating: AMBER; Mode of pathogenicity: None; Publications: 9843210, 12630965, 10790215, 12791041, 15131355, 17259707, 19744334, 22617145, 23638949, 25214170, 27610647, 105875, 1607790279; Phenotypes: Deafness, autosomal dominant 2B OMIM:612644; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.247 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Early onset or syndromic epilepsy v2.246 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.245 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.677 H3F3B Arina Puzriakova changed review comment from: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).; to: Currently not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33268356 (2020) - De novo missense variants identified in 13 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. One individual was reported to have a normal IQ at 15 years. 8/13 patients showed abnormalities on brain MRI including hypomyelination (5), cortical atrophy (4), arachnoid cysts (3), and a thin corpus collosum (2). Variable seizure phenotypes were reported in 6/13 cases, all early-onset where specified, mostly during infancy (latest onset at 10 years of age).
Intellectual disability v3.677 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Intellectual disability v3.676 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.675 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.674 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Intellectual disability v3.674 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (at least 12) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.674 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.673 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Intellectual disability v3.673 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Segmental overgrowth disorders - Deep sequencing v2.8 PADI6 Sarah Leigh Tag for-review tag was added to gene: PADI6.
Segmental overgrowth disorders - Deep sequencing v2.8 PADI6 Sarah Leigh edited their review of gene: PADI6: Added comment: PMID: 32928291 reports three variants associated with Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance in three cases. Five variants have also been associated with Preimplantation embryonic lethality 2, where they have been biallelic in the women affected (pmid 27545678). There is enough evidence for this gene to be reviewed at the next major review.; Changed publications: 32928291, 33221824, 27545678
Malformations of cortical development v2.22 H3F3A Arina Puzriakova commented on gene: H3F3A: Added new-gene-name tag, new approved HGNC gene symbol for H3F3A is H3-3A
Malformations of cortical development v2.22 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Malformations of cortical development v2.22 H3F3A Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.22 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.21 H3F3A Arina Puzriakova gene: H3F3A was added
gene: H3F3A was added to Malformations of cortical development. Sources: Literature
new-gene-name, for-review tags were added to gene: H3F3A.
Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: H3F3A were set to 31942419; 33268356
Phenotypes for gene: H3F3A were set to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Review for gene: H3F3A was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM, but is listed in Gene2Phenotype with a 'confirmed' disease confidence rating for 'Craniofacial with neurodevelopment disorders'.

- PMID: 31942419 (2019) - De novo missense variant identified by trio exome sequencing in a girl with secondary microcephaly, severe DD and ID, growth retardation and dysmorphic features. Brain MRI demonstrated hypoplasia of corpus callosum and cerebellum as well as thin layer of frontal and parietal periventricular gliosis. No functional analyses of the variant or patient cells were performed.

- PMID: 33268356 (2020) - De novo missense variants identified in 33 unrelated individuals with a shared phenotype of GDD/ID, usually severe and often progressive, with mostly minor congenital anomalies. 23/28 patients showed abnormalities on brain MRI including hypoplasia/agenesis of the corpus collosum (9), cortical atrophy (6) and impaired myelination (5). Variable seizure phenotypes were reported in 17/33 cases, all early-onset where specified, mostly during infancy (latest onset at 14 years of age).
Sources: Literature
Segmental overgrowth disorders - Deep sequencing v2.8 PADI6 Sarah Leigh gene: PADI6 was added
gene: PADI6 was added to Segmental overgrowth disorders. Sources: Literature
Mode of inheritance for gene: PADI6 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: PADI6 were set to 32928291; 33221824
Phenotypes for gene: PADI6 were set to Preimplantation embryonic lethality 2 OMIM:617234; Beckwith-Wiedemann syndrome
Review for gene: PADI6 was set to AMBER
Added comment: Sources: Literature
Early onset or syndromic epilepsy v2.243 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.242 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Early onset or syndromic epilepsy v2.241 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.673 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.672 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Intellectual disability v3.671 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.670 H3F3A Arina Puzriakova Deleted their comment
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Intellectual disability v3.670 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promoted to Green at the next GMS panel update (added 'for-review' tag).

Multiple unrelated cases (>30) with GDD/ID associated with de novo variants in this gene.
Intellectual disability v3.670 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.669 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Intellectual disability v3.669 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942419, 33268356; Phenotypes: Developmental delay, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.139 GJB6 Eleanor Williams commented on gene: GJB6: As reviewer Zornitza Stark reports this gene has Refuted status in association with hearing loss by ClinGen. However, leaving as amber, as there is still some evidence to support the possibility that SNV in this gene are associated with hearing loss (Grifa et al and Amritkumar et al).
Monogenic hearing loss v2.139 PMP22 Eleanor Williams Classified gene: PMP22 as Amber List (moderate evidence)
Monogenic hearing loss v2.139 PMP22 Eleanor Williams Added comment: Comment on list classification: After consultation with Genomics England clinical team leaving this gene as amber as the majority of patients do not have a hearing loss phenotype, and there are also issues around the potential predictive nature of the neurological aspects if this panel was applied to a paediatric hearing loss cohort.
Monogenic hearing loss v2.139 PMP22 Eleanor Williams Gene: pmp22 has been classified as Amber List (Moderate Evidence).
DDG2P v2.16 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
DDG2P v2.15 H3F3A Arina Puzriakova Classified gene: H3F3A as Green List (high evidence)
DDG2P v2.15 H3F3A Arina Puzriakova Added comment: Comment on list classification: Changed rating to Green as H3F3A is listed in Gene2Phenotype under the new gene name, H3-3A.

Associated with 'Craniofacial with neurodevelopment disorders' with a disease confidence rating of 'confirmed'
DDG2P v2.15 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Green List (High Evidence).
DDG2P v2.14 H3F3A Arina Puzriakova commented on gene: H3F3A
DDG2P v2.14 H3F3A Arina Puzriakova Tag new-gene-name tag was added to gene: H3F3A.
Monogenic hearing loss v2.138 SCD5 Eleanor Williams Classified gene: SCD5 as Red List (low evidence)
Monogenic hearing loss v2.138 SCD5 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to red. As outlined by the reviewer, one large Chinese family with autosomal dominant non syndromic hearing loss reported, in which a missense variant in the SCD5 gene (c.626G > C, p.W209S, NM_ 001037582) segregated perfectly cases with hearing loss.
Monogenic hearing loss v2.138 SCD5 Eleanor Williams Gene: scd5 has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.137 SCD5 Eleanor Williams Phenotypes for gene: SCD5 were changed from Deafness, autosomal dominant 79, MIM#619086 to Deafness, autosomal dominant 79 OMIM:619086; deafness, autosomal dominant 79 MONDO:0033668
Intellectual disability v3.669 KDM4B Arina Puzriakova Tag for-review tag was added to gene: KDM4B.
Intellectual disability v3.669 KDM4B Arina Puzriakova Classified gene: KDM4B as Amber List (moderate evidence)
Intellectual disability v3.669 KDM4B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but may be promoted to Green at the next GMS panel update (added 'for-review' tag).

9 unrelated individuals reported at present (PMID: 33232677). Although all presented GDD, only 1 individual had severe ID (IQ = 50) and 3 had mild ID. Although ID is too mild in majority of cases, developmental delay was the universal feature amongst affected individuals and other phenotypes were heterogenous (e.g. seizures, brain malformations). Therefore, there may be value in inclusion on this panel for capturing this phenotype.
Intellectual disability v3.669 KDM4B Arina Puzriakova Gene: kdm4b has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.38 ABCC6 Ivone Leong edited their review of gene: ABCC6: Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and expert reviews, this gene should be promoted to Green at the next review.; Changed rating: GREEN
Retinal disorders v2.38 ABCC6 Ivone Leong Tag for-review tag was added to gene: ABCC6.
Retinal disorders v2.38 ABCC6 Ivone Leong Mode of inheritance for gene: ABCC6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.37 ABCC6 Ivone Leong Phenotypes for gene: ABCC6 were changed from to Pseudoxanthoma elasticum, OMIM:264800; inherited pseudoxanthoma elasticum, MONDO:0100091
Retinal disorders v2.36 USP45 Ivone Leong Classified gene: USP45 as Amber List (moderate evidence)
Retinal disorders v2.36 USP45 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Retinal disorders v2.36 USP45 Ivone Leong Gene: usp45 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.35 USP45 Ivone Leong Tag for-review tag was added to gene: USP45.
Retinal disorders v2.35 USP45 Ivone Leong Phenotypes for gene: USP45 were changed from Lebers congenital amaurosis; retinal dystrophy; ?Leber congenital amaurosis 19, 618513 to Lebers congenital amaurosis; retinal dystrophy; ?Leber congenital amaurosis 19, OMIMM:618513
Skeletal Muscle Channelopathies v1.26 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, OMIM:255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Fetal anomalies v1.126 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from DYSSEGMENTAL DYSPLASIA SILVERMAN-HANDMAKER TYPE; SCHWARTZ-JAMPEL SYNDROME to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Skeletal dysplasia v2.41 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Dyssegmental dysplasia, Silverman-Handmaker type 224410; Schwartz-Jampel syndrome, type 1 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Arthrogryposis v3.32 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Paroxysmal central nervous system disorders v1.7 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800; Dyssegmental dysplasia, Silverman-Handmaker type, 224410 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140
Skeletal Muscle Channelopathies v1.25 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800
Intellectual disability v3.668 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Intellectual disability v3.667 HSPG2 Arina Puzriakova Classified gene: HSPG2 as Amber List (moderate evidence)
Intellectual disability v3.667 HSPG2 Arina Puzriakova Added comment: Comment on list classification: While there are sufficient cases to support a gene-disease association, DD/ID is part of a broader phenotype and cognitive impairment is unlikely to represent a main feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Skeletal dysplasia, Arthrogryposis, etc) where this gene is already Green.
Intellectual disability v3.667 HSPG2 Arina Puzriakova Gene: hspg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Classified gene: CSNK1G1 as Amber List (moderate evidence)
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now at least 5 unrelated individuals reported (PMID: 33009664). All present developmental delay of varying severity, although a formal ID assessment was not performed. Tagged 'for-review' to evaluate relevance of the phenotypes to this panel.
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Gene: csnk1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.665 CSNK1G1 Arina Puzriakova Tag for-review tag was added to gene: CSNK1G1.
Dilated and arrhythmogenic cardiomyopathy v1.10 SLC6A6 Ivone Leong Classified gene: SLC6A6 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.10 SLC6A6 Ivone Leong Gene: slc6a6 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.9 SLC6A6 Ivone Leong gene: SLC6A6 was added
gene: SLC6A6 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
watchlist tags were added to gene: SLC6A6.
Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034; 17875433; 20804595
Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy
Review for gene: SLC6A6 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype.

There are 3 unrelated cases with early retinal degeneration and only 2 cases had DCM (PMID: 31903486 and 29886034). The case described in PMID: 29886034 did not report any segregation results for the affected individual with DCM. The case described in 29886034, affected individuals were treated with taurine for 2 years and the cardiomyopathy was corrected.
The mouse model (PMID: 20804595) is a KO taurine transporter showed a cardiac.
Sources: Literature
Skeletal dysplasia v2.40 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Skeletal dysplasia v2.40 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.39 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. After consulting the Genomics England Clinical Team, it was decided that this gene should be added to this panel with an Amber rating. The skeletal phenotype is relatively mild and the GMS specialist group should review whether this gene is appropriate for this panel.
Sources: Literature
Early onset or syndromic epilepsy v2.239 CSNK1G1 Arina Puzriakova Mode of inheritance for gene: CSNK1G1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.39 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.39 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.38 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Red List (low evidence)
Likely inborn error of metabolism v2.38 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber but can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Likely inborn error of metabolism v2.38 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Red List (Low Evidence).
Likely inborn error of metabolism v2.37 SHMT2 Arina Puzriakova commented on gene: SHMT2: SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Likely inborn error of metabolism v2.37 SHMT2 Arina Puzriakova gene: SHMT2 was added
gene: SHMT2 was added to Inborn errors of metabolism. Sources: Literature
for-review tags were added to gene: SHMT2.
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Review for gene: SHMT2 was set to GREEN
Added comment: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

Clinical features include dysmorphism, congenital microcephaly, hypertrophic cardiomyopathy or atrial-septal defects, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy.

SHMT2 encodes the mitochondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

While plasma metabolites were within normal range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts, decrease in glycine/serine ratios, impaired folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.
Sources: Literature
CAKUT v1.157 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
CAKUT v1.157 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
CAKUT v1.156 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to CAKUT. Sources: Literature
watchlist tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene has been given an Amber rating.
Sources: Literature
Holoprosencephaly v2.9 HS2ST1 Ivone Leong changed review comment from: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum (2/3), skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene should be considered for Green gene rating status at the next review.
Sources: Literature; to: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum (2/3), skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene has been given an Amber review.
Holoprosencephaly v2.9 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Holoprosencephaly v2.9 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.8 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Holoprosencephaly. Sources: Literature
watchlist tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum (2/3), skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene should be considered for Green gene rating status at the next review.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.17 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.17 SHMT2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Paediatric or syndromic cardiomyopathy v1.17 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.16 SHMT2 Arina Puzriakova changed review comment from: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5).

Other features include dysmorphism, congenital microcephaly, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Some functional data indicating variants result in impaired SHMT2 enzymatic function.
Sources: Literature; to: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Age of diagnosis of hypertrophic cardiomyopathy ranged from 3 years to 16 years of age.

Other features include dysmorphism, congenital microcephaly, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Some functional data indicating variants result in impaired SHMT2 enzymatic function.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.16 SHMT2 Arina Puzriakova commented on gene: SHMT2: SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Paediatric or syndromic cardiomyopathy v1.16 SHMT2 Arina Puzriakova gene: SHMT2 was added
gene: SHMT2 was added to Cardiomyopathies - including childhood onset. Sources: Literature
for-review tags were added to gene: SHMT2.
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Review for gene: SHMT2 was set to GREEN
Added comment: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5).

Other features include dysmorphism, congenital microcephaly, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. Some functional data indicating variants result in impaired SHMT2 enzymatic function.
Sources: Literature
Likely inborn error of metabolism v2.36 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.36 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.35 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Inborn errors of metabolism. Sources: Literature
for-review tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. This gene should be considered for Green gene rating status at the next review.
Sources: Literature
Undiagnosed metabolic disorders v1.434 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.434 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.433 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism.

There is enough evidence to support a gene-disease association, so this gene has been rated Green.
Sources: Literature
Intellectual disability v3.665 SHMT2 Arina Puzriakova Tag for-review tag was added to gene: SHMT2.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
Intellectual disability v3.665 SHMT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Sufficient number of unrelated cases (>3) with ID of relevant severity to this panel. Some functional data indicating variants result in impaired SHMT2 enzymatic function. Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag)

SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
Cytopenias and congenital anaemias v1.80 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Cytopenias and congenital anaemias v1.80 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Cytopenias and congenital anaemias v1.79 RAP1B Ivone Leong gene: RAP1B was added
gene: RAP1B was added to Cytopenias and congenital anaemias. Sources: Literature
watchlist tags were added to gene: RAP1B.
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability; cytopenia
Review for gene: RAP1B was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings. Cytopenia is not a feature for this patient.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v1.34 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.34 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.33 RAP1B Ivone Leong gene: RAP1B was added
gene: RAP1B was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
watchlist tags were added to gene: RAP1B.
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability; cytopenia
Review for gene: RAP1B was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings. Cytopenia is not a feature for this patient.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Sources: Literature
Intellectual disability v3.664 SHMT2 Arina Puzriakova Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121
Intellectual disability v3.663 ITFG2 Arina Puzriakova Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Intellectual disability v3.662 ITFG2 Arina Puzriakova Classified gene: ITFG2 as Amber List (moderate evidence)
Intellectual disability v3.662 ITFG2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as ITFG2 can only be classified as a possible candidate gene based present evidence. Clinical and pedigree details are limited and there is no supporting functional data. Additional cases required to corroborate this gene-disease association.
Intellectual disability v3.662 ITFG2 Arina Puzriakova Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.661 RAP1B Ivone Leong Tag watchlist tag was added to gene: RAP1B.
Intellectual disability v3.661 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
Intellectual disability v3.661 RAP1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype but not OMIM.

PMID: 32627184 describes 2 patients.
36 yo patient of non-consanguineous parents. Had unclear pancytopenia, multiple congenital malformations, mild intellectual disability, endocrine disorders (short stature with growth hormone deficiency), dysmorphism and other features. Parents and sibling unaffected.
13 yo of non-consanguineous parents with thrombocytopenia, multiple congenital anomalies and learning difficulties. He had normal developmental milestones, walk was achieved at 14 months and there was no speech delay. He attended mainstream school with auxiliary help because of learning difficulties with graphism, syntaxic comprehension, logical reasoning and attention deficit. Parents and siblings unaffected.

PMID: 26280580 describes another patient with variant in RAP1B. The clinical features can be found in supplementary table 2. The table lists ID, but doesn't say severity and lists a host of other features including short stature, facial dysmorphism and skeletal findings.

All 3 cases seem to have a very wide spectrum of differing phenotypes and therefore, this gene has been given an Amber rating until further evidence is available.
Intellectual disability v3.661 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.52 CTDP1 Ivone Leong Classified gene: CTDP1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.52 CTDP1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the new review, this gene has been promoted to Amber and tagged with "for-review" for the next round of GMS panel reviews so the new rating can be considered.
Bilateral congenital or childhood onset cataracts v2.52 CTDP1 Ivone Leong Gene: ctdp1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.51 CTDP1 Ivone Leong Tag for-review tag was added to gene: CTDP1.
Skeletal dysplasia v2.38 COG4 Ivone Leong Classified gene: COG4 as Amber List (moderate evidence)
Skeletal dysplasia v2.38 COG4 Ivone Leong Gene: cog4 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.37 COG4 Ivone Leong gene: COG4 was added
gene: COG4 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: COG4.
Mode of inheritance for gene: COG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COG4 were set to 31949312; 30290151
Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Mode of pathogenicity for gene: COG4 was set to Other
Review for gene: COG4 was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. This gene was added to the Cataracts panel by Zornitza Stark (Australian Genomics).

"Saul-Wilson syndrome (AD): 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). Please note bi-allelic variants cause CDG. Sources: Expert list
Zornitza Stark (Australian Genomics), 7 Jul 2020"

PMID: 30290151 suggests that the Saul-Wilson syndrome variant is gain of function. Therefore, this gene should be considered to be Green at the next review.
Sources: Literature
Monogenic hearing loss v2.136 COG4 Ivone Leong Classified gene: COG4 as Amber List (moderate evidence)
Monogenic hearing loss v2.136 COG4 Ivone Leong Gene: cog4 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.135 COG4 Ivone Leong gene: COG4 was added
gene: COG4 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: COG4.
Mode of inheritance for gene: COG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COG4 were set to 31949312; 30290151
Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Mode of pathogenicity for gene: COG4 was set to Other
Review for gene: COG4 was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. This gene was added to the Cataracts panel by Zornitza Stark (Australian Genomics).

"Saul-Wilson syndrome (AD): 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). Please note bi-allelic variants cause CDG. Sources: Expert list
Zornitza Stark (Australian Genomics), 7 Jul 2020"

PMID: 30290151, many of the affected patients also have hearing loss and the authors suggest that the Saul-Wilson syndrome variant is gain of function. Therefore, this gene should be considered to be Green at the next review.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.51 COG4 Ivone Leong Added comment: Comment on mode of pathogenicity: PMID: 30290151 suggests that Saul-Wilson syndrome variant is gain of function.
Bilateral congenital or childhood onset cataracts v2.51 COG4 Ivone Leong Mode of pathogenicity for gene: COG4 was changed from None to Other
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Tag for-review tag was added to gene: COG4.
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Classified gene: COG4 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Bilateral congenital or childhood onset cataracts v2.50 COG4 Ivone Leong Gene: cog4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.238 EXT2 Zornitza Stark edited their review of gene: EXT2: Changed publications: 26246518, 30288735, 30997052, 30075207; Changed phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM# 616682
Intellectual disability v3.660 MPI Zornitza Stark reviewed gene: MPI: Rating: RED; Mode of pathogenicity: None; Publications: 12414827, 9585601, 10980531, 33098580, 33204592, 32905087, 32266963, 30242110; Phenotypes: Congenital disorder of glycosylation, type Ib, MIM# 602579, MPI-CDG MONDO:0011257; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 GIMAP6 Boaz Palterer gene: GIMAP6 was added
gene: GIMAP6 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: GIMAP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIMAP6 were set to 33328581
Phenotypes for gene: GIMAP6 were set to Lymphopenia; Sinopulmonary Infections
Penetrance for gene: GIMAP6 were set to unknown
Review for gene: GIMAP6 was set to RED
Added comment: Two siblings with an homozygous variant in GIMAP6 and absent protein expression. One with lymphopenia and recurrent sinopulmonary infections, the other clinically asymptomatic.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.66 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from Hyperlysinemia; Saccharopinuria, 268700 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
DDG2P v2.14 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA 238700 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Likely inborn error of metabolism v2.34 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from Intellectual disability; Hyperlysinemia; Hyperlysinaemia (Disorders of histidine, tryptophan or lysine metabolism) to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Fetal anomalies v1.125 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIAHyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Fetal anomalies v1.124 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA to HYPERLYSINEMIAHyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Undiagnosed metabolic disorders v1.432 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from Hyperlysinaemia (Disorders of histidine, tryptophan or lysine metabolism); Intellectual disability; Hyperlysinemia 238700 to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Intellectual disability v3.660 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Neurodegenerative disorders, adult onset v2.35 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Hereditary ataxia, adult onset v2.19 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from CMT 2N 613287; EIEE29, 616339 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Hereditary neuropathy or pain disorder v1.19 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Charcot Marie Tooth disease, axonal, type 2N, 613287; Charcot-Marie-Tooth, Type 2 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Intellectual disability v3.659 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Hereditary neuropathy v1.381 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Charcot-Marie-Tooth, Type 2 ; Charcot Marie Tooth disease, axonal, type 2N, 613287; Charcot-Marie-Tooth, Type 2 to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Early onset or syndromic epilepsy v2.238 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Fetal anomalies v1.123 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from EARLY-ONSET EPILEPTIC ENCEPHALOPATHY WITH PERSISTENT MYELINATION DEFECT. to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Severe microcephaly v2.54 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29, MIM# 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Hereditary ataxia v1.207 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
Retinal disorders v2.34 SLC6A6 Ivone Leong Phenotypes for gene: SLC6A6 were changed from Early retinal degeneration; Dilated cardiomyopathy to Early retinal degeneration; cardiomyopathy
Retinal disorders v2.33 SLC6A6 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. PMID: 29886034 did not look at the eyes of patients so therefore unsure if the affected individual with a variant in SLC6A6 has an eye phenotype.

Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - childhood onset v2.35 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from to Charcot-Marie-Tooth disease, axonal, type 2N, OMIM:613287; Charcot-Marie-Tooth disease axonal type 2N, MONDO:0013212
White matter disorders and cerebral calcification - childhood onset v1.27 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29, MIM# 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Dystonia, chorea or related movement disorder, childhood onset v1.65 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Hereditary ataxia, adult onset v2.18 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550; Triple A syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Fetal anomalies v1.122 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from ACHALASIA-ADDISONIANISM-ALACRIMA SYNDROME to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Neurodegenerative disorders, adult onset v2.34 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Retinal disorders v2.33 SLC6A6 Ivone Leong Phenotypes for gene: SLC6A6 were changed from Early retinal degeneration; cardiomyopathy to Early retinal degeneration; Dilated cardiomyopathy
Hereditary ataxia v1.206 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Ataxia and cerebellar anomalies - childhood onset v2.34 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Familial dysautonomia v1.9 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome, 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Congenital adrenal hypoplasia v2.4 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Triple A syndrome (Addisons, achalasia, alacrima), 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Intellectual disability v3.658 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Retinal disorders v2.32 SLC6A6 Ivone Leong Classified gene: SLC6A6 as Amber List (moderate evidence)
Retinal disorders v2.32 SLC6A6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. There are 2 unrelated cases with early retinal degeneration and a mouse model that replicates the human phenotype. Therefore, there is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Retinal disorders v2.32 SLC6A6 Ivone Leong Gene: slc6a6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.31 SLC6A6 Ivone Leong Tag for-review tag was added to gene: SLC6A6.
Retinal disorders v2.31 SLC6A6 Ivone Leong Added comment: Comment on publications: PMID: 17875433 slc6a6-/- mouse develop retinal degenerative disease.
Retinal disorders v2.31 SLC6A6 Ivone Leong Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034
Retinal disorders v2.30 AHR Ivone Leong commented on gene: AHR: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association so this gene will remain Amber.
Retinal disorders v2.30 AHR Ivone Leong Tag watchlist tag was added to gene: AHR.
Retinal disorders v2.30 AHR Ivone Leong Publications for gene: AHR were set to
Retinal disorders v2.29 AHR Ivone Leong Phenotypes for gene: AHR were changed from ?Retinitis pigmentosa 85, OMIM:618345 to ?Retinitis pigmentosa 85, OMIM:618345; Retinal dystrophy
Retinal disorders v2.28 AHR Ivone Leong Phenotypes for gene: AHR were changed from to ?Retinitis pigmentosa 85, OMIM:618345
Retinal disorders v2.27 AHR Ivone Leong Mode of inheritance for gene: AHR was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.657 GOT2 Arina Puzriakova Tag watchlist was removed from gene: GOT2.
Intellectual disability v3.657 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Early onset or syndromic epilepsy v2.237 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Intellectual disability v3.656 GOT2 Arina Puzriakova Classified gene: GOT2 as Amber List (moderate evidence)
Intellectual disability v3.656 GOT2 Arina Puzriakova Added comment: Comment on list classification: ID of relevant severity to this panel (severe-to-profound) is reported in 4/4 individuals (PMID:31422819). However, intellectual impairment was secondary to epilepsy and there is no evidence of neurodevelopmental delay preceding the onset of seizures. Therefore, maintaining Amber rating on this panel (GOT2 is already Green on the Genetic epilepsy syndromes (v2.236) panel)
Intellectual disability v3.656 GOT2 Arina Puzriakova Gene: got2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.655 GOT2 Arina Puzriakova commented on gene: GOT2
Intellectual disability v3.655 GATA6 Arina Puzriakova Classified gene: GATA6 as Amber List (moderate evidence)
Intellectual disability v3.655 GATA6 Arina Puzriakova Added comment: Comment on list classification: Developmental delay has been reported in some patients with GATA6 variants. However, in view of the pancreatic and cardiac abnormalities that constitute the main phenotypes, cognitive impairment is unlikely to represent a key feature of the disease presentation.

Maintaining Amber rating as the disorder is better represented in other panels (e.g. Diabetes, Severe Paediatric Disorders, etc) where this gene is already Green.
Intellectual disability v3.655 GATA6 Arina Puzriakova Gene: gata6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.654 HS2ST1 Ivone Leong Tag watchlist tag was added to gene: HS2ST1.
Intellectual disability v3.654 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
Intellectual disability v3.654 HS2ST1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.654 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 TBX21 Arina Puzriakova Classified gene: TBX21 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 TBX21 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Rating Red as only single patient reported at present with homozygous variants in the TBX21 gene resulting clinically in MSMD. Additional cases required to support pathogenicity and inclusion on a diagnostic panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.385 TBX21 Arina Puzriakova Gene: tbx21 has been classified as Red List (Low Evidence).
Intellectual disability v3.653 BICRA Ivone Leong Classified gene: BICRA as Amber List (moderate evidence)
Intellectual disability v3.653 BICRA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.653 BICRA Ivone Leong Gene: bicra has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.652 BICRA Ivone Leong Tag for-review tag was added to gene: BICRA.
Intellectual disability v3.652 EMC10 Ivone Leong Classified gene: EMC10 as Red List (low evidence)
Intellectual disability v3.652 EMC10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. As there is only 1 case, this gene has been given a Red rating.
Intellectual disability v3.652 EMC10 Ivone Leong Gene: emc10 has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v2.49 CTDP1 Ivone Leong Tag founder-effect tag was added to gene: CTDP1.
Bilateral congenital or childhood onset cataracts v2.49 CTDP1 Ivone Leong Publications for gene: CTDP1 were set to 14517542; 24690360; 14517542
Bilateral congenital or childhood onset cataracts v2.48 CTDP1 Ivone Leong Phenotypes for gene: CTDP1 were changed from Congenital cataracts, facial dysmorphism, and neuropathy, 604168 to Congenital cataracts, facial dysmorphism, and neuropathy, OMIM:604168, MONDO:0011402
Bilateral congenital or childhood onset cataracts v2.47 CTDP1 Ivone Leong Publications for gene: CTDP1 were set to
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Tag for-review tag was added to gene: POLG.
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Classified gene: POLG as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with the relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence for this gene to be Green; however, the inclusion of this gene to the panel should be reviewed by the GMS specialist group.
Bilateral congenital or childhood onset cataracts v2.46 POLG Ivone Leong Gene: polg has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.45 ABHD12 Ivone Leong Classified gene: ABHD12 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.45 ABHD12 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association; however, the GMS specialist group should review whether this gene should be included in the panel.
Bilateral congenital or childhood onset cataracts v2.45 ABHD12 Ivone Leong Gene: abhd12 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.44 ABHD12 Ivone Leong Tag for-review tag was added to gene: ABHD12.
Skeletal dysplasia v2.36 MIA3 Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver gene: MIA3 was added
gene: MIA3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163
Phenotypes for gene: MIA3 were set to short stature; skeletal dysplasia; amelogenesis
Penetrance for gene: MIA3 were set to unknown
Review for gene: MIA3 was set to RED
Added comment: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.44 ABHD12 Ivone Leong Publications for gene: ABHD12 were set to
Bilateral congenital or childhood onset cataracts v2.43 ABHD12 Ivone Leong Phenotypes for gene: ABHD12 were changed from Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa and Cataract (PHARC); Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, 612674 to Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, OMIM:612674; PHARC syndrome, MONDO:0012984
Bilateral congenital or childhood onset cataracts v2.42 PLOD3 Ivone Leong Classified gene: PLOD3 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.42 PLOD3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence for a gene-disease association. Therefore, this gene should be Green at the next review.
Bilateral congenital or childhood onset cataracts v2.42 PLOD3 Ivone Leong Gene: plod3 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.41 PLOD3 Ivone Leong Tag for-review tag was added to gene: PLOD3.
Bilateral congenital or childhood onset cataracts v2.41 SLC16A12 Ivone Leong Classified gene: SLC16A12 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.41 SLC16A12 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Bilateral congenital or childhood onset cataracts v2.41 SLC16A12 Ivone Leong Gene: slc16a12 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.40 SLC16A12 Ivone Leong Added comment: Comment on publications: This was originally in the Publications section:
Kloeckener-Gruissem et al (2008) Am J Hum Genet 82:772-779 - a nonsense variant in SLC16A12 was identified in a Swiss family with autosomal dominant juvenile cataract, microcornea, and renal glucosuria. High SLC16A12 transcript expression levels in the eye and kidney was observed (PMID: 18304496);
Functional study: Castorino et al (2011) IOVS 52:6774 PMID: 21778275 - reports the variant causes a defect in protein trafficking;
A 5'UTR SNP was identified in one patient with age-related cataract, and caused increased expression in luciferase assays PMID: 20181839
Bilateral congenital or childhood onset cataracts v2.40 SLC16A12 Ivone Leong Publications for gene: SLC16A12 were set to Kloeckener-Gruissem et al (2008) Am J Hum Genet 82:772-779 - a nonsense variant in SLC16A12 was identified in a Swiss family with autosomal dominant juvenile cataract, microcornea, and renal glucosuria. High SLC16A12 transcript expression levels in the eye and kidney was observed; Functional study: Castorino et al (2011) IOVS 52:6774 PMID: 21778275 - reports the variant causes a defect in protein trafficking; A 5'UTR SNP was identified in one patient with age-related cataract, and caused increased expression in luciferase assays PMID: 20181839
Bilateral congenital or childhood onset cataracts v2.39 SLC16A12 Ivone Leong Phenotypes for gene: SLC16A12 were changed from Cataract, juvenile, with microcornea and glucosuria, 612018 to Cataract 47, juvenile, with microcornea, OMIM:612018; juvenile cataract-microcornea-renal glucosuria syndrome, MONDO:0012786
Bilateral congenital or childhood onset cataracts v2.38 COG4 Ivone Leong Phenotypes for gene: COG4 were changed from Saul-Wilson syndrome, OMIM #618150 to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Bilateral congenital or childhood onset cataracts v2.37 EED Ivone Leong reviewed gene: EED: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.37 EED Ivone Leong Tag for-review tag was added to gene: EED.
Bilateral congenital or childhood onset cataracts v2.37 EED Ivone Leong Phenotypes for gene: EED were changed from Cohen-Gibson syndrome 617561 to Cohen-Gibson syndrome, OMIM:617561,MONDO:0060510
Congenital myopathy v2.10 GFER Ivone Leong Classified gene: GFER as Amber List (moderate evidence)
Congenital myopathy v2.10 GFER Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association and this gene should be considered Green at the next review. This gene has been promoted to Amber and tagged with "for-review".
Congenital myopathy v2.10 GFER Ivone Leong Gene: gfer has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.9 GFER Ivone Leong Publications for gene: GFER were set to 19409522
Bilateral congenital or childhood onset cataracts v2.36 GFER Ivone Leong Classified gene: GFER as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.36 GFER Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to promote this gene from Red to Green. This gene should be made Green at the next review.
Bilateral congenital or childhood onset cataracts v2.36 GFER Ivone Leong Gene: gfer has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.35 GFER Ivone Leong Phenotypes for gene: GFER were changed from Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, OMIM:613076 to Myopathy, mitochondrial progressive, with congenital cataract and developmental delay, OMIM:613076
Bilateral congenital or childhood onset cataracts v2.34 GFER Ivone Leong Tag for-review tag was added to gene: GFER.
Bilateral congenital or childhood onset cataracts v2.34 GFER Ivone Leong Phenotypes for gene: GFER were changed from Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, 613076 to Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay, OMIM:613076
Bilateral congenital or childhood onset cataracts v2.33 GFER Ivone Leong Publications for gene: GFER were set to Di Fonzo et al (2009) Am J Hum Genet 84:594-604
Bilateral congenital or childhood onset cataracts v2.32 GEMIN4 Ivone Leong Tag watchlist tag was added to gene: GEMIN4.
Bilateral congenital or childhood onset cataracts v2.32 GEMIN4 Ivone Leong Publications for gene: GEMIN4 were set to 27878435; 25558065
Bilateral congenital or childhood onset cataracts v2.31 GEMIN4 Ivone Leong edited their review of gene: GEMIN4: Added comment: On re-reviewing this gene, the mouse model was not a knockout gene model of GEMIN4. PMID: 30237576 is a new publication that describes another case with the same variant as that reported by PMID: 25558065. The affected individual is from the same region as the previous publication. Therefore, there is insufficient evidence to support a gene-disease status and this gene should be downgraded from Green to Amber at the next review.; Changed rating: AMBER; Changed publications: 30237576
Bilateral congenital or childhood onset cataracts v2.31 GEMIN4 Ivone Leong Tag for-review tag was added to gene: GEMIN4.
Cutaneous photosensitivity with a likely genetic cause v1.7 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Cutaneous photosensitivity with a likely genetic cause v1.7 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Cutaneous photosensitivity with a likely genetic cause v1.6 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Cutaneous photosensitivity with a likely genetic cause. Sources: Expert Review
for-review tags were added to gene: ANAPC1.
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). This gene was suggested to be added to this panel as Amber by the Genomics England Clinical Team. The publication did not mention any affected individuals having photosensitivity; however, as it is a mimic of RECQL4, this gene may be appropriate for this panel.

This gene has been tagged with "for-review" so that the GMS specialist group could review this gene for whether it is appropriate for this panel or not.
Sources: Expert Review
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating.
Sources: Literature; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating.

Have tagged with "for-review" so that GMS could review whether this gene is appropriate for the panel or not.
Sources: Literature
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong Tag for-review tag was added to gene: ANAPC1.
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Skeletal dysplasia v2.36 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.35 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating.
Sources: Literature
Ectodermal dysplasia without a known gene mutation v1.21 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Green List (high evidence)
Ectodermal dysplasia without a known gene mutation v1.21 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Green List (High Evidence).
Ectodermal dysplasia without a known gene mutation v1.20 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Ectodermal dysplasia without a known gene mutation. Sources: Literature
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). All affected individuals have poikiloderma. 9/10 patients had sparse or absent hair, eyebrows, or eyelashes. 5/10 had abnormal teeth and 4/10 had abnormal nails. There is enough evidence to support a gene-disease association.
Sources: Literature
Ectodermal dysplasia v1.13 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Ectodermal dysplasia v1.13 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.12 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Ectodermal dysplasia. Sources: Literature
for-review tags were added to gene: ANAPC1.
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). All affected individuals have poikiloderma. 9/10 patients had sparse or absent hair, eyebrows, or eyelashes. 5/10 had abnormal teeth and 4/10 had abnormal nails. There is enough evidence to support a gene-disease association. This gene should be rated Green pending review from GMS.
Sources: Literature
Corneal dystrophy v1.6 VSX1 Ivone Leong Classified gene: VSX1 as Red List (low evidence)
Corneal dystrophy v1.6 VSX1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support a gene-disease association for this gene; however, this gene has been given a Red rating as it does not fit in the scope of the clinical indication for this panel.
Corneal dystrophy v1.6 VSX1 Ivone Leong Gene: vsx1 has been classified as Red List (Low Evidence).
Corneal dystrophy v1.5 VSX1 Ivone Leong Phenotypes for gene: VSX1 were changed from Keratoconus 1, MIM# 148300 to Keratoconus 1, OMIM:148300, MONDO:0007851
Intellectual disability v3.651 CSNK1G1 Ivone Leong Phenotypes for gene: CSNK1G1 were changed from severe non-syndromic early-onset epilepsy to severe non-syndromic early-onset epilepsy; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of the face; Abnormality of limbs
Intellectual disability v3.650 CSNK1G1 Ivone Leong Publications for gene: CSNK1G1 were set to 24463883
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 TBX21 Boaz Palterer gene: TBX21 was added
gene: TBX21 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TBX21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBX21 were set to 33296702
Phenotypes for gene: TBX21 were set to Defects with susceptibility to mycobacterial infection (MSMD); Defects in Intrinsic and Innate Immunity
Penetrance for gene: TBX21 were set to unknown
Review for gene: TBX21 was set to RED
Added comment: One patient from consanguineous parents with homozygous indel. Corroborated by in vitro and mouse model.
Sources: Literature
Pigmentary skin disorders v1.9 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Pigmentary skin disorders v1.9 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.8 ANAPC1 Ivone Leong gene: ANAPC1 was added
gene: ANAPC1 was added to Pigmentary skin disorders. Sources: Literature
for-review tags were added to gene: ANAPC1.
Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANAPC1 were set to 31303264
Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Review for gene: ANAPC1 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome 1. All affected individuals have Poikiloderma. There is enough evidence to support a gene-disease association. This gene should be rated Green at next review.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.31 ANAPC1 Ivone Leong Classified gene: ANAPC1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.31 ANAPC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at next review.
Bilateral congenital or childhood onset cataracts v2.31 ANAPC1 Ivone Leong Gene: anapc1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.30 ANAPC1 Ivone Leong Tag for-review tag was added to gene: ANAPC1.
Bilateral congenital or childhood onset cataracts v2.30 ANAPC1 Ivone Leong Phenotypes for gene: ANAPC1 were changed from Rothmund Thomson syndrome type 1, OMIM 618625 to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368
Optic neuropathy v2.28 INTS8 Ivone Leong gene: INTS8 was added
gene: INTS8 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: INTS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS8 were set to 28542170
Phenotypes for gene: INTS8 were set to Optic atrophy
Review for gene: INTS8 was set to RED
Added comment: PMID: 28542170 describes one Dutch family with 3 affected siblings. All three are compound heterozygous for variants in this gene. Optic atrophy was listed as a phenotype for 2/3 siblings.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.29 INTS1 Ivone Leong Classified gene: INTS1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.29 INTS1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made Green at the next review.
Bilateral congenital or childhood onset cataracts v2.29 INTS1 Ivone Leong Gene: ints1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.28 INTS1 Ivone Leong Tag for-review tag was added to gene: INTS1.
Bilateral congenital or childhood onset cataracts v2.28 INTS1 Ivone Leong Phenotypes for gene: INTS1 were changed from Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, MIM# 618571 to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571, MONDO:0032817
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Tag for-review tag was added to gene: PIK3C2A.
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Classified gene: PIK3C2A as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene should be Green at the next review.
Bilateral congenital or childhood onset cataracts v2.27 PIK3C2A Ivone Leong Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.26 PIK3C2A Ivone Leong Phenotypes for gene: PIK3C2A were changed from Oculoskeletodental syndrome, 618440 to Oculoskeletodental syndrome, OMIM:618440, MONDO:0034145
Bilateral congenital or childhood onset cataracts v2.25 PANK4 Ivone Leong Classified gene: PANK4 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.25 PANK4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in Gene2Phenotype but not OMIM. There is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Bilateral congenital or childhood onset cataracts v2.25 PANK4 Ivone Leong Gene: pank4 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.24 PANK4 Ivone Leong Tag watchlist tag was added to gene: PANK4.
Bilateral congenital or childhood onset cataracts v2.24 NACC1 Ivone Leong Classified gene: NACC1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.24 NACC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Bilateral congenital or childhood onset cataracts v2.24 NACC1 Ivone Leong Gene: nacc1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.23 NACC1 Ivone Leong Tag for-review tag was added to gene: NACC1.
Bilateral congenital or childhood onset cataracts v2.23 NACC1 Ivone Leong Phenotypes for gene: NACC1 were changed from Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination, OMIM:617393, MONDO:0044306 to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, OMIM:617393, MONDO:0044306
Bilateral congenital or childhood onset cataracts v2.22 NACC1 Ivone Leong Phenotypes for gene: NACC1 were changed from Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination (MIM# 617393) to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination, OMIM:617393, MONDO:0044306
Bilateral congenital or childhood onset cataracts v2.21 SREBF1 Ivone Leong Classified gene: SREBF1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.21 SREBF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Bilateral congenital or childhood onset cataracts v2.21 SREBF1 Ivone Leong Gene: srebf1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.20 SREBF1 Ivone Leong Tag for-review tag was added to gene: SREBF1.
Intellectual disability v3.649 GATA6 Ivone Leong Publications for gene: GATA6 were set to
Bilateral congenital or childhood onset cataracts v2.20 SREBF1 Ivone Leong Phenotypes for gene: SREBF1 were changed from Mucoepithelial dysplasia, hereditary, MIM#158310 to Mucoepithelial dysplasia, hereditary, OMIM:158310, MONDO:0008017
Bilateral congenital or childhood onset cataracts v2.19 PSMC3 Ivone Leong Classified gene: PSMC3 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.19 PSMC3 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. There is not enough evidence to support a gene-disease association; therefore, this gene has been given an Amber rating.
Bilateral congenital or childhood onset cataracts v2.19 PSMC3 Ivone Leong Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.33 FAT1 Ivone Leong Publications for gene: FAT1 were set to 30862798; 26905694
Anophthalmia or microphthalmia v1.32 FAT1 Ivone Leong Classified gene: FAT1 as Green List (high evidence)
Anophthalmia or microphthalmia v1.32 FAT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence for this gene to be Green on this panel.

This is also a Green gene on the GMS Structural eye disease (Version 1.22) with the following review:
"DB Lahrouchi: five families; Ciani mouse mouse model
Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust), 19 Jun 2019"
Anophthalmia or microphthalmia v1.32 FAT1 Ivone Leong Gene: fat1 has been classified as Green List (High Evidence).
Bardet Biedl syndrome v1.7 C8orf37 Ivone Leong Classified gene: C8orf37 as Amber List (moderate evidence)
Bardet Biedl syndrome v1.7 C8orf37 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber as there are 2 cases.
Bardet Biedl syndrome v1.7 C8orf37 Ivone Leong Gene: c8orf37 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.13 C8orf37 Ivone Leong Classified gene: C8orf37 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.13 C8orf37 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Ophthalmological ciliopathies v1.13 C8orf37 Ivone Leong Gene: c8orf37 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.12 C8orf37 Ivone Leong Tag for-review tag was added to gene: C8orf37.
Ophthalmological ciliopathies v1.12 C8orf37 Ivone Leong Publications for gene: C8orf37 were set to 26854863; 27008867
Retinal disorders v2.26 C8orf37 Ivone Leong Phenotypes for gene: C8orf37 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Eye Disorders; Retinitis pigmentosa 64, 614500Cone-rod dystrophy 16, 614500; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive to Bardet-Biedl syndrome 21, OMIM:617406, MONDO:0044308; Cone-rod dystrophy 16, OMIM:614500, MONDO:0013786; Retinitis pigmentosa 64, OMIM:614500, MONDO:0019200
Bardet Biedl syndrome v1.6 C8orf37 Ivone Leong Phenotypes for gene: C8orf37 were changed from Bardet-Biedl syndrome 21, 617406; Cone-rod dystrophy 16; Retinitis pigmentosa 64, 614500 to Bardet-Biedl syndrome 21, OMIM:617406, MONDO:0044308; Cone-rod dystrophy 16, OMIM:614500, MONDO:0013786; Retinitis pigmentosa 64, OMIM:614500, MONDO:0019200
Ophthalmological ciliopathies v1.11 C8orf37 Ivone Leong Phenotypes for gene: C8orf37 were changed from Bardet-Biedl syndrome 21, 617406 to Bardet-Biedl syndrome 21, OMIM:617406, MONDO:0044308; Cone-rod dystrophy 16, OMIM:614500, MONDO:0013786; Retinitis pigmentosa 64, OMIM:614500, MONDO:0019200
Retinal disorders v2.25 KIF3B Ivone Leong Classified gene: KIF3B as Amber List (moderate evidence)
Retinal disorders v2.25 KIF3B Ivone Leong Gene: kif3b has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.24 KIF3B Ivone Leong gene: KIF3B was added
gene: KIF3B was added to Retinal disorders. Sources: Expert list,Literature
watchlist tags were added to gene: KIF3B.
Mode of inheritance for gene: KIF3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF3B were set to 32386558
Phenotypes for gene: KIF3B were set to hepatic fibrosis; Retinitis pigmentosa 89, OMIM:618955, MONDO:0030071; postaxial polydactyly
Review for gene: KIF3B was set to AMBER
Added comment: New gene added by Zornitza Stark (Australian Genomics) to the Ophthalmological ciliopathies (Version 1.10). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association so this gene has been given an Amber rating.

"Two unrelated families with a ciliopathy phenotype including RP and some functional data. Sources: Literature
Zornitza Stark (Australian Genomics), 3 Jun 2020"
Sources: Expert list, Literature
Ophthalmological ciliopathies v1.10 KIF3B Ivone Leong Classified gene: KIF3B as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.10 KIF3B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Ophthalmological ciliopathies v1.10 KIF3B Ivone Leong Gene: kif3b has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.9 KIF3B Ivone Leong Tag watchlist tag was added to gene: KIF3B.
Severe microcephaly v2.53 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Severe microcephaly v2.53 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Severe microcephaly v2.53 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.53 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.52 NARS Arina Puzriakova gene: NARS was added
gene: NARS was added to Severe microcephaly. Sources: Literature
new-gene-name, for-review tags were added to gene: NARS.
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225; 32788587
Phenotypes for gene: NARS were set to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Review for gene: NARS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). Microcephaly was observed in the majority of cases (90%), with severity relevant to this panel (≥ 3 SD). These cases predominantly presented with primary microcephaly; however, secondary microcephaly was also noted. Other features include GDD/ID, seizures, ataxia, and dysmorphism. Supportive functional data.
Sources: Literature
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Tag new-gene-name tag was added to gene: NARS.
Tag for-review tag was added to gene: NARS.
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Ophthalmological ciliopathies v1.9 KIF3B Ivone Leong Phenotypes for gene: KIF3B were changed from hepatic fibrosis; retinitis pigmentosa; postaxial polydactyly to hepatic fibrosis; Retinitis pigmentosa 89, OMIM:618955, MONDO:0030071; postaxial polydactyly
Intellectual disability v3.648 NARS Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 6 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.; to: Associated with relevant phenotype in OMIM, and in Gene2Phenotype with 'confirmed' disease confidence for 'NARS1 Neurodevelopmental Disorder (monoallelic)' and 'probable' for 'NARS1 Neurodevelopmental Disorder (biallelic)'

Total of 23 patients from 13 unrelated families with biallelic variants in the NARS1 gene (PMIDs: 32738225 and 32788587) and 8 unrelated patients with de novo heterozygous nonsense variants (PMIDs: 32738225). All individuals had GDD and ID, which varied in severity from moderate to profound. Other features include microcephaly, seizures, ataxia, and dysmorphism. Supportive functional data.
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Early onset or syndromic epilepsy v2.234 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Intellectual disability v3.648 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Intellectual disability v3.648 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Intellectual disability v3.648 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.648 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.647 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.647 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Intellectual disability v3.646 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Intellectual disability v3.645 ATP2A2 Ivone Leong reviewed gene: ATP2A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Clefting v2.11 MED25 Eleanor Williams Phenotypes for gene: MED25 were changed from BASEL-VANAGAITE-SMIRIN-YOSEF SYNDROME; BVSYS to Basel-Vanagait-Smirin-Yosef syndrome OMIM:616449
Clefting v2.10 MED25 Eleanor Williams Publications for gene: MED25 were set to 25792360
Clefting v2.9 MED25 Eleanor Williams Classified gene: MED25 as Amber List (moderate evidence)
Clefting v2.9 MED25 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Amber for now, but there are sufficient cases with clefting to promote this gene to green on this panel after the next GMS review.
Clefting v2.9 MED25 Eleanor Williams Gene: med25 has been classified as Amber List (Moderate Evidence).
Clefting v2.8 MED25 Eleanor Williams Tag for-review tag was added to gene: MED25.
Clefting v2.8 MED25 Eleanor Williams reviewed gene: MED25: Rating: ; Mode of pathogenicity: None; Publications: 31602195, 32324310, 32816121; Phenotypes: Basel-Vanagait-Smirin-Yosef syndrome OMIM:616449; Mode of inheritance: None
Intellectual disability v3.645 ISCA-37418-Loss Arina Puzriakova Phenotypes for Region: ISCA-37418-Loss were changed from Potocki-Lupski syndrome; hypotonia, poor feeding, failure to thrive, developmental delay particularly cognitive and language deficity, mild-moderate intellectual deficit, and neuropsychiatric disorders; Smith-Magenis syndrome; Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance; 182290; moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems; hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, congenital anomalies; Dental abnormalities to Smith-Magenis syndrome, OMIM:182290; Smith-Magenis syndrome, MONDO:0008434
Intellectual disability v3.644 RAP1B Zornitza Stark gene: RAP1B was added
gene: RAP1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability
Review for gene: RAP1B was set to GREEN
Added comment: Three unrelated individuals reported with de novo variants, some functional data. One of them described as Kabuki-like but lacks typical facial gestalt.
Sources: Literature
Intellectual disability v3.644 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Early onset or syndromic epilepsy v2.233 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Laterality disorders and isomerism v1.20 CFAP52 Zornitza Stark gene: CFAP52 was added
gene: CFAP52 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: CFAP52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP52 were set to 25469542; 33139725
Phenotypes for gene: CFAP52 were set to Heterotaxy
Review for gene: CFAP52 was set to GREEN
Added comment: Five unrelated families and functional data.
Sources: Literature
Laterality disorders and isomerism v1.20 CFAP45 Zornitza Stark gene: CFAP45 was added
gene: CFAP45 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP45 were set to 33139725
Phenotypes for gene: CFAP45 were set to Situs inversus; asthenospermia
Review for gene: CFAP45 was set to GREEN
Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype.
Sources: Literature
Fetal anomalies v1.121 GDF6 Zornitza Stark reviewed gene: GDF6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32737436; Phenotypes: Syndromic CAKUT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuric renal disease v2.33 DAAM2 Zornitza Stark gene: DAAM2 was added
gene: DAAM2 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: DAAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAAM2 were set to 33232676
Phenotypes for gene: DAAM2 were set to Steroid-resistant nephrotic syndrome (SRNS)
Review for gene: DAAM2 was set to GREEN
Added comment: - steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis on histologic analysis of kidney biopsies and foot process effacement shown by electron microscopy (authors have suggested the term nephrotic syndrome type 22 (NPHS22))
- 4 unrelated families, 3 of which were consanguineous
- 4 unique missense and 1 stop
- in vitro studies for the missense variants
Sources: Literature
Intellectual disability v3.644 BICRA Zornitza Stark gene: BICRA was added
gene: BICRA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICRA were set to 33232675
Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features
Review for gene: BICRA was set to GREEN
Added comment: 12 individuals reported, 11 de novo (1 not resolved), with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features. Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association.
Sources: Literature
Neuronal ceroid lipofuscinosis v1.4 CLCN6 Zornitza Stark reviewed gene: CLCN6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25794116, 21107136, 33217309; Phenotypes: Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 HS2ST1 Zornitza Stark gene: HS2ST1 was added
gene: HS2ST1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: Four affected individuals from 3 unrelated families. 3 unique missense and 2 PTCs. Clinical features included developmental delay, corpus callosum hypoplasia or aplasia, and skeletal and renal abnormalities as well as joint contractures/arthrogryposis.
Sources: Literature
Intellectual disability v3.644 KDM4B Zornitza Stark gene: KDM4B was added
gene: KDM4B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Congenital myopathy v2.8 UNC45B Zornitza Stark gene: UNC45B was added
gene: UNC45B was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: UNC45B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45B were set to 33217308
Phenotypes for gene: UNC45B were set to Progressive Myopathy with Eccentric Cores
Review for gene: UNC45B was set to GREEN
Added comment: 10 individuals from 8 families reported with biallelic variants clinically manifesting with childhood-onset, progressive proximal and axial muscle weakness and various degrees of respiratory insufficiency. 4 missense variants and a +5 splice variant reported, p.Arg754Gln is recurrent. Functional studies support pathogenicity.
Sources: Literature
Intellectual disability v3.644 SMG8 Zornitza Stark edited their review of gene: SMG8: Added comment: Four more families reported in PMID 33242396. Some functional data also provided.; Changed rating: GREEN; Changed publications: 31130284, 33242396
Hereditary ataxia, adult onset v2.17 RFC1 Zornitza Stark edited their review of gene: RFC1: Added comment: A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families reported in PMID 33103729. Both of these need to be added as STRs but I haven't quite figured out how to do it!; Changed publications: 30926972, 33103729
Ataxia and cerebellar anomalies - childhood onset v2.33 MINPP1 Zornitza Stark gene: MINPP1 was added
gene: MINPP1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Review for gene: MINPP1 was set to GREEN
Added comment: 8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI.

Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions.
Sources: Literature
Severe microcephaly v2.51 RRP7A Zornitza Stark gene: RRP7A was added
gene: RRP7A was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RRP7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP7A were set to 33199730
Phenotypes for gene: RRP7A were set to Microcephaly
Review for gene: RRP7A was set to AMBER
Added comment: 10 affected individuals from a single large consanguineous family where bi-allelic variant segregated with severe microcephaly (-6-8SD), variable ID. Supportive functional data from mouse and zebrafish.
Sources: Literature
Intellectual disability v3.644 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability; regression; seizures
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Skeletal dysplasia v2.34 HHAT Zornitza Stark gene: HHAT was added
gene: HHAT was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092
Review for gene: HHAT was set to AMBER
Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: Literature
Intellectual disability v3.644 H3F3B Zornitza Stark reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.644 H3F3A Zornitza Stark reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Intellectual disability, regression, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.51 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Mitochondrial disorders v2.12 COX16 Zornitza Stark Deleted their comment
Mitochondrial disorders v2.12 COX16 Zornitza Stark edited their review of gene: COX16: Added comment: 2 unrelated patients with the same homozygous (non-consanguineous) nonsense variant c.244C>T (p.Arg82*), and isolated complex IV deficiency present in both patient fibroblasts/skeletal muscle biopsy. COX16 is involved in the biogenesis of complex IV, the terminal complex of the mitochondrial respiratory chain.; Changed rating: AMBER; Changed publications: 33169484; Changed phenotypes: Hypertrophic cardiomyopathy, encephalopathy, severe fatal lactic acidosis; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v2.7 CHD4 Zornitza Stark gene: CHD4 was added
gene: CHD4 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: CHD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD4 were set to 31474762
Phenotypes for gene: CHD4 were set to Moya Moya; Sifrim-Hitz-Weiss syndrome, MIM# 617159
Review for gene: CHD4 was set to RED
Added comment: 5 individuals reported with Moya Moya and ID, but only in one was de novo inheritance confirmed. 4 missense variants and one canonical splice.
Sources: Literature
Cerebral vascular malformations v2.7 SETD5 Zornitza Stark gene: SETD5 was added
gene: SETD5 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: SETD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD5 were set to 31474762
Phenotypes for gene: SETD5 were set to Moya Moya; Mental retardation, autosomal dominant 23, MIM# 615761
Review for gene: SETD5 was set to RED
Added comment: Single family reported with de novo SETD5 frameshift in a child with ID and Moya Moya. 2 other families with novel missense and concordant phenotypes but no parental segregation performed.
Sources: Literature
Cerebral vascular malformations v2.7 CNOT3 Zornitza Stark gene: CNOT3 was added
gene: CNOT3 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: CNOT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT3 were set to 31474762
Phenotypes for gene: CNOT3 were set to Moya Moya; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM# 618672
Review for gene: CNOT3 was set to AMBER
Added comment: 2 families with de novo variants (one nonsense and one missense) in individuals with ID and Moya Moya
Sources: Literature
Intellectual disability v3.644 HDAC4 Zornitza Stark edited their review of gene: HDAC4: Added comment: New report of 4 different missense present in the 14-3-3 binding site, identified de novo in 7 individuals with an intellectual disability syndrome, and supporting in vitro functional assays.; Changed rating: GREEN; Changed publications: 24715439, 20691407, 31209962, https://doi.org/10.1016/j.xhgg.2020.100015
Neurological ciliopathies v1.10 TMEM218 Zornitza Stark gene: TMEM218 was added
gene: TMEM218 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; https://doi.org/10.1016/j.xhgg.2020.100016
Phenotypes for gene: TMEM218 were set to Joubert syndrome; retinal dystrophy; polycystic kidneys; occipital encephalocele
Review for gene: TMEM218 was set to GREEN
Added comment: 11 individuals in 6 families with homozygous or compound heterozygous missense and nonsense (1) variants, with a Joubert/Meckel syndrome phenotype. Clinical features included the molar tooth sign (N=2), occipital encephalocele (N=5, all fetuses), retinal dystrophy (N=4, all living individuals), polycystic kidneys (N=2), and polydactyly (N=2), without liver involvement. A null mouse model had nephronophthisis and retinal degeneration.
Sources: Literature
Congenital disorders of glycosylation v2.18 SSR3 Zornitza Stark gene: SSR3 was added
gene: SSR3 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: SSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SSR3 were set to 30945312
Phenotypes for gene: SSR3 were set to Congenital disorder of glycosylation, type Iu, MIM#615042
Review for gene: SSR3 was set to AMBER
Added comment: Single individual reported with an unsolved type I CDG, intellectual disability, homozygous LOF variant in SSR3, supportive functional evidence.
Sources: Literature
Congenital disorders of glycosylation v2.18 DPM2 Zornitza Stark reviewed gene: DPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23109149, 33129689; Phenotypes: Congenital disorder of glycosylation, type Iu, MIM#615042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.121 MYL9 Zornitza Stark reviewed gene: MYL9: Rating: AMBER; Mode of pathogenicity: None; Publications: 29453416, 33031641; Phenotypes: Megacystis-microcolon-intestinal hypoperistalsis syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.33 MTCL1 Zornitza Stark gene: MTCL1 was added
gene: MTCL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: MTCL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTCL1 were set to 30548255; 28283581; 32961396
Phenotypes for gene: MTCL1 were set to slowly progressive cerebellar ataxia; mild intellectual disability; seizures; episodic pain; spinocerebellar ataxia
Review for gene: MTCL1 was set to GREEN
Added comment: Two families reported with bi-allelic LOF variants, early onset ataxia and a supportive null mouse model.
Single family with mono-allelic variant in two individuals and adult-onset ataxia (not pertinent to this panel, and less compelling).
Sources: Literature
Rare anaemia v1.4 ADH5 Zornitza Stark gene: ADH5 was added
gene: ADH5 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: ADH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADH5 were set to 33147438
Phenotypes for gene: ADH5 were set to Aplastic anaemia; myelodysplasia; short stature
Review for gene: ADH5 was set to GREEN
Added comment: 7 individuals reported with bi-allelic variants in this gene and a Fanconi syndrome-like phenotype. All had aplastic anaemia, 4 developed a myelodysplastic syndrome, and one developed AML. Short stature and abnormal skin pigmentation were additional features.

Note, all also had the ALDH2*2 allele, which is common in East Asian populations, and may be contributory.

Extensive experimental data.
Sources: Literature
Mitochondrial disorders v2.12 NDUFB10 Zornitza Stark edited their review of gene: NDUFB10: Added comment: Second family reported, including more functional data.; Changed rating: GREEN; Changed publications: 28040730, 32025618, 33169436; Changed phenotypes: fatal infantile lactic acidosis, cardiomyopathy, Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Monogenic hearing loss v2.134 SCD5 Zornitza Stark gene: SCD5 was added
gene: SCD5 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: SCD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCD5 were set to 31972369
Phenotypes for gene: SCD5 were set to Deafness, autosomal dominant 79, MIM#619086
Review for gene: SCD5 was set to RED
Added comment: Single 5-generation family reported with a missense variant segregating in 19 affected individuals. Variant is found at a low frequency in ExAC.
Sources: Literature
Intellectual disability v3.644 ATP2A2 Ivone Leong Publications for gene: ATP2A2 were set to 19250991; 20456342
Intellectual disability v3.643 SMARCA2 Arina Puzriakova Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, 601358; COFFIN SIRIS to Nicolaides-Baraitser syndrome, OMIM:601358; Coffin-siris syndrome; Blepharophimosis intellectual disability syndrome
Intellectual disability v3.642 SMARCA2 Arina Puzriakova Publications for gene: SMARCA2 were set to
Monogenic hearing loss v2.134 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Monogenic hearing loss v2.134 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Furthermore, some cases with hearing loss would not be tested for other panels related to this phenotype (e.g. ID, severe microcephaly) as they did not exhibit the relevant features.

Therefore, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag).
Monogenic hearing loss v2.134 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.133 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688 to Sensorineural hearing loss; Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Monogenic hearing loss v2.132 MORC2 Arina Puzriakova gene: MORC2 was added
gene: MORC2 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: MORC2.
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to 32693025
Phenotypes for gene: MORC2 were set to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Review for gene: MORC2 was set to GREEN
Added comment: MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Hearing loss was observed in 11/19 subjects, primarily SNHL.
Sources: Literature
Severe microcephaly v2.51 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Severe microcephaly v2.51 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.51 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.50 MORC2 Arina Puzriakova gene: MORC2 was added
gene: MORC2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: MORC2.
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MORC2 were set to 32693025
Phenotypes for gene: MORC2 were set to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Review for gene: MORC2 was set to GREEN
Added comment: MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Severity of microcephaly relevant to this panel (≥ 3 SD) was observed in 7 subjects.
Sources: Literature
Congenital myopathy v2.8 HNRNPA2B1 Anna Sarkozy reviewed gene: HNRNPA2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: oculopharyngodistal myopathy, muscular dystrophy, congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.8 HNRNPA2B1 Anna Sarkozy Deleted their review
Congenital muscular dystrophy v2.4 HNRNPA2B1 Anna Sarkozy gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Congenital muscular dystrophy. Sources: Other,Expert list,Research
Mode of inheritance for gene: HNRNPA2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HNRNPA2B1 were set to oculopharyngodistal myopathy, muscular dystrophy, congenital myopathy
Review for gene: HNRNPA2B1 was set to GREEN
Added comment: de novo variants in this gene have been reported in multiple unrelated families and presented at the World muscle society congress 2020, a full publication is currently in progress. see abstract:
https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext
Sources: Other, Expert list, Research
Congenital myopathy v2.8 HNRNPA2B1 Anna Sarkozy gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Congenital myopathy. Sources: Expert list,Literature
Mode of inheritance for gene: HNRNPA2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HNRNPA2B1 were set to oculopharyngodistal myopathy; muscular dystrophy; congenital myopathy
Review for gene: HNRNPA2B1 was set to GREEN
Added comment: variants in this gene have now been reported in several unrelated families
this was presented at the world muscle society conference in 2020 and it is currently submitted for full publication
https://doi.org/10.1016/j.nmd.2020.08.006
Sources: Expert list, Literature
Congenital myopathy v2.8 KY Anna Sarkozy edited their review of gene: KY: Added comment: recent reports at the WMS 2020 reported unrelated family with KY gene variants.
"Novel mutation in KY gene causes a novel congenital myopathy with early contractures" see
https://www.nmd-journal.com/article/S0960-8966(20)30298-4/fulltext; Changed rating: GREEN; Changed phenotypes: congenital myopathy
Intellectual disability v3.641 MORC2 Arina Puzriakova Phenotypes for gene: MORC2 were changed from Charcot-Marie-Tooth disease, axonal, type 2Z, MIM #616688 to Developmental delay; Intellectual disability; Growth retardation; Microcephaly; Craniofacial dysmorphism; Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Intellectual disability v3.640 MORC2 Arina Puzriakova Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Intellectual disability v3.639 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
Intellectual disability v3.639 MORC2 Arina Puzriakova Added comment: Comment on list classification: Though signs suggestive of neuropathy were observed in the cohort presented by Sacoto et al (PMID:32693025), these were not the predominant feature of the disease presentation or the primary indication for diagnostic testing. Inclusion on this panel would be of value for detecting such cases, and so this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.639 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.638 MORC2 Arina Puzriakova Tag for-review tag was added to gene: MORC2.
Intellectual disability v3.638 MORC2 Arina Puzriakova reviewed gene: MORC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32693025; Phenotypes: Developmental delay, Intellectual disability, Growth retardation, Microcephaly, Craniofacial dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.638 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Intellectual disability v3.638 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Intellectual disability v3.638 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Developmental delay is prevalent among affected individuals, and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This may serve as a possible route for diagnostic testing as currently there are no relevant panels for detecting the hepatic phenotype of the disease presentation, and so there may be value in rating Green at the next major panel review (added 'for-review tag).
Intellectual disability v3.638 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Tag for-review tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag for-review tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Seizures are prevalent among affected individuals, often triggered by infections. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 NUS1 Arina Puzriakova Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.637 NUS1 Arina Puzriakova Gene: nus1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.636 NUS1 Arina Puzriakova Tag for-review tag was added to gene: NUS1.
Congenital hypothyroidism v2.4 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from GH,TSH, ACTH, LH, FSH deficiency, variable mental retardation, undescended posterior pituitary, anterior pituitary hypoplasia, or persistence of the craniopharyngeal canal to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
DDG2P v2.13 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from MENTAL RETARDATION X-LINKED WITH ISOLATED GROWTH HORMONE DEFICIENCY 300123; SEX REVERSAL TYPE 3 300833 to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Fetal anomalies v1.121 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from SEX REVERSAL TYPE 3; MENTAL RETARDATION X-LINKED WITH ISOLATED GROWTH HORMONE DEFICIENCY to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Hypogonadotropic hypogonadism (GMS) v1.11 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked to Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Hypogonadotropic hypogonadism v1.29 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked to Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
IUGR and IGF abnormalities v1.34 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked, 312000; Mental retardation, X-linked, with isolated growth hormone deficiency, 300123 to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Pituitary hormone deficiency v2.6 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Panhypopituitarism, X-linked (312000); Mental retardation, X-linked, with isolated growth hormone deficiency (300123) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Familial hypoparathyroidism v2.5 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123; Panhypopituitarism, X-linked, 312000 to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712
Intellectual disability v3.636 SOX3 Arina Puzriakova Phenotypes for gene: SOX3 were changed from Mental retardation, X-linked, with isolated growth hormone deficiency, 300123Panhypopituitarism, X-linked, 312000; SEX REVERSAL TYPE 3 (SRXX3) to Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
Intellectual disability v3.635 SOX3 Arina Puzriakova commented on gene: SOX3
Intellectual disability v3.635 SOX3 Arina Puzriakova Tag for-review tag was added to gene: SOX3.
Intellectual disability v3.635 PSAT1 Arina Puzriakova Publications for gene: PSAT1 were set to 17436247
Intellectual disability v3.634 PSAT1 Arina Puzriakova Phenotypes for gene: PSAT1 were changed from PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY to Phosphoserine aminotransferase deficiency, OMIM:610992; Neu-Laxova syndrome 2, OMIM:616038
Intellectual disability v3.633 PRKAR1A Arina Puzriakova Phenotypes for gene: PRKAR1A were changed from Gene2Phenotype confirmed gene with ID HPO to Acrodysostosis 1, with or without hormone resistance, OMIM:101800
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Classified gene: SH3PXD2B as Red List (low evidence)
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.632 SH3PXD2B Arina Puzriakova Gene: sh3pxd2b has been classified as Red List (Low Evidence).
Intellectual disability v3.631 SEC23B Arina Puzriakova Classified gene: SEC23B as Red List (low evidence)
Intellectual disability v3.631 SEC23B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.631 SEC23B Arina Puzriakova Gene: sec23b has been classified as Red List (Low Evidence).
Intellectual disability v3.630 SCN11A Arina Puzriakova Classified gene: SCN11A as Red List (low evidence)
Intellectual disability v3.630 SCN11A Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.630 SCN11A Arina Puzriakova Gene: scn11a has been classified as Red List (Low Evidence).
Intellectual disability v3.629 SCARF2 Arina Puzriakova Classified gene: SCARF2 as Red List (low evidence)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.629 SCARF2 Arina Puzriakova Gene: scarf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.628 SBDS Arina Puzriakova Classified gene: SBDS as Red List (low evidence)
Intellectual disability v3.628 SBDS Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.628 SBDS Arina Puzriakova Gene: sbds has been classified as Red List (Low Evidence).
Intellectual disability v3.627 SALL4 Arina Puzriakova Classified gene: SALL4 as Red List (low evidence)
Intellectual disability v3.627 SALL4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.627 SALL4 Arina Puzriakova Gene: sall4 has been classified as Red List (Low Evidence).
Intellectual disability v3.626 PRSS56 Arina Puzriakova Classified gene: PRSS56 as Red List (low evidence)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.626 PRSS56 Arina Puzriakova Gene: prss56 has been classified as Red List (Low Evidence).
Intellectual disability v3.625 PROP1 Arina Puzriakova Classified gene: PROP1 as Red List (low evidence)
Intellectual disability v3.625 PROP1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.625 PROP1 Arina Puzriakova Gene: prop1 has been classified as Red List (Low Evidence).
Intellectual disability v3.624 PRDM12 Arina Puzriakova Classified gene: PRDM12 as Red List (low evidence)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.624 PRDM12 Arina Puzriakova Gene: prdm12 has been classified as Red List (Low Evidence).
Intellectual disability v3.623 PPA2 Arina Puzriakova Classified gene: PPA2 as Red List (low evidence)
Intellectual disability v3.623 PPA2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.623 PPA2 Arina Puzriakova Gene: ppa2 has been classified as Red List (Low Evidence).
Intellectual disability v3.622 POLR1D Arina Puzriakova Classified gene: POLR1D as Red List (low evidence)
Intellectual disability v3.622 POLR1D Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.622 POLR1D Arina Puzriakova Gene: polr1d has been classified as Red List (Low Evidence).
Intellectual disability v3.621 POLD1 Arina Puzriakova Classified gene: POLD1 as Red List (low evidence)
Intellectual disability v3.621 POLD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.621 POLD1 Arina Puzriakova Gene: pold1 has been classified as Red List (Low Evidence).
Intellectual disability v3.620 POC1B Arina Puzriakova Classified gene: POC1B as Red List (low evidence)
Intellectual disability v3.620 POC1B Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.620 POC1B Arina Puzriakova Gene: poc1b has been classified as Red List (Low Evidence).
Intellectual disability v3.619 PMS2 Arina Puzriakova Classified gene: PMS2 as Red List (low evidence)
Intellectual disability v3.619 PMS2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.619 PMS2 Arina Puzriakova Gene: pms2 has been classified as Red List (Low Evidence).
Intellectual disability v3.618 PLOD2 Arina Puzriakova Classified gene: PLOD2 as Red List (low evidence)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.618 PLOD2 Arina Puzriakova Gene: plod2 has been classified as Red List (Low Evidence).
Intellectual disability v3.617 PKHD1 Arina Puzriakova Classified gene: PKHD1 as Red List (low evidence)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.617 PKHD1 Arina Puzriakova Gene: pkhd1 has been classified as Red List (Low Evidence).
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Classified gene: PKD1L1 as Red List (low evidence)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Gene: pkd1l1 has been classified as Red List (Low Evidence).
Intellectual disability v3.615 PITX3 Arina Puzriakova Classified gene: PITX3 as Red List (low evidence)
Intellectual disability v3.615 PITX3 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.615 PITX3 Arina Puzriakova Gene: pitx3 has been classified as Red List (Low Evidence).
Intellectual disability v3.614 PITX2 Arina Puzriakova Classified gene: PITX2 as Red List (low evidence)
Intellectual disability v3.614 PITX2 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark (Australian Genomics)
Intellectual disability v3.614 PITX2 Arina Puzriakova Gene: pitx2 has been classified as Red List (Low Evidence).
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Classified gene: PIK3R1 as Red List (low evidence)
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Gene: pik3r1 has been classified as Red List (Low Evidence).
Intellectual disability v3.612 POLR1C Arina Puzriakova Phenotypes for gene: POLR1C were changed from Treacher Collins syndrome 3, 248390 to Leukodystrophy, hypomyelinating, 11, OMIM:616494
Intellectual disability v3.611 POLR1C Arina Puzriakova Publications for gene: POLR1C were set to
Intellectual disability v3.610 POLR1C Arina Puzriakova Tag for-review tag was added to gene: POLR1C.
Intellectual disability v3.610 POLR1C Arina Puzriakova Classified gene: POLR1C as Amber List (moderate evidence)
Intellectual disability v3.610 POLR1C Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment (ID and/or cognitive regression) may be variable amongst affected individuals; however, there are sufficient unrelated cases (>3) for inclusion on this panel as Green.
Intellectual disability v3.610 POLR1C Arina Puzriakova Gene: polr1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.609 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Early onset or syndromic epilepsy v2.232 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, MIM 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Classified gene: PNPT1 as No list
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Gene: pnpt1 has been removed from the panel.
Early onset or syndromic epilepsy v2.229 PNPT1 Arina Puzriakova Tag for-review tag was added to gene: PNPT1.
Intellectual disability v3.608 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Added comment: Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.608 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Classified gene: CEP85L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Gene: cep85l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.228 CEP85L Arina Puzriakova gene: CEP85L was added
gene: CEP85L was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CEP85L.
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CEP85L were set to 32097630; 32097629
Phenotypes for gene: CEP85L were set to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Review for gene: CEP85L was set to GREEN
Added comment: - PMID: 32097630 (2020) - 13 patients from 9 unrelated families with lissencephaly and heterozygous variants in the CEP85L gene. Seizures are part of the phenotype, present in all cases (except 1 unknown) which were intractable in most. Age of seizure onset was variable, ranging from 5 months to 14 years. Mouse model supports a role of CEP85L in neuronal migration. Gene-disease association included in OMIM.
Sources: Literature
Malformations of cortical development v2.20 CEP85L Arina Puzriakova Phenotypes for gene: CEP85L were changed from Lissencephaly, posterior predominant to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Malformations of cortical development v2.19 CEP85L Arina Puzriakova Publications for gene: CEP85L were set to 32097630
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Tag for-review tag was added to gene: CEP85L.
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Classified gene: CEP85L as Amber List (moderate evidence)
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).

At least 13 patients from 9 unrelated families with lissencephaly and heterozygous variants in the CEP85L gene. Mouse model supports a role in neuronal migration. Gene-disease association also included in OMIM.
Malformations of cortical development v2.18 CEP85L Arina Puzriakova Gene: cep85l has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.7 CCM2 Eleanor Williams Phenotypes for gene: CCM2 were changed from Cerebral Cavernous Malformation; Cerebral cavernous malformations 2; Cerebral Cavernous Malformations; Capillary malformation-arteriovenous malformation 608354 to Cerebral cavernous malformations-2 603284; Capillary malformation-arteriovenous malformation 608354
Cerebral vascular malformations v2.6 ACTA2 Eleanor Williams Phenotypes for gene: ACTA2 were changed from Moyamoya disease 5; Moyamoya Disease; Moyamoya disease 5,614042; Aortic aneurysm familial thoracic 6,611788; Multisystemic smooth muscle dysfunction syndrome,613834 to Moyamoya disease 5,614042; Aortic aneurysm familial thoracic 6,611788; Multisystemic smooth muscle dysfunction syndrome,613834
Intellectual disability v3.607 SCN1B Arina Puzriakova Classified gene: SCN1B as Amber List (moderate evidence)
Intellectual disability v3.607 SCN1B Arina Puzriakova Added comment: Comment on list classification: Biallelic variants associated with developmental epileptic encephalopathy characterised by early onset epileptic seizures followed by cognitive decline. At least 5 unrelated families in literature (PMIDs: 19710327; 23148524; 28218389).

Rating Amber as seizures are the prominent feature of the disease presentation, to which cognitive impairment is secondary. Cases would be detected via the epilepsy route (SCN1B is already Green on Genetic epilepsy syndromes panel).
Intellectual disability v3.607 SCN1B Arina Puzriakova Gene: scn1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.606 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from EPILEPSY, GENERALIZED, WITH FEBRILE SEIZURES PLUS, TYPE 1 to Developmental and epileptic encephalopathy 52, OMIM:617350; Developmental and epileptic encephalopathy, 52, MONDO:0033361
Intellectual disability v3.605 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 18464934
Intellectual disability v3.604 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Corneal dystrophy v1.4 MIR184 Ivone Leong reviewed gene: MIR184: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Corneal dystrophy v1.4 MIR184 Ivone Leong Tag for-review tag was added to gene: MIR184.
Corneal dystrophy v1.4 MIR184 Ivone Leong Phenotypes for gene: MIR184 were changed from EDICT syndrome 614303 to EDICT syndrome OMIM:614303, MONDO:0013678
Intellectual disability v3.603 ZFHX4 Ivone Leong Publications for gene: ZFHX4 were set to 26350204; 21802062
Intellectual disability v3.602 ZFHX4 Ivone Leong Phenotypes for gene: ZFHX4 were changed from to Developmental disorders; intellectual disability, dysmorphic features
Intellectual disability v3.601 ZFHX4 Ivone Leong Classified gene: ZFHX4 as Amber List (moderate evidence)
Intellectual disability v3.601 ZFHX4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence there is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Intellectual disability v3.601 ZFHX4 Ivone Leong Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.600 ZFHX4 Ivone Leong Mode of inheritance for gene: ZFHX4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.599 ZFHX4 Ivone Leong Tag for-review tag was added to gene: ZFHX4.
Intellectual disability v3.599 UPF1 Ivone Leong Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v3.599 UPF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics).

PMID: 28539120 describes a patient with significant ID. The patient has SNVs in SQSTM1 and UPF1. The authors suggests that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

As the patient in the second case has another variant in another gene, there is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.599 UPF1 Ivone Leong Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.598 UPF1 Ivone Leong Publications for gene: UPF1 were set to 33057194
Intellectual disability v3.597 U2AF2 Ivone Leong Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v3.597 U2AF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.597 U2AF2 Ivone Leong Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.596 TCF7L2 Ivone Leong Classified gene: TCF7L2 as Amber List (moderate evidence)
Intellectual disability v3.596 TCF7L2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.596 TCF7L2 Ivone Leong Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.595 SRRM2 Ivone Leong Classified gene: SRRM2 as Amber List (moderate evidence)
Intellectual disability v3.595 SRRM2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.595 SRRM2 Ivone Leong Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.594 SPEN Ivone Leong Classified gene: SPEN as Amber List (moderate evidence)
Intellectual disability v3.594 SPEN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.594 SPEN Ivone Leong Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.593 SATB1 Ivone Leong Phenotypes for gene: SATB1 were changed from intellectual disability to intellectual disability; developmental disorders
Intellectual disability v3.592 SATB1 Ivone Leong Classified gene: SATB1 as Amber List (moderate evidence)
Intellectual disability v3.592 SATB1 Ivone Leong Added comment: Comment on list classification: Gene promoted from Red to Amber based on the provided evidence.
Intellectual disability v3.592 SATB1 Ivone Leong Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.591 SATB1 Ivone Leong Publications for gene: SATB1 were set to
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate evidence)
Intellectual disability v3.590 MSL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.590 MSL2 Ivone Leong Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.589 RAB14 Ivone Leong Classified gene: RAB14 as Amber List (moderate evidence)
Intellectual disability v3.589 RAB14 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.589 RAB14 Ivone Leong Gene: rab14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.588 PSMC5 Ivone Leong Classified gene: PSMC5 as Amber List (moderate evidence)
Intellectual disability v3.588 PSMC5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.588 PSMC5 Ivone Leong Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.587 MMGT1 Ivone Leong Classified gene: MMGT1 as Amber List (moderate evidence)
Intellectual disability v3.587 MMGT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.587 MMGT1 Ivone Leong Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.586 HNRNPD Ivone Leong Classified gene: HNRNPD as Amber List (moderate evidence)
Intellectual disability v3.586 HNRNPD Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.586 HNRNPD Ivone Leong Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.585 FBXO31 Ivone Leong Classified gene: FBXO31 as Amber List (moderate evidence)
Intellectual disability v3.585 FBXO31 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.585 FBXO31 Ivone Leong Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.584 FBXO31 Ivone Leong Tag watchlist tag was added to gene: FBXO31.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Classified gene: PIK3C2A as Amber List (moderate evidence)
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2/2 individuals assessed for ID (both from the same family) are reported with it (PMID:31034465). Although authors state that 'most affected individuals exhibited neurological involvement including developmental delay', this was not formally assessed or otherwise reported on in the remaining cases.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.583 FBXO31 Ivone Leong Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant to ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant
Intellectual disability v3.582 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Intellectual disability v3.582 FOXP4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Intellectual disability v3.582 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.581 DHX32 Ivone Leong Classified gene: DHX32 as Amber List (moderate evidence)
Intellectual disability v3.581 DHX32 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.581 DHX32 Ivone Leong Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.580 GIGYF1 Ivone Leong Classified gene: GIGYF1 as Amber List (moderate evidence)
Intellectual disability v3.580 GIGYF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.580 GIGYF1 Ivone Leong Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.578 DDX23 Ivone Leong Classified gene: DDX23 as Amber List (moderate evidence)
Intellectual disability v3.578 DDX23 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.578 DDX23 Ivone Leong Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.577 DDX23 Ivone Leong Tag watchlist tag was added to gene: DDX23.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Classified gene: ARHGAP35 as Amber List (moderate evidence)
Intellectual disability v3.577 ARHGAP35 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 ARHGAP35 Ivone Leong Tag watchlist tag was added to gene: ARHGAP35.
Ataxia and cerebellar anomalies - childhood onset v2.33 SVBP Arina Puzriakova Classified gene: SVBP as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.33 SVBP Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). SVBP is associated with a relevant phenotype in OMIM. 12 individuals from 5 independent families (PMIDs: 31363758 and 30607023) reported at present with biallelic variants.

Rating Amber as phenotypes include ataxia in only 2 families (remaining cases present spasticity rather than ataxia).
Ataxia and cerebellar anomalies - childhood onset v2.33 SVBP Arina Puzriakova Gene: svbp has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.32 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Severe microcephaly v2.49 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Severe microcephaly v2.48 SVBP Arina Puzriakova Tag for-review tag was added to gene: SVBP.
Severe microcephaly v2.48 SVBP Arina Puzriakova Classified gene: SVBP as Amber List (moderate evidence)
Severe microcephaly v2.48 SVBP Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).

12 individuals from 5 independent families (PMIDs: 31363758 and 30607023). Phenotypes include severe microcephaly in >3 families. SVBP is associated with a relevant phenotype in OMIM.
Severe microcephaly v2.48 SVBP Arina Puzriakova Gene: svbp has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 SVBP Arina Puzriakova Phenotypes for gene: SVBP were changed from Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, 618569 to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM:618569; Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, MONDO:0032816
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Tag watchlist tag was added to gene: SCYL2.
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Classified gene: SCYL2 as Amber List (moderate evidence)
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 2 unrelated families reported at present with different SCYL2 variants and a syndromic form of severe AMC comprising microcephaly, absent corpus callosum, optic atrophy, limb fractures, profound GDD, and early lethality. Rating Amber as additional cases required before inclusion on a diagnostic panel (added 'watchlist' tag).
Arthrogryposis v3.31 SCYL2 Arina Puzriakova Gene: scyl2 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.30 SCYL2 Arina Puzriakova Phenotypes for gene: SCYL2 were changed from Arthrogryposis multiplex congenita (AMC); Zain syndrome to Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766; Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, MONDO:0032903
Congenital myaesthenic syndrome v2.7 TOR1AIP1 Arina Puzriakova Publications for gene: TOR1AIP1 were set to 24856141
Intellectual disability v3.575 AP2S1 Ivone Leong Classified gene: AP2S1 as Amber List (moderate evidence)
Intellectual disability v3.575 AP2S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Intellectual disability v3.575 AP2S1 Ivone Leong Gene: ap2s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.574 AP2S1 Ivone Leong Tag watchlist tag was added to gene: AP2S1.
Congenital myaesthenic syndrome v2.6 TOR1AIP1 Arina Puzriakova Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, 617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Paediatric or syndromic cardiomyopathy v1.15 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.15 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Paediatric or syndromic cardiomyopathy v1.15 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.14 TOR1AIP1 Arina Puzriakova gene: TOR1AIP1 was added
gene: TOR1AIP1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
for-review tags were added to gene: TOR1AIP1.
Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1AIP1 were set to 24856141; 27342937; 32055997; 25425325
Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Review for gene: TOR1AIP1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here.

Muscular dystrophy is the prominent feature of the disease presentation observed in at least one case individual each family, but specifically proximal limb-girdle dystrophy was recorded in 4 unrelated kindreds. Additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam).

Age of onset for cardiomyopathy was variable ranging from childhood to adulthood.

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Note that one additional homozygous case (3-year-old boy) has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325)
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.12 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.12 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.12 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.11 TOR1AIP1 Arina Puzriakova gene: TOR1AIP1 was added
gene: TOR1AIP1 was added to Limb girdle muscular dystrophy. Sources: Literature
for-review tags were added to gene: TOR1AIP1.
Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1AIP1 were set to 24856141; 27342937; 30723199; 31299614; 32055997
Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Review for gene: TOR1AIP1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here.

Muscular dystrophy is the prominent feature of the disease presentation observed in at least one case individual each family, but specifically proximal limb-girdle dystrophy was recorded in 4 unrelated kindreds. Additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam).

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Note that one additional homozygous case has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325)
Sources: Literature
Arthrogryposis v3.29 TOR1AIP1 Arina Puzriakova Phenotypes for gene: TOR1AIP1 were changed from joint contractures; ?Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, 617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Autosomal recessive limb-girdle muscular dystrophy type 2Y, MONDO:0014900
Arthrogryposis v3.28 TOR1AIP1 Arina Puzriakova Publications for gene: TOR1AIP1 were set to 24856141
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Tag for-review tag was added to gene: TOR1AIP1.
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). Joint contractures observed in at least 4/6 families reported to date (when considering 5 kindreds with same founder variant collectively).
Arthrogryposis v3.27 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.26 TOR1AIP1 Arina Puzriakova reviewed gene: TOR1AIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24856141, 27342937, 30723199, 31299614, 32055997; Phenotypes: Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.574 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.227 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.120 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.33 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.431 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.26 ADCY6 Arina Puzriakova Phenotypes for gene: ADCY6 were changed from Lethal congenital contracture syndrome 8 616287 to Lethal congenital contracture syndrome 8, OMIM:616287; Lethal congenital contracture syndrome 8, MONDO:0014570
Arthrogryposis v3.25 ADCY6 Arina Puzriakova Publications for gene: ADCY6 were set to 24319099
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Tag for-review tag was added to gene: ADCY6.
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Classified gene: ADCY6 as Amber List (moderate evidence)
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). At least 4 individuals from 3 unrelated families with distal AMC and distinct variants in the ADCY6 gene.
Arthrogryposis v3.24 ADCY6 Arina Puzriakova Gene: adcy6 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Tag for-review tag was added to gene: ABCC8.
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Classified gene: ABCC8 as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pulmonary arterial hypertension v2.9 ABCC8 Ivone Leong Gene: abcc8 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.8 ABCC8 Ivone Leong Publications for gene: ABCC8 were set to 31406341; 30354297
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Tag watchlist tag was added to gene: KDR.
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Classified gene: KDR as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. Based on the available evidence this gene has been given an Amber rating.
Pulmonary arterial hypertension v2.7 KDR Ivone Leong Gene: kdr has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.6 KDR Ivone Leong Added comment: Comment on publications: PMID: 32880713 describes a mouse model where Kdr was conditionally knocked out. Kdr knockout led to mild pulmonary hypertension under normoxia that worsened under hypoxia. Kdr knockout mice had significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen.
Pulmonary arterial hypertension v2.6 KDR Ivone Leong Publications for gene: KDR were set to 31980491
Anophthalmia or microphthalmia v1.31 CAPN15 Eleanor Williams Classified gene: CAPN15 as Amber List (moderate evidence)
Anophthalmia or microphthalmia v1.31 CAPN15 Eleanor Williams Added comment: Comment on list classification: Promoting gene from red to amber, but with recommendation for green rating following next major review.
Anophthalmia or microphthalmia v1.31 CAPN15 Eleanor Williams Gene: capn15 has been classified as Amber List (Moderate Evidence).
Anophthalmia or microphthalmia v1.30 CAPN15 Eleanor Williams Tag for-review tag was added to gene: CAPN15.
Anophthalmia or microphthalmia v1.30 CAPN15 Eleanor Williams gene: CAPN15 was added
gene: CAPN15 was added to Anophthalmia or microphthalmia. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 32885237
Phenotypes for gene: CAPN15 were set to microphthalmia HP:0000568; coloboma HP:0000589
Review for gene: CAPN15 was set to GREEN
Added comment: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.
Sources: Literature
Fetal anomalies v1.120 FKBP8 Eleanor Williams Classified gene: FKBP8 as Amber List (moderate evidence)
Fetal anomalies v1.120 FKBP8 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber. 5 cases reported with plausible disease causing variants but only the FKBP8 gene looked at.
Fetal anomalies v1.120 FKBP8 Eleanor Williams Gene: fkbp8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.119 FKBP8 Eleanor Williams gene: FKBP8 was added
gene: FKBP8 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FKBP8 were set to 32969478
Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414
Review for gene: FKBP8 was set to AMBER
Added comment: Not associated with a phenotype in OMIM.

PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects.

Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered.
Sources: Literature
Skeletal dysplasia v2.34 TONSL Eleanor Williams Classified gene: TONSL as Amber List (moderate evidence)
Skeletal dysplasia v2.34 TONSL Eleanor Williams Added comment: Comment on list classification: updating from red to amber, but with a recommendation for green rating at the next GMS review.
Skeletal dysplasia v2.34 TONSL Eleanor Williams Gene: tonsl has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.33 TONSL Eleanor Williams Tag for-review tag was added to gene: TONSL.
Skeletal dysplasia v2.33 TONSL Eleanor Williams gene: TONSL was added
gene: TONSL was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TONSL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TONSL were set to 32959051; 30773278; 30773277
Phenotypes for gene: TONSL were set to Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510; spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068
Review for gene: TONSL was set to GREEN
Added comment: Associated with Spondyloepimetaphyseal dysplasia, sponastrime type MIM#271510 (AR) in OMIM.

PMID: 30773277 - Burrage et al 2019 - identified, using WES or Sanger sequencing, compound heterozygous variants in TONSL in 9 individuals (8 families) with SPONASTRIME dysplasia. 4 other probands with SPONASTRIME dysplasia did not have biallelic variants in TONSL or in MMS22L, but two of them did have a single heterozygous variants in TONSL. The authors say they cannot exclude deep intronic, promotor variants or large intragenic rearrangements/deletions in these patients. An additional 4 individuals (3 families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities were also found to have compound heterozygous variants in TONSL.

PMID: 30773278 - Chang et al 2019 - Using WES they identified homozygous or compound heterozygous TONSL variants in 10 of 13 individuals (9 families) with SPONASTRIME dysplasia.

PMID: 32959051 - Micale et al 2020 - report a 9-year-old Italian girl with typical SPONASTRIME dysplasia who was found to have two novel missense variants in TONSL. Each parent was heterozygous for one of the variants. Both variants were found to be very rare in the gnomad database. Patient-derived fibroblasts show increased levels of spontaneous chromosomal breaks, reduced cell proliferation and enhanced apoptosis.
Sources: Literature
Arthrogryposis v3.23 NEK9 Arina Puzriakova Phenotypes for gene: NEK9 were changed from Arthrogryposis, Perthes disease, and upward gaze palsy 614262 to ?Arthrogryposis, Perthes disease, and upward gaze palsy, OMIM:614262; Arthrogryposis, Perthes disease, and upward gaze palsy, MONDO:0013660; Lethal congenital contracture syndrome 10, OMIM:617022; NEK9-related lethal skeletal dysplasia, MONDO:0014870
Arthrogryposis v3.22 NEK9 Arina Puzriakova Publications for gene: NEK9 were set to 26633546; 21271645
Arthrogryposis v3.21 NEK9 Arina Puzriakova Classified gene: NEK9 as Amber List (moderate evidence)
Arthrogryposis v3.21 NEK9 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber in line with the recent review by Rhiannon Mellis (GOSH). Additional cases/clinical evidence required before inclusion on a diagnostic panel.
Arthrogryposis v3.21 NEK9 Arina Puzriakova Gene: nek9 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.13 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Hypertrophic cardiomyopathy; Cardiomyopathy, dilated, 1S; Left ventricular noncompaction 5; Cardiomyopathy, familial hypertrophic, 1, to Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Left ventricular noncompaction 5, OMIM:613426
Paediatric disorders - additional genes v1.68 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Cardiomyopathy, dilated, 1S; Left ventricular noncompaction 5; Cardiomyopathy, hypertrophic, 1; Myopathy, myosin storage, autosomal recessive; Myopathy, myosin storage, autosomal dominant; Scapuloperoneal syndrome, myopathic type; Laing distal myopathy to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018; Left ventricular noncompaction 5, OMIM:613426
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.10 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500 Laing early-onset distal myopathy, MONDO:0008050 Scapuloperoneal syndrome, myopathic type, OMIM:181430 MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600 Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426 Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358 Myopathy, myosin storage, autosomal dominant, MONDO:0012018 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018
Dilated and arrhythmogenic cardiomyopathy v1.8 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Cardiomyopathy, dilated, 1S (613426); Cardiomyopathy, dilated, 1S; Myopathy, myosin storage, autosomal recessive (255160); Scapuloperoneal syndrome, myopathic type (181430); Myopathy, myosin storage, autosomal dominant (608358); Cardiomyopathy, hypertrophic, 1 (192600); Left ventricular noncompaction 5 (613426); Laing distal myopathy (160500) to Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.9 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, 160500; cardiomyopathy; distal myopathy to Laing distal myopathy, OMIM:160500 Laing early-onset distal myopathy, MONDO:0008050 Scapuloperoneal syndrome, myopathic type, OMIM:181430 MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600 Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426 Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358 Myopathy, myosin storage, autosomal dominant, MONDO:0012018
Left Ventricular Noncompaction Cardiomyopathy v1.4 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Left ventricular noncompaction 5 ; Hypertrophic cardiomyopathy to Left ventricular noncompaction 5, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262
Distal myopathies v1.26 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409
Congenital myopathy v2.8 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing Distal Myopathy 160500 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018
Arthrogryposis v3.20 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing Distal Myopathy; Cardiomyopathy, familial hypertrophic, 1, 192600; Myopathy, myosin storage, autosomal recessive 255160; Myopathy, myosin storage, autosomal dominant 608358 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050
Dilated Cardiomyopathy and conduction defects v1.66 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Left ventricular noncompaction 5 (613426); Myopathy, myosin storage, autosomal dominant (608358); Laing distal myopathy (160500); Myopathy, myosin storage, autosomal recessive (255160); Cardiomyopathy, hypertrophic, 1 (192600); Cardiomyopathy, dilated, 1S (613426); Cardiomyopathy, dilated, 1S ; Scapuloperoneal syndrome, myopathic type (181430) to Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262
Hypertrophic cardiomyopathy v2.15 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Left ventricular noncompaction 5 (613426); Myopathy, myosin storage, autosomal dominant (608358); Laing distal myopathy (160500); Myopathy, myosin storage, autosomal recessive (255160); Cardiomyopathy, hypertrophic, 1 (192600); Cardiomyopathy, dilated, 1S (613426); Scapuloperoneal syndrome, myopathic type (181430); Cardiomyopathy, familial hypertrophic, 1, to Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647
Structural eye disease v1.22 CAPN15 Eleanor Williams changed review comment from: Publication relating to previous conference abstract now available:
PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).; to: Publication relating to previous conference abstract now available:
PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.
Structural eye disease v1.22 CAPN15 Eleanor Williams Phenotypes for gene: CAPN15 were changed from Anophthalmia, microphthalmia and coloboma to microphthalmia HP:0000568; coloboma HP:0000589
Structural eye disease v1.21 CAPN15 Eleanor Williams Publications for gene: CAPN15 were set to
Structural eye disease v1.20 CAPN15 Eleanor Williams Tag watchlist was removed from gene: CAPN15.
Tag for-review tag was added to gene: CAPN15.
Distal myopathies v1.25 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, 160500 to Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050
Structural eye disease v1.20 CAPN15 Eleanor Williams Classified gene: CAPN15 as Amber List (moderate evidence)
Structural eye disease v1.20 CAPN15 Eleanor Williams Added comment: Comment on list classification: Promoting gene from red to amber, but with recommendation for green rating following GMS review.
Structural eye disease v1.20 CAPN15 Eleanor Williams Gene: capn15 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.19 CAPN15 Eleanor Williams edited their review of gene: CAPN15: Added comment: Publication relating to previous conference abstract now available:
PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).; Changed rating: GREEN; Changed publications: 32885237; Changed phenotypes: microphthalmia HP:0000568, coloboma HP:0000589
Arthrogryposis v3.19 MYH7 Arina Puzriakova Classified gene: MYH7 as Green List (high evidence)
Arthrogryposis v3.19 MYH7 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the next GMS panel update (added 'for-review' tag) as variants are associated with distal myopathy rather than arthrogryposis and therefore MYH7 should be demoted to RED on this panel.
Arthrogryposis v3.19 MYH7 Arina Puzriakova Gene: myh7 has been classified as Green List (High Evidence).
Arthrogryposis v3.18 MYH7 Arina Puzriakova Tag for-review tag was added to gene: MYH7.
Pigmentary skin disorders v1.7 XRCC2 Arina Puzriakova Publications for gene: XRCC2 were set to 22232082
Pigmentary skin disorders v1.6 XRCC2 Arina Puzriakova Phenotypes for gene: XRCC2 were changed from FANCONI ANEMIA, COMPLEMENTATION GROUP U; FANCU to ?Fanconi anemia, complementation group U, OMIM:617247; Fanconi anemia complementation group U, MONDO:0014987
Fanconi anaemia or Bloom syndrome v1.11 XRCC2 Arina Puzriakova Phenotypes for gene: XRCC2 were changed from 617247 ?Fanconi anemia, complementation group U to ?Fanconi anemia, complementation group U, OMIM:617247; Fanconi anemia complementation group U, MONDO:0014987
Fanconi anaemia or Bloom syndrome v1.10 XRCC2 Arina Puzriakova Publications for gene: XRCC2 were set to
Fanconi anaemia or Bloom syndrome v1.9 XRCC2 Arina Puzriakova Classified gene: XRCC2 as Amber List (moderate evidence)
Fanconi anaemia or Bloom syndrome v1.9 XRCC2 Arina Puzriakova Added comment: Comment on list classification: Single FA-U patient in literature at present but with supportive functional data. Additional published cases required to confirm pathogenicity and support inclusion of XRCC2 on a diagnostic FA panel.
Fanconi anaemia or Bloom syndrome v1.9 XRCC2 Arina Puzriakova Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.19 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis, 609218 to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Structural eye disease v1.18 SLC38A8 Eleanor Williams Publications for gene: SLC38A8 were set to 24045842
Structural eye disease v1.17 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: ; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.8 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis 609218 AR to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Albinism or congenital nystagmus v1.7 SLC38A8 Eleanor Williams Publications for gene: SLC38A8 were set to 24290379; 29345414; 24045842
Retinal disorders v2.23 SLC38A8 Eleanor Williams Phenotypes for gene: SLC38A8 were changed from Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis, 609218 to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Retinal disorders v2.22 SLC38A8 Eleanor Williams Publications for gene: SLC38A8 were set to 24290379; 24045842; 15466012; 24290379; 24045842
Retinal disorders v2.21 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: ; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.6 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.41 SPEF2 Ivone Leong Classified gene: SPEF2 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.41 SPEF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM. As respiratory phenotype is not in all affected individuals, this gene has been given an Amber rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.41 SPEF2 Ivone Leong Gene: spef2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.118 SCN1A Arina Puzriakova Phenotypes for gene: SCN1A were changed from SCN1A-RELATED SEIZURE DISORDERS to Dravet syndrome, OMIM:607208; Arthrogryposis multiplex congenita
Fetal anomalies v1.117 SCN1A Arina Puzriakova Publications for gene: SCN1A were set to
Fetal anomalies v1.116 SCN1A Arina Puzriakova Classified gene: SCN1A as Red List (low evidence)
Fetal anomalies v1.116 SCN1A Arina Puzriakova Added comment: Comment on list classification: Although it is anticipated that following birth early-onset seizures will likely represent the predominant characteristic of the phenotype, arthrogryposis multiplex congenita may be detected in utero as demonstrated with the cases in PMID:32928894. Therefore, this gene will be flagged for review at the next GMS panel update to assess whether this is sufficient for inclusion on this panel (added 'for-review' tag).
Fetal anomalies v1.116 SCN1A Arina Puzriakova Gene: scn1a has been classified as Red List (Low Evidence).
Fetal anomalies v1.115 SCN1A Arina Puzriakova Tag for-review tag was added to gene: SCN1A.
Fetal anomalies v1.115 SCN1A Arina Puzriakova reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32928894, 29543227; Phenotypes: Dravet syndrome, OMIM:607208, Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Respiratory ciliopathies including non-CF bronchiectasis v1.40 SPEF2 Ivone Leong Phenotypes for gene: SPEF2 were changed from Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype to Spermatogenic failure 43, OMIM:618751, MONDO:0032898; Primary ciliary dyskinesia-like phenotype
Respiratory ciliopathies including non-CF bronchiectasis v1.39 DNAJB13 Ivone Leong reviewed gene: DNAJB13: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.39 DNAJB13 Ivone Leong Tag for-review tag was added to gene: DNAJB13.
Respiratory ciliopathies including non-CF bronchiectasis v1.39 DNAJB13 Ivone Leong Publications for gene: DNAJB13 were set to
Arthrogryposis v3.18 SCN1A Arina Puzriakova Classified gene: SCN1A as Amber List (moderate evidence)
Arthrogryposis v3.18 SCN1A Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases (4) reported in 2 papers (PMIDs: 32928894 and 29543227) with ACM and variants in this gene.

It is anticipated that early-onset seizures likely represent the predominant feature of the disease presentation (already Green on the Genetic epilepsy syndromes panel), however this gene will be flagged for review to assess whether inclusion on this panel is likely to be of clinical benefit.
Arthrogryposis v3.18 SCN1A Arina Puzriakova Gene: scn1a has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.38 DNAJB13 Ivone Leong Phenotypes for gene: DNAJB13 were changed from Ciliary dyskinesia, primary, 34, 617091 to Ciliary dyskinesia, primary, 34, OMIM:617091, MONDO:0014909
Respiratory ciliopathies including non-CF bronchiectasis v1.37 TTC12 Ivone Leong Classified gene: TTC12 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.37 TTC12 Ivone Leong Gene: ttc12 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.36 TTC12 Ivone Leong Classified gene: TTC12 as Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.36 TTC12 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Respiratory ciliopathies including non-CF bronchiectasis v1.36 TTC12 Ivone Leong Gene: ttc12 has been classified as Green List (High Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.35 TTC12 Ivone Leong Tag for-review tag was added to gene: TTC12.
Respiratory ciliopathies including non-CF bronchiectasis v1.35 TTC12 Ivone Leong Phenotypes for gene: TTC12 were changed from Ciliary dyskinesia to Ciliary dyskinesia, primary, 45, OMIM:618801; MONDO:0032924
Respiratory ciliopathies including non-CF bronchiectasis v1.34 FOXJ1 Ivone Leong Classified gene: FOXJ1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.34 FOXJ1 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
Respiratory ciliopathies including non-CF bronchiectasis v1.34 FOXJ1 Ivone Leong Gene: foxj1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.33 FOXJ1 Ivone Leong Tag for-review tag was added to gene: FOXJ1.
Respiratory ciliopathies including non-CF bronchiectasis v1.33 FOXJ1 Ivone Leong Phenotypes for gene: FOXJ1 were changed from Motile ciliopathy; situs inversus, hydrocephalus to Ciliary dyskinesia, primary, 43, OMIM:618699, MONDO:0032874
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Tag for-review tag was added to gene: NEK10.
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Classified gene: NEK10 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at next review.
Respiratory ciliopathies including non-CF bronchiectasis v1.32 NEK10 Ivone Leong Gene: nek10 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.31 NEK10 Ivone Leong Added comment: Comment on publications: PMID: 32414360 is an additional case
Respiratory ciliopathies including non-CF bronchiectasis v1.31 NEK10 Ivone Leong Publications for gene: NEK10 were set to 31959991
Respiratory ciliopathies including non-CF bronchiectasis v1.30 NEK10 Ivone Leong Phenotypes for gene: NEK10 were changed from Ciliary dyskinesia, primary, 44, MIM# 618781 to Ciliary dyskinesia, primary, 44, OMIM:618781, MONDO:0032914
Arthrogryposis v3.17 SCN1A Arina Puzriakova Phenotypes for gene: SCN1A were changed from Arthrogryposis multiplex congenita to Arthrogryposis multiplex congenita; Dravet syndrome, OMIM:607208
Arthrogryposis v3.16 SCN1A Arina Puzriakova Publications for gene: SCN1A were set to 32928894
Arthrogryposis v3.15 SCN1A Arina Puzriakova Tag for-review tag was added to gene: SCN1A.
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong edited their review of gene: RPGR: Added comment: This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.; Changed rating: GREEN
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong Tag for-review tag was added to gene: RPGR.
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong Added comment: Comment on publications: PMID: 22888088 and 14627685 are extra cases
Respiratory ciliopathies including non-CF bronchiectasis v1.29 RPGR Ivone Leong Publications for gene: RPGR were set to 10094550; 12920075; 16055928
Respiratory ciliopathies including non-CF bronchiectasis v1.28 RPGR Ivone Leong Phenotypes for gene: RPGR were changed from Ciliopathies to Ciliopathies; Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, OMIM:300455; primary ciliary dyskinesia-retinitis pigmentosa syndrome, MONDO:0010330
Respiratory ciliopathies including non-CF bronchiectasis v1.27 RPGR Ivone Leong Publications for gene: RPGR were set to
Respiratory ciliopathies including non-CF bronchiectasis v1.26 CFAP46 Ivone Leong reviewed gene: CFAP46: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.26 CFAP46 Ivone Leong Tag for-review tag was added to gene: CFAP46.
Respiratory ciliopathies including non-CF bronchiectasis v1.26 CFAP46 Ivone Leong Phenotypes for gene: CFAP46 were changed from to Heterotaxy
Respiratory ciliopathies including non-CF bronchiectasis v1.25 CFAP46 Ivone Leong Publications for gene: CFAP46 were set to
Sarcoma susceptibility v1.5 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from Pleuropulmonary blastoma, 601200; Rhabdomyosarcoma, embryonal, 2, 180295 to Pleuropulmonary blastoma, OMIM:601200; Pleuropulmonary blastoma, MONDO:0011014; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; Embryonal rhabdomyosarcoma (disease), MONDO:0009993
Adult solid tumours cancer susceptibility v2.7 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from DICER1 syndrome, Familial Multinodular Goiter to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Pleuropulmonary blastoma, OMIM:601200; Pleuropulmonary blastoma, MONDO:0011014; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; Embryonal rhabdomyosarcoma (disease), MONDO:0009993; DICER1 syndrome
Inherited non-medullary thyroid cancer v1.5 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors 138800; Pleuropulmonary blastoma 601200 to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800
Childhood solid tumours v2.16 DICER1 Arina Puzriakova Publications for gene: DICER1 were set to 21205968
Childhood solid tumours v2.15 DICER1 Arina Puzriakova Phenotypes for gene: DICER1 were changed from Familial Multinodular Goiter; DICER1 syndrome; 601200 to Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, OMIM:138800; Pleuropulmonary blastoma, OMIM:601200; Pleuropulmonary blastoma, MONDO:0011014; Rhabdomyosarcoma, embryonal, 2, OMIM:180295; Embryonal rhabdomyosarcoma (disease), MONDO:0009993; DICER1 syndrome; GLOW syndrome; Global developmental delay, lung cysts, overgrowth, and wilms tumor, MONDO:0032647
Hereditary neuropathy or pain disorder v1.18 UBA5 Arina Puzriakova gene: UBA5 was added
gene: UBA5 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: UBA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBA5 were set to 32179706
Phenotypes for gene: UBA5 were set to Hypomyelinating neuropathy
Added comment: Note that UBA5 variants have been associated with a range of neurological phenotypes including epilepsy, ID and ataxia.

PMID: 32179706 (2020) - Five affected individuals from a consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Some in vitro functional data included. Due to early mortality, unclear whether additional features previously associated with UBA5 variants would have developed.
Sources: Literature
Intellectual disability v3.574 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Respiratory ciliopathies including non-CF bronchiectasis v1.24 CFAP54 Ivone Leong Tag for-review tag was added to gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v1.24 CFAP54 Ivone Leong reviewed gene: CFAP54: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.24 CFAP54 Ivone Leong Publications for gene: CFAP54 were set to
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Early onset or syndromic epilepsy v2.226 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 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 v3.574 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Intellectual disability v3.574 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 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)
Respiratory ciliopathies including non-CF bronchiectasis v1.23 CFAP57 Ivone Leong Classified gene: CFAP57 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.23 CFAP57 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with any phenotypes in OMIM or Gene2Phenotype and based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.23 CFAP57 Ivone Leong Gene: cfap57 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.22 CFAP57 Ivone Leong Added comment: Comment on publications: bioRxiv 773028 doi: https://doi.org/10.1101/773028 has now been published and is PMID: 32764743
Respiratory ciliopathies including non-CF bronchiectasis v1.22 CFAP57 Ivone Leong Publications for gene: CFAP57 were set to 32764743
Respiratory ciliopathies including non-CF bronchiectasis v1.21 CFAP57 Ivone Leong Publications for gene: CFAP57 were set to bioRxiv 773028 doi: https://doi.org/10.1101/773028
Respiratory ciliopathies including non-CF bronchiectasis v1.20 ITCH Ivone Leong Classified gene: ITCH as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.20 ITCH Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.20 ITCH Ivone Leong Gene: itch has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.19 ITCH Ivone Leong Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism 613385; primary ciliary dyskinesia to Autoimmune disease, multisystem, with facial dysmorphism OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245; primary ciliary dyskinesia
Respiratory ciliopathies including non-CF bronchiectasis v1.18 GOLGA3 Ivone Leong Classified gene: GOLGA3 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.18 GOLGA3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.18 GOLGA3 Ivone Leong Gene: golga3 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.17 AKNA Ivone Leong Classified gene: AKNA as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.17 AKNA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Based on the available evidence this gene has been given a Red rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.17 AKNA Ivone Leong Gene: akna has been classified as Red List (Low Evidence).
Intellectual disability v3.573 ISCA-37418-Loss Zornitza Stark reviewed Region: ISCA-37418-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Smith-Magenis syndrome, MIM# 182290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.131 MET Eleanor Williams Classified gene: MET as Amber List (moderate evidence)
Monogenic hearing loss v2.131 MET Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as two cases reported, with segregation data.
Monogenic hearing loss v2.131 MET Eleanor Williams Gene: met has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.130 MET Eleanor Williams gene: MET was added
gene: MET was added to Hearing loss. Sources: Expert list
Mode of inheritance for gene: MET was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MET were set to 25941349; 27717089
Phenotypes for gene: MET were set to Deafness, autosomal recessive 97 OMIM:616705; autosomal recessive nonsyndromic deafness 97 MONDO:0014739
Review for gene: MET was set to AMBER
Added comment: Gene suggested by Professor Sadaf Naz, PhD, School of Biological Sciences, University of the Punjab, Pakistan

Provisionally associated with ?Deafness, autosomal recessive 97 MIM#616705 in OMIM. 2 cases reported:

PMID: 25941349 - Mujtaba et al 2015 - report a large consanguineous Pakistani family with some members affected by hearing loss. They identified, through genome-wide homozygosity mapping and then whole exome sequencing, a homozygous missense variant located in MET (NM_000245.2), c.2521T>G (p.F841V) that segregates with hearing loss in 9 affected individuals.

PMID: 27717089 - Alabdullatif et al 2017 - from a review of clinical and molecular data for 227 individuals from a highly consanguineous population who underwent a combined (CGH+SNP) CMA test, they report 2 brothers with hearing loss and arthrogryposis in which a homozygous variant c.3557T>G (p.F1186C) in MET was identified through WES after a region of homozygosity was identified. The first cousin parents were both heterozygous for this variant. They suggest that the arthrogryposis could be a variable feature of the disease or be caused by a second recessive disease not detected in this study.
Sources: Expert list
Structural eye disease v1.17 CDH2 Arina Puzriakova Classified gene: CDH2 as Amber List (moderate evidence)
Structural eye disease v1.17 CDH2 Arina Puzriakova Added comment: Comment on list classification: Gene added following discussion with Helen Brittain (Genomics England Clinical Team) who indicated this panel may be applicable in view of the ocular abnormalities observed in some individuals with CDH2 variants. However, as the eye phenotypes were diverse, this warrants phenotypic consideration by the GMS team to assess the relevance to this panel (added 'for-review' tag)
Structural eye disease v1.17 CDH2 Arina Puzriakova Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.16 CDH2 Arina Puzriakova gene: CDH2 was added
gene: CDH2 was added to Structural eye disease. Sources: Literature
for-review tags were added to gene: CDH2.
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDH2 were set to 31585109; 31650526
Phenotypes for gene: CDH2 were set to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Review for gene: CDH2 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects' in Gene2Phenotype.

2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various ocular abnormalities (11/13). Eye phenotype was variable and includes Peters anomaly, glaucoma, cataract, Duane anomaly, strabismus.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Paediatric disorders - additional genes v1.67 CDH2 Arina Puzriakova Classified gene: CDH2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.67 CDH2 Arina Puzriakova Added comment: Comment on list classification: Gene added following discussion with Helen Brittain (Genomics England Clinical Team) who indicated this panel is relevant in view of the multiple congenital malformations associated with CDH2 variants.

Tagged 'for-review' as there is sufficient evidence to rate this gene Green at the next GMS panel update.
Paediatric disorders - additional genes v1.67 CDH2 Arina Puzriakova Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.66 CDH2 Arina Puzriakova gene: CDH2 was added
gene: CDH2 was added to Paediatric disorders - additional genes. Sources: Literature
for-review tags were added to gene: CDH2.
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDH2 were set to 31585109; 31650526
Phenotypes for gene: CDH2 were set to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Review for gene: CDH2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects' in Gene2Phenotype.

2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Malformations of cortical development v2.17 CDH2 Arina Puzriakova changed review comment from: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature; to: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects' in Gene2Phenotype.

2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Intellectual disability v3.573 CDH2 Arina Puzriakova reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31650526; Phenotypes: Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.17 CDH2 Arina Puzriakova Classified gene: CDH2 as Amber List (moderate evidence)
Malformations of cortical development v2.17 CDH2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Malformations of cortical development v2.17 CDH2 Arina Puzriakova Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.16 CDH2 Arina Puzriakova changed review comment from: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.
Sources: Literature; to: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganisation and CCA similar to the human phenotypes (PMIDs: 9015265, 17222817).
Sources: Literature
Malformations of cortical development v2.16 CDH2 Arina Puzriakova gene: CDH2 was added
gene: CDH2 was added to Malformations of cortical development. Sources: Literature
for-review tags were added to gene: CDH2.
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDH2 were set to 31585109; 31650526
Phenotypes for gene: CDH2 were set to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Review for gene: CDH2 was set to GREEN
Added comment: 2 papers (PMID: 31585109 and 31650526) describing 13 unrelated individuals with a neurodevelopmental disorder and variants in the CDH2 gene. Clinical features include GDD/ID (10/12), brain malformations - particularly agenesis of corpus callosum (11/13), cardiovascular abnormalities (9/13), and various eye abnormalities (11/13).

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.
Sources: Literature
Intellectual disability v3.573 CDH2 Arina Puzriakova Phenotypes for gene: CDH2 were changed from Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929 to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Respiratory ciliopathies including non-CF bronchiectasis v1.16 NME5 Ivone Leong Classified gene: NME5 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.16 NME5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Therefore, there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.16 NME5 Ivone Leong Gene: nme5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.572 CDH2 Arina Puzriakova Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Respiratory ciliopathies including non-CF bronchiectasis v1.15 NME5 Ivone Leong Tag watchlist tag was added to gene: NME5.
Respiratory ciliopathies including non-CF bronchiectasis v1.15 CFAP74 Ivone Leong Tag watchlist tag was added to gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v1.15 NME5 Ivone Leong Publications for gene: NME5 were set to 32185794
Respiratory ciliopathies including non-CF bronchiectasis v1.14 CFAP74 Ivone Leong Classified gene: CFAP74 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.14 CFAP74 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. Based on the available evidence there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Respiratory ciliopathies including non-CF bronchiectasis v1.14 CFAP74 Ivone Leong Gene: cfap74 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.13 OFD1 Ivone Leong reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.13 OFD1 Ivone Leong Mode of inheritance for gene: OFD1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Respiratory ciliopathies including non-CF bronchiectasis v1.12 OFD1 Ivone Leong Tag for-review tag was added to gene: OFD1.
Respiratory ciliopathies including non-CF bronchiectasis v1.12 OFD1 Ivone Leong Publications for gene: OFD1 were set to 31366608; 32276433; 31373179; 16783569
Respiratory ciliopathies including non-CF bronchiectasis v1.11 OFD1 Ivone Leong Publications for gene: OFD1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Tag watchlist tag was added to gene: LCP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Classified gene: LCP2 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer (University of Florence). Rating Red pending publication of the Lev et al., 2021 article. Paper only describes a single individual and additional cases would be required before inclusion of LCP2 on an immunodeficiency panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.384 LCP2 Arina Puzriakova Gene: lcp2 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.10 OFD1 Ivone Leong Phenotypes for gene: OFD1 were changed from Ciliopathies; Primary ciliary dyskinesia to Ciliopathies; Primary ciliary dyskinesia; Simpson-Golabi-Behmel syndrome, type 2, OMIM:300209, MONDO:0010265
Primary immunodeficiency or monogenic inflammatory bowel disease v2.383 LCP2 Arina Puzriakova reviewed gene: LCP2: Rating: ; Mode of pathogenicity: None; Publications: 33231617; Phenotypes: Severe immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.9 OFD1 Ivone Leong Phenotypes for gene: OFD1 were changed from Ciliopathies to Ciliopathies; Primary ciliary dyskinesia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.383 RNU7-1 Arina Puzriakova Tag watchlist tag was added to gene: RNU7-1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.383 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Type I interferonopathy, Aicardi-Goutières syndrome to Type I interferonopathy; Aicardi-Goutières syndrome
Primary immunodeficiency or monogenic inflammatory bowel disease v2.382 RNU7-1 Arina Puzriakova Classified gene: RNU7-1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.382 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Currently only one paper (PMID: 33230297) indicating pathogenicity of RNU7-1 variants, which also reports on a healthy individual with biallelic rare variants in this gene. Rating Amber awaiting further publications/clinical evidence to corroborate this gene-disease association (added 'watchlist' tag)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.382 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.381 RNU7-1 Arina Puzriakova reviewed gene: RNU7-1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Type I interferonopathy, Aicardi–Goutières syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.381 LSM11 Arina Puzriakova Phenotypes for gene: LSM11 were changed from Type I interferonopathy, Aicardi-Goutières syndrome to Type I interferonopathy; Aicardi-Goutières syndrome
Primary immunodeficiency or monogenic inflammatory bowel disease v2.380 LSM11 Arina Puzriakova Classified gene: LSM11 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.380 LSM11 Arina Puzriakova Gene: lsm11 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LSM11 Arina Puzriakova reviewed gene: LSM11: Rating: ; Mode of pathogenicity: None; Publications: 33230297; Phenotypes: Type I interferonopathy, Aicardi–Goutières syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.571 ISCA-37415-Gain Arina Puzriakova Phenotypes for Region: ISCA-37415-Gain were changed from to Intellectual disability; Developmental delay; Autism; Aortopathy
Intellectual disability v3.570 ISCA-37415-Gain Arina Puzriakova Publications for Region: ISCA-37415-Gain were set to 23637818; 24352232; 21614007
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 Arina Puzriakova Tag for-review tag was added to gene: PALB2.
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 Arina Puzriakova changed review comment from: Comment on list classification: Kept rating Red, as it remains unclear whether the risk is sufficiently high to warrant the inclusion of PALB2 in the ovarian cancer gene panel.; to: Comment on list classification: Kept rating Red, but this gene will be flagged for review (added 'for-review' tag) at the next GMS panel update to assess whether the risk is sufficiently high to warrant inclusion of PALB2 on the ovarian cancer gene panel in the context of two recent publications (PMIDs: 31841383 and 32546565) identified by the expert reviewer.
Intellectual disability v3.569 ISCA-37415-Gain Zornitza Stark reviewed Region: ISCA-37415-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: 30287593; Phenotypes: Intellectual disability, autism, aortopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.115 MN1 Rhiannon Mellis gene: MN1 was added
gene: MN1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Mode of pathogenicity for gene: MN1 was set to Other
Review for gene: MN1 was set to GREEN
Added comment: Copied from MN1 review on Cortical malformations panel:

Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum - rhombencephalosynapsis).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Paediatric disorders - additional genes v1.65 PIGQ Sarah Leigh Classified gene: PIGQ as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.65 PIGQ Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Paediatric disorders - additional genes v1.65 PIGQ Sarah Leigh Gene: pigq has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.64 PIGQ Sarah Leigh commented on gene: PIGQ: Comments from Konstantinos Varvagiannis
Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548). Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362). Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality. PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis. More than 10 variants have been reported to date (missense / pLoF). Overall PIGQ can be considered for green rating in both ID and epilepsy gene panels.
Paediatric disorders - additional genes v1.64 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, OMIM:618548 as the name for this phenotype (12/11/2020).
Paediatric disorders - additional genes v1.64 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548 to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Paediatric disorders - additional genes v1.63 PIGQ Sarah Leigh gene: PIGQ was added
gene: PIGQ was added to Paediatric disorders - additional genes. Sources: Literature
for-review tags were added to gene: PIGQ.
Mode of inheritance for gene: PIGQ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGQ were set to 32588908; 24463883; 25558065; 31148362
Phenotypes for gene: PIGQ were set to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Review for gene: PIGQ was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for severe early onset epilepsy. At least 11 variants reported in seven unrelated cases of multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4)(Epileptic encephalopathy, early infantile, 77 618548)(OMIM:618548).
Sources: Literature
Intellectual disability v3.569 ATP2A2 Andrea Nemeth reviewed gene: ATP2A2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 25704118; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v1.62 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.62 STN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.

There is enough evidence for this gene to be rated GREEN at the next major review.
Paediatric disorders - additional genes v1.62 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia, childhood onset v2.21 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
Hereditary spastic paraplegia, childhood onset v2.21 STN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.

There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary spastic paraplegia, childhood onset v2.21 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.32 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.32 STN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.

There is enough evidence for this gene to be rated GREEN at the next major review.
Cytopenia - NOT Fanconi anaemia v1.32 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.61 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Paediatric disorders - additional genes. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v1.31 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.20 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Hypophosphataemia or rickets v2.14 FAH Ivone Leong Classified gene: FAH as Amber List (moderate evidence)
Hypophosphataemia or rickets v2.14 FAH Ivone Leong Added comment: Comment on list classification: This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association.

FAH causes type I tyrosinemia and hypophosphataemic rickets is a feature of chronic disease, but patients present with liver phenotypes at the beginning before developing hypophosphataemic rickets. After consultation with the Genomics England Clinical Team, I have given this gene an Amber gene rating and tagged with "for-review" so that GMS experts can consider this gene in the scope of testing for the next iteration.

This gene is already Green on Undiagnosed metabolic disorders (v1.431) and Inborn errors of metabolism (v2.33) panels
Hypophosphataemia or rickets v2.14 FAH Ivone Leong Gene: fah has been classified as Amber List (Moderate Evidence).
Hypophosphataemia or rickets v2.13 FAH Ivone Leong Tag for-review tag was added to gene: FAH.
Hypophosphataemia or rickets v2.13 FAH Ivone Leong Phenotypes for gene: FAH were changed from Tyrosinemia, type I, 276700 to Tyrosinemia, type I, OMIM:276700, MONDO:0010161
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Tag for-review tag was added to gene: ALPL.
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Classified gene: ALPL as Amber List (moderate evidence)
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Added comment: Comment on list classification: This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association. However, phosphate levels in the blood is normal for this phenotype. After consultation with the Genomics England Clinical Team, I have given this gene an Amber gene rating and tagged with "for-review" so that GMS experts can consider this gene in the scope of testing for the next iteration.
Hypophosphataemia or rickets v2.12 ALPL Ivone Leong Gene: alpl has been classified as Amber List (Moderate Evidence).
Hypophosphataemia or rickets v2.11 ALPL Ivone Leong Phenotypes for gene: ALPL were changed from Hypophosphatasia, infantile, 241500; Hypophosphatasia, childhood, 241500 to Hypophosphatasia, infantile, OMIM:241500, MONDO:0009427; Hypophosphatasia, childhood, OMIM:241500, MONDO:0009428
Pituitary hormone deficiency v2.5 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Pituitary hormone deficiency. Sources: Literature,Expert Review
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As the second case has low levels of prolactin and GH, this gene was added to this panel as a Red gene.
Sources: Literature, Expert Review
Bilateral congenital or childhood onset cataracts v2.18 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Cataracts. Sources: Expert Review,Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; congenital cataracts
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As only 1 affected family has congenital cataracts, this gene is given a Red rating.
Sources: Expert Review, Literature
Intellectual disability v3.569 RNPC3 Ivone Leong gene: RNPC3 was added
gene: RNPC3 was added to Intellectual disability. Sources: Expert Review,Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Phenotypes for gene: RNPC3 were set to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty
Review for gene: RNPC3 was set to RED
Added comment: This gene is an Amber gene on the Growth failure in early childhood panel (v1.16). The following reviews are present for this gene on that panel:

"Comment on list classification: Based on the available evidence and expert review, this gene has been promoted from Red to Amber. This gene is associated with a relevant phenotype on OMIM. The family described in PMIDs 24480542 and 29866761 are the same. The 3 sisters in this family had GH deficiency only. PMID: 32462814 had GH deficiency and almost undetectable levels of prolactin as well.
Ivone Leong (Genomics England Curator), 15 Oct 2020

Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Zornitza Stark (Australian Genomics), 5 Oct 2020"

As only 1 affected family has developmental delay/intellectual deficiency, this gene is given a Red rating.
Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 RNU7-1 Boaz Palterer gene: RNU7-1 was added
gene: RNU7-1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Type I interferonopathy, Aicardi-Goutières syndrome
Penetrance for gene: RNU7-1 were set to unknown
Review for gene: RNU7-1 was set to AMBER
Added comment: 16 patients belonging to 11 independent pedigrees harbored biallelic variants, with a frequency of ≤0.005 alleles in the Genome Aggregation Database (gnomAD), in the RNU7-1 gene encoding small nuclear RNA (snRNA) U7
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LSM11 Boaz Palterer gene: LSM11 was added
gene: LSM11 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM11 were set to 33230297
Phenotypes for gene: LSM11 were set to Type I interferonopathy, Aicardi-Goutières syndrome
Penetrance for gene: LSM11 were set to unknown
Review for gene: LSM11 was set to AMBER
Added comment: Two siblings with AGS from consanguineous parents were found to have homozygous LSM11 mutation.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 LCP2 Boaz Palterer gene: LCP2 was added
gene: LCP2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LCP2 were set to 33231617
Phenotypes for gene: LCP2 were set to SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation
Penetrance for gene: LCP2 were set to unknown
Review for gene: LCP2 was set to AMBER
Added comment: One patient with severe combined immunodeficiency was found to have biallelic mutations in SLP76.
Sources: Literature
Monogenic hearing loss v2.129 PMP22 Eleanor Williams Classified gene: PMP22 as Amber List (moderate evidence)
Monogenic hearing loss v2.129 PMP22 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. Three independent cases reported in which patients have Charcot-Marie-Tooth disease plus hearing loss and variants in PMP22, but waiting for feedback from Genomics England clinical team as to whether this gene is appropriate to be green as HL is part of a syndrome of features.
Monogenic hearing loss v2.129 PMP22 Eleanor Williams Gene: pmp22 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.128 PMP22 Eleanor Williams Phenotypes for gene: PMP22 were changed from to Charcot-Marie-Tooth disease, type 1E OMIM:118300; Charcot-Marie-Tooth disease type 1E MONDO:0007311
Monogenic hearing loss v2.127 PMP22 Eleanor Williams Publications for gene: PMP22 were set to
Monogenic hearing loss v2.126 PMP22 Eleanor Williams Mode of inheritance for gene: PMP22 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.125 PMP22 Eleanor Williams changed review comment from: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.; to: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ in 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.
Familial Meniere Disease v1.1 COCH Eleanor Williams commented on gene: COCH: Several cases of biallelic variants reported in families with hearing loss (see https://panelapp.genomicsengland.co.uk/panels/126/gene/COCH/) but none report Meniere disease combination of phenotype so leaving the mode of inheritance as monoallelic on the Familial Meniere Disease panel.
Monogenic hearing loss v2.125 COCH Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as Monoallelic only for now, but with recommendation that it should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next GMS review.
Monogenic hearing loss v2.125 COCH Eleanor Williams Mode of inheritance for gene: COCH was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.124 COCH Eleanor Williams edited their review of gene: COCH: Changed publications: 29449721, 31126177, 32562050, 32939038
Monogenic hearing loss v2.124 COCH Eleanor Williams edited their review of gene: COCH: Changed publications: 31126177
Monogenic hearing loss v2.124 COCH Eleanor Williams Publications for gene: COCH were set to PMID: 10400989; 11332404; 11709536; 12928864; 14512963; 16078052; 16261627; 16481359; 18312449; 19161137; 20097680; 22139968; 23684986; 7829101; 8817345; 9441737; 9806553; 9931344
Monogenic hearing loss v2.123 COCH Eleanor Williams Phenotypes for gene: COCH were changed from hearing loss; #601369:Deafness, autosomal dominant 9; Nonsyndromic Hearing Loss, Dominant to Deafness, autosomal recessive 110 OMIM:618094; Deafness, autosomal dominant 9 OMIM:601369; deafness, autosomal recessive 110 MONDO:0054860; autosomal dominant nonsyndromic deafness 9 MONDO:0011058
Monogenic hearing loss v2.122 COCH Eleanor Williams Tag for-review tag was added to gene: COCH.
Monogenic hearing loss v2.122 COCH Eleanor Williams reviewed gene: COCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 29449721, 29449721, 31126177, 32562050; Phenotypes: Deafness, autosomal recessive 110 OMIM:618094, Deafness, autosomal dominant 9 OMIM:601369, deafness, autosomal recessive 110 MONDO:0054860, autosomal dominant nonsyndromic deafness 9 MONDO:0011058; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.122 THOC1 Eleanor Williams Phenotypes for gene: THOC1 were changed from Nonsyndromic hearing loss to Nonsyndromic hearing loss; nonsyndromic genetic deafness MONDO:0019497
Monogenic hearing loss v2.121 THOC1 Eleanor Williams Classified gene: THOC1 as Amber List (moderate evidence)
Monogenic hearing loss v2.121 THOC1 Eleanor Williams Added comment: Comment on list classification: Following review from Zornitza Stark changing the rating of THOC1 from grey to amber as there is one large family plus functional data to support the proposal that a variant in THOC1 is associated with hearing loss.
Monogenic hearing loss v2.121 THOC1 Eleanor Williams Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Tag watchlist tag was added to gene: LMX1A.
Tag for-review tag was added to gene: LMX1A.
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Classified gene: LMX1A as Amber List (moderate evidence)
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber but with a recommendation for a green rating following GMS review.
Monogenic hearing loss v2.120 LMX1A Eleanor Williams Gene: lmx1a has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.119 LMX1A Eleanor Williams Added comment: Comment on mode of inheritance: Setting MOI to Monoallelic as only one case of biallelic reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Monogenic hearing loss v2.119 LMX1A Eleanor Williams Mode of inheritance for gene: LMX1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.118 LMX1A Eleanor Williams Phenotypes for gene: LMX1A were changed from to Deafness, autosomal dominant 7 OMIM:601412; autosomal dominant nonsyndromic deafness 7 MONDO:0011074
Monogenic hearing loss v2.117 LMX1A Eleanor Williams Publications for gene: LMX1A were set to
Monogenic hearing loss v2.116 LMX1A Eleanor Williams edited their review of gene: LMX1A: Changed rating: GREEN; Changed publications: 29754270, 29971487, 32840933, 19540218, 18985389; Changed phenotypes: Deafness, autosomal dominant 7 OMIM:601412, autosomal dominant nonsyndromic deafness 7 MONDO:0011074; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.116 LMX1A Eleanor Williams commented on gene: LMX1A
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 marc tischkowitz commented on gene: PALB2: From the key paper (Yang 2020):
Table 3 - 16% risk to age 80 ( 95% CI 8-28%) if 2 first degree relatives affected at age 50, 11% risk to age 80 (95% CI 6-21) if mother and maternal grandmother diagnosed at age 50.

Therefore clinically actionable if there is a strong family history.

This paper and that of Song 2020 supersede previous published studies which are based on many fewer cases.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams changed review comment from: Comment on list classification: Changing the rating from red to amber for NARS2. Only one family with non-syndromic deafness, but several with deafness in conjunction with other clinical features.; to: Comment on list classification: Changing the rating from red to amber for NARS2. Only one family with non-syndromic deafness, but several with deafness in conjunction with other clinical features. This gene should be reviewed at the next major GMS update to decide whether it would be appropriate for the panel as a green gene.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Tag for-review tag was added to gene: NARS2.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Classified gene: NARS2 as Amber List (moderate evidence)
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Added comment: Comment on list classification: Changing the rating from red to amber for NARS2. Only one family with non-syndromic deafness, but several with deafness in conjunction with other clinical features.
Monogenic hearing loss v2.116 NARS2 Eleanor Williams Gene: nars2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.115 NARS2 Eleanor Williams commented on gene: NARS2: PMID: 25807530 - Simon et al 2015 - report 2 unrelated families with 3 different variants in NARS2. One family is segregating nonsyndromic hearing loss (DFNB94) and another with Leigh syndrome. In the family with Leigh syndrome two affected children failed the newborn hearing test.

PMID: 28077841 - Mizuguchi et al 2017 - report 4 individuals from 3 families with homozygous or compound het variants in NARS2 found by WES. All had hearing impairment (detected <2 years of age) among other clinical features including seizures and hypotonia.

PMID: 30327238 - Seaver et al 2018 - report two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. Compound het missense variants found by WES in NARS2. The younger brother failed the newborn hearing screen.

PMID: 25385316 - Vanlander et al 2015 - report 2 siblings born to consanguineous parents in which a homozygous missense mutation (c.822G>C) was found in NARS2). One sibling had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Hearing loss NOT reported.
Monogenic hearing loss v2.115 NARS2 Eleanor Williams Phenotypes for gene: NARS2 were changed from to Deafness, autosomal recessive 94 OMIM:618434; Combined oxidative phosphorylation deficiency 24 OMIM:616239; deafness, autosomal recessive 94 MONDO:0032749; combined oxidative phosphorylation defect type 24 MONDO:0014547
Monogenic hearing loss v2.114 NARS2 Eleanor Williams Publications for gene: NARS2 were set to 25807530
Skeletal Muscle Channelopathies v1.24 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal central nervous system disorders v1.6 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal central nervous system disorders v1.5 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Skeletal muscle channelopathy v1.6 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Skeletal muscle channelopathy v1.6 CNBP_CCTG Arina Puzriakova Tag STR tag was added to STR: CNBP_CCTG.
Skeletal muscle channelopathy v1.6 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal muscle channelopathy v1.6 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Distal myopathies v1.24 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal Muscle Channelopathies v1.23 CNBP_CCTG Arina Puzriakova Phenotypes for STR: CNBP_CCTG were changed from Myotonic dystrophy 2 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal muscle channelopathy v1.5 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Paroxysmal central nervous system disorders v1.5 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonia; MYOTONIC DYSTROPHY 2 (DM2) to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
COVID-19 research v1.70 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Steinert- myotonica dystrophia to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Distal myopathies v1.23 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Skeletal Muscle Channelopathies v1.22 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonia; MYOTONIC DYSTROPHY 2 (DM2) to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Steinert- myotonica dystrophia to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Added comment: Comment on list classification: Hypogammaglobulinemia has been reported in some cases which is relevant to this panel. However, patients are more likely to be recognised for skeletal muscle features of the disease presentation. Furthermore, the review is relevant to the CCTG repeat expansion rather than small variants (i.e. LoF, missense, etc) in this gene and therefore maintaining the Red rating on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.378 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.377 CNBP Arina Puzriakova Publications for gene: CNBP were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.376 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.568 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from None to Other
Intellectual disability v3.568 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from OVERGROWTH SYNDROME WITH INTELLECTUAL DISABILITY to Tatton-Brown-Rahman syndrome OMIM:615879; Heyn-Sproul-Jackson syndrome OMIM:618724; MONDO:0032882
Intellectual disability v3.567 DNMT3A Sarah Leigh Added comment: Comment on mode of pathogenicity: Tatton-Brown-Rahman syndrome 615879 is associated with loss of function variants and Heyn-Sproul-Jackson syndrome OMIM:618724 is associated with gain of function variants.
Intellectual disability v3.567 DNMT3A Sarah Leigh Mode of pathogenicity for gene: DNMT3A was changed from to None
Severe microcephaly v2.47 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from Heyn-Sproul-Jackson syndrome 618724 to Heyn-Sproul-Jackson syndrome OMIM:618724; MONDO:0032882
Severe microcephaly v2.46 DNMT3A Sarah Leigh edited their review of gene: DNMT3A: Added comment: Associated with relevant phenotype (Heyn-Sproul-Jackson syndrome 618724) in OMIM and as probable Gen2Phen gene for Microcephalic primordial dwarfism. At least two gain of function variants reported in three unrelated cases, together with supportive functional studies (pmid 30478443).; Changed rating: GREEN
Severe microcephaly v2.46 DNMT3A Sarah Leigh Tag for-review tag was added to gene: DNMT3A.
Severe microcephaly v2.46 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from intellectual disability; microcephaly; short stature to Heyn-Sproul-Jackson syndrome 618724
Severe microcephaly v2.45 DNMT3A Sarah Leigh Classified gene: DNMT3A as Amber List (moderate evidence)
Severe microcephaly v2.45 DNMT3A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Note gain of function variants associated with this phenotype.
Severe microcephaly v2.45 DNMT3A Sarah Leigh Gene: dnmt3a has been classified as Amber List (Moderate Evidence).
RASopathies v1.74 HRAS Arina Puzriakova Publications for gene: HRAS were set to 16170316; 16969868; 16443854; 21396583
Primary immunodeficiency or monogenic inflammatory bowel disease v2.375 UBA1 Arina Puzriakova Classified gene: UBA1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.375 UBA1 Arina Puzriakova Gene: uba1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Classified gene: UBA1 as No list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Relevant phenotype but rating Red as this panel is not appropriate for somatic variant detection due to the coverage and therefore variants are unlikely to be picked up by our current pipeline (added 'somatic' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.374 UBA1 Arina Puzriakova Gene: uba1 has been removed from the panel.
Severe microcephaly v2.44 LMNB2 Sarah Leigh edited their review of gene: LMNB2: Added comment: Not associated with a relevant phenotype in OMIM or in Gen2Phen. PMID 33033404 reports five individuals with heterozygous variants in LMNB2. One of these cases was de novo for c.160A>C p.N54H (NM_032737.4) and the remaining cases had c.1192G>A, p.Glu398Lys (NM_032737.4), which was shown to be de novo in two cases, inherited from the unaffected mother (who was mosaic for the variant) and the inheritance in the remaining case was not established. All of these cases had moderate to severe developmental delay and microcephaly.; Changed rating: GREEN
Severe microcephaly v2.44 LMNB2 Sarah Leigh Tag for-review tag was added to gene: LMNB2.
Severe microcephaly v2.44 LMNB2 Sarah Leigh Classified gene: LMNB2 as Amber List (moderate evidence)
Severe microcephaly v2.44 LMNB2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.44 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.566 LMNB2 Sarah Leigh Classified gene: LMNB2 as Amber List (moderate evidence)
Intellectual disability v3.566 LMNB2 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 v3.566 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.565 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: RED; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.373 UBA1 Arina Puzriakova Phenotypes for gene: UBA1 were changed from Autoinflammatory disease, adult onset; VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) to VEXAS syndrome, somatic, OMIM:301054
Primary immunodeficiency or monogenic inflammatory bowel disease v2.372 UBA1 Arina Puzriakova Tag somatic tag was added to gene: UBA1.
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 16826530
Primary immunodeficiency or monogenic inflammatory bowel disease v2.372 SOCS1 Arina Puzriakova Phenotypes for gene: SOCS1 were changed from Common variable immunodeficiency to Common variable immunodeficiency; Early-onset autoimmunity
Primary immunodeficiency or monogenic inflammatory bowel disease v2.371 SOCS1 Arina Puzriakova Publications for gene: SOCS1 were set to 32499645; 10490099; 10490100
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Tag for-review tag was added to gene: SOCS1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Classified gene: SOCS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) - at least 7 unrelated families with immune dysfunction associated with variants in this gene, as well as supportive functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.370 SOCS1 Arina Puzriakova Gene: socs1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 CNBP Boaz Palterer reviewed gene: CNBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12601109; Phenotypes: myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, cardiac conduction defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 CNBP Boaz Palterer Deleted their review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 CNBP Boaz Palterer reviewed gene: CNBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12601109/; Phenotypes: myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, cardiac conduction defects.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.565 DDC Arina Puzriakova Publications for gene: DDC were set to 20505134
Dystonia, chorea or related movement disorder, childhood onset v1.64 DDC Arina Puzriakova Publications for gene: DDC were set to 27830117; 27604308; 24816252
Dystonia, chorea or related movement disorder, childhood onset v1.63 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency, 608643; Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Intellectual disability v3.564 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Dystonia, chorea or related movement disorder, adult onset v1.16 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency, 608643; Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Early onset or syndromic epilepsy v2.224 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643; floppy child; dystonia; hypotonia; developmental delay; oculogyric crisis to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Likely inborn error of metabolism v2.33 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643 to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Fetal anomalies v1.115 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Undiagnosed metabolic disorders v1.431 DDC Arina Puzriakova Publications for gene: DDC were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.430 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643 to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Neurodegenerative disorders, adult onset v2.33 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Neurotransmitter disorders v1.6 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency, 608643 to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Neurotransmitter disorders v1.5 DDC Arina Puzriakova Publications for gene: DDC were set to 27604308; 24816252; 27830117
Early onset dystonia v1.85 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Dystonia to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084; Floppy child; Dystonia; Hypotonia; Developmental delay; Oculogyric crisis
Early onset dystonia v1.84 DDC Arina Puzriakova Publications for gene: DDC were set to
Early onset dystonia v1.83 DDC Arina Puzriakova Mode of inheritance for gene: DDC was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.82 DDC Arina Puzriakova Classified gene: DDC as Green List (high evidence)
Early onset dystonia v1.82 DDC Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Green, in line with the review by Lothar Schlueter. Dystonia as a feature of the phenotype, most commonly arising in infancy. DDC is already Green on the GMS 'Childhood onset dystonia or chorea or related movement disorder' version 1.62 panel.
Early onset dystonia v1.82 DDC Arina Puzriakova Gene: ddc has been classified as Green List (High Evidence).
Intellectual disability v3.563 AGAP1 Arina Puzriakova Classified gene: AGAP1 as Amber List (moderate evidence)
Intellectual disability v3.563 AGAP1 Arina Puzriakova Added comment: Comment on list classification: New gene added as Amber. Clinical reports are generally limited and the contribution of secondary variants in other genes in 2 subjects cannot be ruled out. Additional cases necessary to corroborate this gene-disease association.
Intellectual disability v3.563 AGAP1 Arina Puzriakova Gene: agap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.562 AGAP1 Arina Puzriakova reviewed gene: AGAP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31700678, 30472483, 25666757; Phenotypes: Cerebral palsy, Developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.562 MPP5 Arina Puzriakova Classified gene: MPP5 as Amber List (moderate evidence)
Intellectual disability v3.562 MPP5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. ased on the evidence provided in PMID:33073849, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 3 unrelated individuals with de novo variants in the MPP5 gene associated with ID/GDD, language delay/regression and behavioural changes. Supportive animal model.
Intellectual disability v3.562 MPP5 Arina Puzriakova Gene: mpp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.561 MPP5 Arina Puzriakova Tag for-review tag was added to gene: MPP5.
Intellectual disability v3.561 JARID2 Arina Puzriakova Classified gene: JARID2 as Amber List (moderate evidence)
Intellectual disability v3.561 JARID2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). Multiple unrelated individuals all with DD as the common feature, as well as ID in the majority of cases.
Intellectual disability v3.561 JARID2 Arina Puzriakova Gene: jarid2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.560 JARID2 Arina Puzriakova Phenotypes for gene: JARID2 were changed from Intellectual disability to Intellectual disability; Neurodevelopmental syndrome
Intellectual disability v3.559 JARID2 Arina Puzriakova Tag for-review tag was added to gene: JARID2.
Intellectual disability v3.559 JARID2 Arina Puzriakova reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077894; Phenotypes: Neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.43 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).; to: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 1 was found in 2 unrelated patients who also had epileptic seizures (PMID 32910914; 33033404).
Intellectual disability v3.559 LMNB1 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; to: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).
Severe microcephaly v2.43 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN
Severe microcephaly v2.43 LMNB1 Sarah Leigh Tag for-review tag was added to gene: LMNB1.
Severe microcephaly v2.43 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Severe microcephaly v2.43 LMNB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.43 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.42 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 33033404
Severe microcephaly v2.41 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Congenital microcephaly; Global developmental delay; Intellectual disability; LMNB1-associated developmental disorder
Intellectual disability v3.559 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Early onset or syndromic epilepsy v2.222 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.220 LMNB1 Sarah Leigh Tag watchlist tag was added to gene: LMNB1.
Intellectual disability v3.558 LMNB1 Sarah Leigh edited their review of gene: LMNB1: Added comment: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly (PMID 32910914; 33033404).; Changed rating: GREEN; Changed phenotypes: LMNB1-associated developmental disorder
Intellectual disability v3.558 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Intellectual disability v3.558 LMNB1 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 v3.558 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.557 LMNB1 Sarah Leigh Tag for-review tag was added to gene: LMNB1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.15 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.15 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Classified gene: PJA1 as Red List (low evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on evidence provided in a single publication (PMID:32530565). Additional case supporting pathogenicity of other PJA1 variants required prior to inclusion on a diagnostic panel.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.14 PJA1 Arina Puzriakova Gene: pja1 has been classified as Red List (Low Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.13 PJA1 Arina Puzriakova gene: PJA1 was added
gene: PJA1 was added to Craniosynostosis. Sources: Expert list
founder-effect tags were added to gene: PJA1.
Mode of inheritance for gene: PJA1 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: PJA1 were set to 32530565
Phenotypes for gene: PJA1 were set to Trigonocephaly; Intellectual disability
Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals from 5 independent families, of which 5 patients were diagnosed with mild trigonocephaly. Some supportive data in a mouse model. Individuals shared a common haplotype, suggestive of founder effect.
Sources: Expert list
Intellectual disability v3.557 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Intellectual disability v3.557 PJA1 Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber - 7 individuals reported in PMID:32530565 all with ID, albeit due to a founder variant. Some cases with deletions encompassing this gene reported with mild DD, however contribution of other affected genes cannot be ruled out. Evidence of pathogenicity of other PJA1 variants is required prior to inclusion on a diagnostic panel.
Intellectual disability v3.557 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.556 PJA1 Arina Puzriakova Tag founder-effect tag was added to gene: PJA1.
Intellectual disability v3.556 PJA1 Arina Puzriakova Publications for gene: PJA1 were set to 17941886; 12036302; 11533224
Intellectual disability v3.555 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Intellectual disability v3.554 MAPK1 Catherine Snow Tag for-review tag was added to gene: MAPK1.
Intellectual disability v3.554 MAPK1 Catherine Snow Classified gene: MAPK1 as Amber List (moderate evidence)
Intellectual disability v3.554 MAPK1 Catherine Snow Gene: mapk1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.220 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Intellectual disability v3.553 MAPK1 Catherine Snow reviewed gene: MAPK1: 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: 32721402; Phenotypes: Noonan syndrome 13, OMIM:619087, MONDO:0018997; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:32703943) reporting seizures in 3/6 individuals from 2 families with variants in this gene.
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.553 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Intellectual disability v3.552 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Intellectual disability v3.552 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided in PMID:32703943, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 6 individuals from 5 families, all exhibiting GDD/ID as the common presenting feature.
Intellectual disability v3.552 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.551 FAM50A Arina Puzriakova Tag for-review tag was added to gene: FAM50A.
Limb disorders v2.18 PRKACB Arina Puzriakova Classified gene: PRKACB as Amber List (moderate evidence)
Limb disorders v2.18 PRKACB Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - 4 unrelated cases, all presenting polydactyly of the hands and/or feet as well as other postaxial anomalies.
Limb disorders v2.18 PRKACB Arina Puzriakova Gene: prkacb has been classified as Amber List (Moderate Evidence).
Limb disorders v2.17 PRKACB Arina Puzriakova gene: PRKACB was added
gene: PRKACB was added to Limb disorders. Sources: Literature
for-review tags were added to gene: PRKACB.
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Review for gene: PRKACB was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACB variants, included postaxial polydactyly of hands (3/4 bilateral, 1/4 unilateral) and feet (3/4 bilateral), clinodactyly (2/4), brachydactyly (1/4) and congenital heart defects (CHD 4/4) namely a common atrium or AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumours. Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe).

WES was carried out in all. 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signalling likely underlies the developmental defects observed in affected individuals.
Sources: Literature
Intellectual disability v3.551 PRKACB Arina Puzriakova Classified gene: PRKACB as Amber List (moderate evidence)
Intellectual disability v3.551 PRKACB Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:33058759) reporting 2/4 unrelated individuals with ID among other features, although this presentation was mild in one of these cases.
Intellectual disability v3.551 PRKACB Arina Puzriakova Gene: prkacb has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.113 MPZL2 Eleanor Williams Tag for-review tag was added to gene: MPZL2.
Monogenic hearing loss v2.113 MPZL2 Eleanor Williams Phenotypes for gene: MPZL2 were changed from Deafness, autosomal recessive 111, MIM#618145 to Deafness, autosomal recessive 111 OMIM:618145; deafness, autosomal recessive 111 MONDO:0029142
Monogenic hearing loss v2.112 MPZL2 Eleanor Williams Publications for gene: MPZL2 were set to 29982980; 29961571
Monogenic hearing loss v2.111 MPZL2 Eleanor Williams Classified gene: MPZL2 as Amber List (moderate evidence)
Monogenic hearing loss v2.111 MPZL2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation of a green rating following GMS review. 15 cases reported, 3 different variants. Mouse model supports role of gene in hearing loss.
Monogenic hearing loss v2.111 MPZL2 Eleanor Williams Gene: mpzl2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.110 MPZL2 Eleanor Williams edited their review of gene: MPZL2: Changed rating: GREEN
Monogenic hearing loss v2.110 MPZL2 Eleanor Williams edited their review of gene: MPZL2: Changed publications: 29982980, 29961571, 32203226
Monogenic hearing loss v2.110 MPZL2 Eleanor Williams reviewed gene: MPZL2: Rating: ; Mode of pathogenicity: None; Publications: 29982980, 29961571; Phenotypes: Deafness, autosomal recessive 111 OMIM:618145, deafness, autosomal recessive 111 MONDO:0029142; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v2.33 NOP10 Moin Saleem gene: NOP10 was added
gene: NOP10 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: NOP10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOP10 were set to 32554502
Phenotypes for gene: NOP10 were set to steroid-resistant 6 nephrotic syndrome; cataracts (prior to steroid treatment); sensorineural deafness; enterocolitis
Penetrance for gene: NOP10 were set to unknown
Review for gene: NOP10 was set to RED
Added comment: 2 affected females in one pedigree
Sources: Literature
Proteinuric renal disease v2.33 DKC1 Moin Saleem gene: DKC1 was added
gene: DKC1 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: DKC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DKC1 were set to 32554502
Phenotypes for gene: DKC1 were set to steroid-resistant 6 nephrotic syndrome; cataracts (prior to steroid treatment); sensorineural deafness; enterocolitis
Penetrance for gene: DKC1 were set to unknown
Review for gene: DKC1 was set to RED
Added comment: six affected males in one pedigree
Sources: Literature
Monogenic hearing loss v2.110 PLS1 Eleanor Williams Tag for-review tag was added to gene: PLS1.
Monogenic hearing loss v2.110 PLS1 Eleanor Williams Phenotypes for gene: PLS1 were changed from Deafness to Deafness, autosomal dominant 76 OMIM:618787; deafness, autosomal dominant 76 MONDO:0032917
Monogenic hearing loss v2.109 PLS1 Eleanor Williams Classified gene: PLS1 as Amber List (moderate evidence)
Monogenic hearing loss v2.109 PLS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation of green rating at the next GMS review.
Monogenic hearing loss v2.109 PLS1 Eleanor Williams Gene: pls1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.108 PLS1 Eleanor Williams edited their review of gene: PLS1: Changed rating: GREEN
Monogenic hearing loss v2.108 PLS1 Eleanor Williams edited their review of gene: PLS1: Changed publications: 31397523, 31432506, 30872814; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.108 PLS1 Eleanor Williams reviewed gene: PLS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal dominant 76 OMIM:618787, deafness, autosomal dominant 76 MONDO:0032917; Mode of inheritance: None
Cholestasis v1.74 MPI Ivone Leong Tag for-review tag was added to gene: MPI.
Cholestasis v1.74 LIPA Ivone Leong Tag for-review tag was added to gene: LIPA.
Cholestasis v1.74 HADHA Ivone Leong Tag for-review tag was added to gene: HADHA.
Cholestasis v1.74 TRMU Ivone Leong Tag for-review tag was added to gene: TRMU.
Cholestasis v1.74 SMPD1 Ivone Leong Tag for-review tag was added to gene: SMPD1.
Cholestasis v1.74 POLG Ivone Leong Tag for-review tag was added to gene: POLG.
Cholestasis v1.74 MVK Ivone Leong Tag for-review tag was added to gene: MVK.
Cholestasis v1.74 GBE1 Ivone Leong Tag for-review tag was added to gene: GBE1.
Cholestasis v1.74 CFTR Ivone Leong Tag for-review tag was added to gene: CFTR.
Cholestasis v1.74 ADK Ivone Leong Tag for-review tag was added to gene: ADK.
Cholestasis v1.74 MPI Ivone Leong reviewed gene: MPI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 LIPA Ivone Leong reviewed gene: LIPA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 HADHA Ivone Leong reviewed gene: HADHA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 TRMU Ivone Leong reviewed gene: TRMU: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 SMPD1 Ivone Leong reviewed gene: SMPD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 POLG Ivone Leong reviewed gene: POLG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 MVK Ivone Leong reviewed gene: MVK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 GBE1 Ivone Leong reviewed gene: GBE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 CFTR Ivone Leong reviewed gene: CFTR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.74 ADK Ivone Leong reviewed gene: ADK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cholestasis v1.73 MPI Ivone Leong gene: MPI was added
gene: MPI was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: MPI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPI were set to 12414827; 10980531; 9585601; 28108845
Phenotypes for gene: MPI were set to Congenital disorder of glycosylation, type Ib, OMIM:602579
Cholestasis v1.73 LIPA Ivone Leong gene: LIPA was added
gene: LIPA was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: LIPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPA were set to 8254026; 29702543; 8617513; 7759067; 8598644; 26137452; 29731497; 23485521
Phenotypes for gene: LIPA were set to lysosomal acid lipase deficiency; Wolman disease, OMIM:278000, MONDO:0019148; Cholesteryl ester storage disease, OMIM:278000, MONDO:0019149; Neonatal and Adult Cholestasis; cholestasis
Cholestasis v1.73 HADHA Ivone Leong gene: HADHA was added
gene: HADHA was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HADHA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HADHA were set to 10518281; 9003853
Phenotypes for gene: HADHA were set to LCHAD deficiency, OMIM:609016, MONDO:0012173
Cholestasis v1.73 TRMU Ivone Leong gene: TRMU was added
gene: TRMU was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: TRMU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMU were set to 21153446; 21931168; 19732863; 23625533
Phenotypes for gene: TRMU were set to Liver failure, transient infantile, OMIM:613070
Cholestasis v1.73 SMPD1 Ivone Leong gene: SMPD1 was added
gene: SMPD1 was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: SMPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SMPD1 were set to Niemann-Pick disease, type A, OMIM:257200, MONDO:0009756
Cholestasis v1.73 POLG Ivone Leong gene: POLG was added
gene: POLG was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: POLG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POLG were set to Mitochondrial DNA depletion syndrome 4A (Alpers type), OMIM:203700, MONDO:0008758
Cholestasis v1.73 MVK Ivone Leong gene: MVK was added
gene: MVK was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: MVK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MVK were set to Mevalonic aciduria, OMIM:610377, MONDO:0012481
Cholestasis v1.73 GBE1 Ivone Leong gene: GBE1 was added
gene: GBE1 was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 8613547
Phenotypes for gene: GBE1 were set to Glycogen storage disease IV, OMIM:232500
Cholestasis v1.73 CFTR Ivone Leong gene: CFTR was added
gene: CFTR was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: CFTR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFTR were set to 21194565; 27806795; 22798282; 9934970
Phenotypes for gene: CFTR were set to Cholestasis; Neonatal and Adult Cholestasis; Cystic fibrosis, OMIM:219700, MONDO:0009061; {Pancreatitis, hereditary}, OMIM:167800
Cholestasis v1.73 ADK Ivone Leong gene: ADK was added
gene: ADK was added to Cholestasis. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: ADK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADK were set to 21963049; 27500280; 26642971
Phenotypes for gene: ADK were set to Hypermethioninemia due to adenosine kinase deficiency, OMIM:614300, MONDO:0013676
Inherited non-medullary thyroid cancer v1.4 VTRNA2-1 Sarah Leigh Tag locus-type-rna-vault tag was added to gene: VTRNA2-1.
White matter disorders and cerebral calcification - childhood onset v1.26 STN1 Sarah Leigh edited their review of gene: STN1: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in three unrelated cases, together with a supportive zebrafish model and other functional studies.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.26 STN1 Sarah Leigh Tag for-review tag was added to gene: STN1.
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Multiple congenital anomalies-hypotonia-seizures syndrome-4, OMIM:618548
White matter disorders and cerebral calcification - childhood onset v1.26 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.26 STN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - childhood onset v1.26 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.25 STN1 Sarah Leigh Phenotypes for gene: STN1 were changed from Cerebroretinal microangiopathy with calcifications and cysts 2, MIM# 617341 to Cerebroretinal microangiopathy with calcifications and cysts 2, OMIM:617341
Intellectual disability v3.550 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, OMIM:618548 as the name for this phenotype (12/11/2020).
Intellectual disability v3.550 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, OMIM:618548 to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
DDG2P v2.12 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).
DDG2P v2.12 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY to Multiple congenital anomalies-hypotonia-seizures syndrome-4 OMIM:618548
Intellectual disability v3.549 NARS Sarah Leigh Tag new-gene-name tag was added to gene: NARS.
Intellectual disability v3.549 PIGQ Sarah Leigh edited their review of gene: PIGQ: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for severe early onset epilepsy. At least 11 variants reported in seven unrelated cases of multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4)(Epileptic encephalopathy, early infantile, 77 618548)(OMIM:618548).; Changed rating: GREEN; Changed phenotypes: OMIM:618548; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.549 PIGQ Sarah Leigh Classified gene: PIGQ as Amber List (moderate evidence)
Intellectual disability v3.549 PIGQ 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 v3.549 PIGQ Sarah Leigh Gene: pigq has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.548 PIGQ Sarah Leigh Tag for-review tag was added to gene: PIGQ.
Possible mitochondrial disorder, nuclear genes v1.21 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Mitochondrial disorders v2.12 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Likely inborn error of metabolism v2.32 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 27604308
Mitochondrial disorder with complex IV deficiency v1.6 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Fetal anomalies v1.114 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Paediatric or syndromic cardiomyopathy v1.12 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Likely inborn error of metabolism v2.31 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex IV deficiency; Cytochrome c oxidase deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Paediatric or syndromic cardiomyopathy v1.11 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Fetal anomalies v1.113 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Mitochondrial disorders v2.11 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Isolated complex IV deficiency; Cytochrome c oxidase deficiency, 220110; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Mitochondrial disorder with complex IV deficiency v1.5 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Possible mitochondrial disorder, nuclear genes v1.20 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Undiagnosed metabolic disorders v1.429 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 27604308
Undiagnosed metabolic disorders v1.428 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex IV deficiency; Cytochrome c oxidase deficiency, 220110; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Intellectual disability v3.548 COX6B1 Arina Puzriakova Phenotypes for gene: COX6B1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 7, OMIM:619051
Intellectual disability v3.547 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 0
Intellectual disability v3.546 COX6B1 Arina Puzriakova Classified gene: COX6B1 as Green List (high evidence)
Intellectual disability v3.546 COX6B1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red and will be flagged for evaluation at the next GMS panel update (added 'for-review' tag) in view of the recent review by Zornitza Stark. As discussed the disease presentation is not prominent for ID, and rather is primarily characterised by lactate acidosis and encephalopathy which should be sufficient indications for diagnostic testing - COX6B1 is already Green on relevant metabolic/mitochondrial panels.
Intellectual disability v3.546 COX6B1 Arina Puzriakova Gene: cox6b1 has been classified as Green List (High Evidence).
Intellectual disability v3.545 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile 77, 618548 to Epileptic encephalopathy, early infantile 77, OMIM:618548
Intellectual disability v3.544 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548 to Epileptic encephalopathy, early infantile 77, 618548
Intellectual disability v3.543 PIGQ Sarah Leigh Publications for gene: PIGQ were set to 24463883
Early onset or syndromic epilepsy v2.217 PIGQ Sarah Leigh Publications for gene: PIGQ were set to 24463883; 25558065; 31148362
Intellectual disability v3.542 COX6B1 Arina Puzriakova Tag for-review tag was added to gene: COX6B1.
Paediatric or syndromic cardiomyopathy v1.10 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Mitochondrial disorders v2.10 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to
Mitochondrial disorders v2.9 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Isolated complex IV deficiency; Hepatic failure, early onset, and neurologic disorder; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Early onset or syndromic epilepsy v2.216 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Fetal anomalies v1.112 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Likely inborn error of metabolism v2.30 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Hepatic failure, early onset, and neurologic disorder to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Possible mitochondrial disorder, nuclear genes v1.19 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Likely inborn error of metabolism v2.29 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 27604308
Early onset or syndromic epilepsy v2.215 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Undiagnosed metabolic disorders v1.427 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 27604308
Undiagnosed metabolic disorders v1.426 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Hepatic failure, early onset, and neurologic disorder; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Early onset or syndromic epilepsy v2.214 TFE3 Sarah Leigh Tag for-review tag was added to gene: TFE3.
Mitochondrial disorder with complex IV deficiency v1.4 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Early onset or syndromic epilepsy v2.214 TFE3 Sarah Leigh reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595499, 31833172, 32409512; Phenotypes: ; Mode of inheritance: None
Inherited white matter disorders v1.87 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Mitochondrial liver disease v1.4 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Intellectual disability v3.542 TFE3 Sarah Leigh changed review comment from: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.; to: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).
Intellectual disability v3.542 TFE3 Sarah Leigh Classified gene: TFE3 as Amber List (moderate evidence)
Intellectual disability v3.542 TFE3 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 v3.542 TFE3 Sarah Leigh Gene: tfe3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.541 TFE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.; to: Not associated with a relevant phenotype in OMIM, but as a confirmed Gen2Phen gene for X-linked dominant Intellectual disability with pigmentary mosaicism and storage disorder and hemizygous TFE3-related intellectual disability with pigmentary mosaicism. At least 14 variants reported as de novo events in 17 unrelated cases of severe intellectual disability with pigmentary mosaicism and storage disorder-like features (no relevant OMIM or MONDO title as of 16/11/2020).

There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - childhood onset v1.24 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Intellectual disability v3.541 TFE3 Sarah Leigh reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.541 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY (MT-C4D) to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Intellectual disability v3.540 SCO1 Arina Puzriakova Classified gene: SCO1 as Green List (high evidence)
Intellectual disability v3.540 SCO1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red and will be flagged for evaluation at the next GMS panel update (added 'for-review' tag), in view of the recent review by Zornitza Stark. As discussed the phenotype is primarily characterised by lactate acidosis and encephalopathy which should be sufficient indications for diagnostic testing - SCO1 is already Green on relevant metabolic/mitochondrial panels.
Intellectual disability v3.540 SCO1 Arina Puzriakova Gene: sco1 has been classified as Green List (High Evidence).
Intellectual disability v3.539 TFE3 Sarah Leigh Publications for gene: TFE3 were set to
Intellectual disability v3.538 TFE3 Sarah Leigh Tag for-review tag was added to gene: TFE3.
Intellectual disability v3.538 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 0
Intellectual disability v3.537 SCO1 Arina Puzriakova Tag for-review tag was added to gene: SCO1.
Intellectual disability v3.537 EXOC2 Arina Puzriakova Classified gene: EXOC2 as Amber List (moderate evidence)
Intellectual disability v3.537 EXOC2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32639540) reporting 2 families with EXOC2 variants and variable ID, among other features. Additional cases with a significant ID phenotype are required before inclusion of this gene on a diagnostic panel.
Intellectual disability v3.537 EXOC2 Arina Puzriakova Gene: exoc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Tag for-review tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794).

There are sufficient cases to rate this gene Green at the next GMS panel update (added 'for-review' tag) - all 4 individuals (3 families) present seizures, although the age of onset is variable (19-years, 18-months, 3-months).
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Tag watchlist tag was added to gene: TBC1D2B.
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794). Manifestation of ID is variable amongst cases, but is mostly within the mild range. Additional cases would help determine the relevance of ID to the overall disease presentation (added 'watchlist' tag)
Intellectual disability v3.536 TBC1D2B Arina Puzriakova Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.535 PAX1 Arina Puzriakova Classified gene: PAX1 as Amber List (moderate evidence)
Intellectual disability v3.535 PAX1 Arina Puzriakova Added comment: Comment on list classification: New gene added and rated Amber by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on 2 papers (PMID:29681087 and PMID:23851939) reporting 2 unrelated cases with mild ID.
Intellectual disability v3.535 PAX1 Arina Puzriakova Gene: pax1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.534 ABCA2 Arina Puzriakova Phenotypes for gene: ABCA2 were changed from Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808 to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM:618808; Intellectual developmental disorder with poor growth and with or without seizures or ataxia, MONDO:0032930
Early onset or syndromic epilepsy v2.213 ABCA2 Arina Puzriakova Phenotypes for gene: ABCA2 were changed from Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808 to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM:618808; Intellectual developmental disorder with poor growth and with or without seizures or ataxia, MONDO:0032930
Ataxia and cerebellar anomalies - childhood onset v2.31 ABCA2 Arina Puzriakova Phenotypes for gene: ABCA2 were changed from Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808 to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM:618808; Intellectual developmental disorder with poor growth and with or without seizures or ataxia, MONDO:0032930
Ataxia and cerebellar anomalies - childhood onset v2.30 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.30 ABCA2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2 unrelated families with ataxia and ABCA2 variants reported at present.
Ataxia and cerebellar anomalies - childhood onset v2.30 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.29 ABCA2 Arina Puzriakova gene: ABCA2 was added
gene: ABCA2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808
Added comment: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 7 individuals from 4 unrelated families reported at present with different biallelic variants in the ABCA2 gene. Overlapping clinical features include psychomotor delay (6/7), microcephaly (3/7), ataxia (3/7), and epilepsy (2/7).

- Hu et al (PMID: 29302074) reported 3 sibs, of which one (III:2) was unable to walk and had ataxic gait.
- Aslam and Naz (PMID: 31047799) provided clinical details on 2 siblings, both of whom presented delayed ambulation, staggered gait ataxia, limb incoordination and dysarthria, but no abnormalities on brain MRI.
Sources: Literature
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as 1) only 2 cases with seizures; 2) epilepsy is not a prominent feature of the overall phenotype; 3) seizures were either resolved or managed by medication.
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.211 ABCA2 Arina Puzriakova reviewed gene: ABCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30237576, 29302074, 31047799; Phenotypes: Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.533 ABCA2 Arina Puzriakova Tag for-review tag was added to gene: ABCA2.
Intellectual disability v3.533 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Intellectual disability v3.533 ABCA2 Arina Puzriakova Added comment: Comment on list classification: Although not all published cases have a diagnosis of ID (and of those that do, only 1 family with moderate ID), global developmental delay is the most commonly observed features and therefore, this panel may be the most applicable for detecting patients.

Rating Amber, but this will be flagged for review at the next GMS panel update to assess the relevance of the phenotype and determine whether there is sufficient evidence to rate this gene Green (added 'for-review' tag).
Intellectual disability v3.533 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Neonatal cholestasis v1.16 WDR83OS Ivone Leong gene: WDR83OS was added
gene: WDR83OS was added to Neonatal cholestasis. Sources: Expert Review
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to 30250217
Phenotypes for gene: WDR83OS were set to Cholestasis
Review for gene: WDR83OS was set to RED
Added comment: New gene added by Zornitza Stark on the Cholestasis panel. This gene has been given a Red rating as there is only one case available.

"One consanguineous family with 3 affected individuals found to carry a homozygous splice site variant in WDR83OS. The variant results in an aberrant truncated RNA transcript as demonstrated by RT-PCR. Sources: Literature
Zornitza Stark (Australian Genomics), 2 May 2020"
Sources: Expert Review
Neonatal cholestasis v1.15 GALM Ivone Leong Classified gene: GALM as Green List (high evidence)
Neonatal cholestasis v1.15 GALM Ivone Leong Gene: galm has been classified as Green List (High Evidence).
Neonatal cholestasis v1.14 GALM Ivone Leong gene: GALM was added
gene: GALM was added to Neonatal cholestasis. Sources: Expert Review
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to 30451973; 30910422
Phenotypes for gene: GALM were set to Galactosemia IV, OMIM:618881; MONDO:0030105
Review for gene: GALM was set to GREEN
Added comment: This gene is associated with an appropriate phenotype in OMIM but not in Gene2Phenotype. There is enough evidence for this gene to be Green.

This gene was added to the Cholestasis panel by Zornitza Stark with the following review:
"Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973) Note only two individuals were reported as having transient cholestasis. Sources: Literature
Zornitza Stark (Australian Genomics), 2 May 2020"
Sources: Expert Review
Intellectual disability v3.532 ABCA2 Arina Puzriakova reviewed gene: ABCA2: Rating: ; Mode of pathogenicity: None; Publications: 30237576, 29302074, 31047799; Phenotypes: Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.72 PKHD1 Ivone Leong Classified gene: PKHD1 as Amber List (moderate evidence)
Cholestasis v1.72 PKHD1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is Green on the Neonatal cholestasis panel (v1.13). There is enough evidence to support a gene-disease association; however, this gene has been given an Amber rating and a "for-review" tag for consideration of promoting to Green status at the next major review.
Cholestasis v1.72 PKHD1 Ivone Leong Gene: pkhd1 has been classified as Amber List (Moderate Evidence).
Neonatal cholestasis v1.13 PKHD1 Ivone Leong Tag watchlist was removed from gene: PKHD1.
Neonatal cholestasis v1.13 PKHD1 Ivone Leong Classified gene: PKHD1 as Green List (high evidence)
Neonatal cholestasis v1.13 PKHD1 Ivone Leong Added comment: Comment on list classification: New review from Zornitza Stark (Australian Genomics) added to PKHD1 on Cholestasis panel with the following review:

"Periportal fibrosis is a key feature, cholestasis reported. Sources: Expert list
Zornitza Stark (Australian Genomics), 9 Aug 2020"

PMID: 25771912 shows another case of isolated hepatic presentation. After discussion with the Genomics England Clinical Team, it was decided that there is now enough evidence for this gene to be Green on this panel.
Neonatal cholestasis v1.13 PKHD1 Ivone Leong Gene: pkhd1 has been classified as Green List (High Evidence).
Neonatal cholestasis v1.12 PKHD1 Ivone Leong Publications for gene: PKHD1 were set to
Cholestasis v1.71 PKHD1 Ivone Leong Phenotypes for gene: PKHD1 were changed from Polycystic kidney disease 4, with or without hepatic disease, 263200 to Polycystic kidney disease 4, with or without hepatic disease, OMIM:263200; MONDO:0044327
Cholestasis v1.70 PKHD1 Ivone Leong Tag for-review tag was added to gene: PKHD1.
Cholestasis v1.70 GALK1 Ivone Leong Classified gene: GALK1 as Amber List (moderate evidence)
Cholestasis v1.70 GALK1 Ivone Leong Gene: galk1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.69 GALK1 Ivone Leong Classified gene: GALK1 as Amber List (moderate evidence)
Cholestasis v1.69 GALK1 Ivone Leong Gene: galk1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.68 GALK1 Ivone Leong gene: GALK1 was added
gene: GALK1 was added to Cholestasis. Sources: Expert Review
for-review tags were added to gene: GALK1.
Mode of inheritance for gene: GALK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GALK1 were set to Galactokinase deficiency with cataracts, OMIM:230200; MONDO:0009255 Edit
Review for gene: GALK1 was set to AMBER
Added comment: This gene is associated with an appropriate phenotype in OMIM and Gene2phenotype. It is a Green gene on Inborn errors of metabolism (v2.28) and Fetal anomalies (v1.111). There is enough evidence for a gene-disease association.

After discussion with the Genomics England Clinical Team, it was decided that this gene should be added as an Amber gene on this panel as the phenotype can mimic cholestasis with a presentation with jaundice.
Sources: Expert Review
Cholestasis v1.67 GALE Ivone Leong Classified gene: GALE as Amber List (moderate evidence)
Cholestasis v1.67 GALE Ivone Leong Gene: gale has been classified as Amber List (Moderate Evidence).
Cholestasis v1.66 GALE Ivone Leong gene: GALE was added
gene: GALE was added to Cholestasis. Sources: Expert Review
for-review tags were added to gene: GALE.
Mode of inheritance for gene: GALE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALE were set to 27604308
Phenotypes for gene: GALE were set to Galactose epimerase deficiency, OMIM:230350; MONDO:0009257
Review for gene: GALE was set to AMBER
Added comment: This gene is associated with an appropriate phenotype in OMIM and Gene2phenotype. It is a Green gene on Inborn errors of metabolism (v2.28) and Fetal anomalies (v1.111). There is enough evidence for a gene-disease association.

After discussion with the Genomics England Clinical Team, it was decided that this gene should be added as an Amber gene on this panel as the phenotype can mimic cholestasis with a presentation with jaundice.
Sources: Expert Review
Neonatal cholestasis v1.11 GALK1 Ivone Leong Classified gene: GALK1 as Green List (high evidence)
Neonatal cholestasis v1.11 GALK1 Ivone Leong Gene: galk1 has been classified as Green List (High Evidence).
Neonatal cholestasis v1.10 GALK1 Ivone Leong gene: GALK1 was added
gene: GALK1 was added to Neonatal cholestasis. Sources: Expert Review
Mode of inheritance for gene: GALK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GALK1 were set to Galactokinase deficiency with cataracts, OMIM:230200; MONDO:0009255
Review for gene: GALK1 was set to GREEN
Added comment: This gene is associated with an appropriate phenotype in OMIM and Gene2phenotype. It is a Green gene on Inborn errors of metabolism (v2.28) and Fetal anomalies (v1.111). There is enough evidence to support a gene-disease association. After discussion with the Genomics England Clinical Team, it was decided that this gene should be added a Green gene on this panel as the phenotype can mimic cholestasis with a presentation with jaundice.
Sources: Expert Review
Neonatal cholestasis v1.9 GALE Ivone Leong changed review comment from: This gene is associated with an appropriate phenotype in OMIM and Gene2phenotype. It is a Green gene on Inborn errors of metabolis (v2.28) and Fetal anomalies (v1.111). There is enough evidence to support a gene-disease association.

After discussion with the Genomics England Clinical Team, it was decided that this gene should be added a Green gene on this panel as the phenotype can mimic cholestasis with a presentation with jaundice.
Sources: Expert Review, Literature; to: This gene is associated with an appropriate phenotype in OMIM and Gene2phenotype. It is a Green gene on Inborn errors of metabolism (v2.28) and Fetal anomalies (v1.111). There is enough evidence to support a gene-disease association.

After discussion with the Genomics England Clinical Team, it was decided that this gene should be added a Green gene on this panel as the phenotype can mimic cholestasis with a presentation with jaundice.
Sources: Expert Review, Literature
Neonatal cholestasis v1.9 GALE Ivone Leong Classified gene: GALE as Green List (high evidence)
Neonatal cholestasis v1.9 GALE Ivone Leong Gene: gale has been classified as Green List (High Evidence).
Neonatal cholestasis v1.8 GALE Ivone Leong gene: GALE was added
gene: GALE was added to Neonatal cholestasis. Sources: Expert Review,Literature
Mode of inheritance for gene: GALE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALE were set to 27604308
Phenotypes for gene: GALE were set to Galactose epimerase deficiency, OMIM:230350; MONDO:0009257
Review for gene: GALE was set to GREEN
Added comment: This gene is associated with an appropriate phenotype in OMIM and Gene2phenotype. It is a Green gene on Inborn errors of metabolis (v2.28) and Fetal anomalies (v1.111). There is enough evidence to support a gene-disease association.

After discussion with the Genomics England Clinical Team, it was decided that this gene should be added a Green gene on this panel as the phenotype can mimic cholestasis with a presentation with jaundice.
Sources: Expert Review, Literature
Likely inborn error of metabolism v2.28 GALE Ivone Leong Phenotypes for gene: GALE were changed from Intellectual disability; Uridine diphosphate galactose-4-epimerase deficiency (Disorders of galactose metabolism) to Intellectual disability; Uridine diphosphate galactose-4-epimerase deficiency (Disorders of galactose metabolism); Galactose epimerase deficiency, OMIM:230350; MONDO:0009257
Likely inborn error of metabolism v2.27 GALM Ivone Leong Phenotypes for gene: GALM were changed from Galactosemia IV, 618881 to Galactosemia IV, OMIM:618881; MONDO:0030105
Likely inborn error of metabolism v2.26 GALM Ivone Leong Classified gene: GALM as Amber List (moderate evidence)
Likely inborn error of metabolism v2.26 GALM Ivone Leong Gene: galm has been classified as Amber List (Moderate Evidence).
Cholestasis v1.65 GALT Ivone Leong Classified gene: GALT as Amber List (moderate evidence)
Cholestasis v1.65 GALT Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is Green on the Neonatal cholestasis panel (v1.7) with the following review:
"Sarah Leigh (Genomics England Curator):

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 14 variants reported.
Sarah Leigh (Genomics England Curator), 14 Aug 2018

Comment on phenotypes: Phenotype appears to include features relevant to the neonatal cholestasis panel
Sarah Leigh (Genomics England Curator), 14 Aug 2018"

Therefore, this gene has been given an Amber rating and will be promoted to Green status at the next major review.
Cholestasis v1.65 GALT Ivone Leong Gene: galt has been classified as Amber List (Moderate Evidence).
Cholestasis v1.64 GALT Ivone Leong Classified gene: GALT as Amber List (moderate evidence)
Cholestasis v1.64 GALT Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is Green on the Neonatal cholestasis panel (v1.7) with the following review:
"Sarah Leigh (Genomics England Curator):

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 14 variants reported.
Sarah Leigh (Genomics England Curator), 14 Aug 2018

Comment on phenotypes: Phenotype appears to include features relevant to the neonatal cholestasis panel
Sarah Leigh (Genomics England Curator), 14 Aug 2018"

Therefore, this gene has been given an Amber rating and will be promoted to Green status at the next major review.
Cholestasis v1.64 GALT Ivone Leong Gene: galt has been classified as Amber List (Moderate Evidence).
Cholestasis v1.63 GALT Ivone Leong Tag for-review tag was added to gene: GALT.
Cholestasis v1.63 GALM Ivone Leong Phenotypes for gene: GALM were changed from Galactosemia IV, 618881 to Galactosemia IV, OMIM:618881; MONDO:0030105
Cholestasis v1.62 GALT Ivone Leong Phenotypes for gene: GALT were changed from Galactosemia, MIM# 230400 to Galactosemia, OMIM:230400; MONDO:0018116
RASopathies v1.73 HRAS Mehdi Montazer reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: Other; Publications: https://doi.org/10.1038/s41431-020-0662-4; Phenotypes: hypertrophic cardiomyopathy, Chiari 1 malformation, ectodermal findings; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.25 GALM Ivone Leong gene: GALM was added
gene: GALM was added to Inborn errors of metabolism. Sources: Expert Review,Literature
for-review tags were added to gene: GALM.
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to 30451973; 30910422
Phenotypes for gene: GALM were set to Galactosemia IV, 618881
Review for gene: GALM was set to GREEN
Added comment: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with an appropriate phenotype in OMIM but not in Gene2Phenotype. There is enough evidence for this gene to be Green. The gene has been given an Amber rating and will be promoted to Green at the next review.

Review from Zornitza Stark (Australian Genomics) on the Cholestasis panel:
Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973) Note only two individuals were reported as having transient cholestasis. Sources: Literature
Zornitza Stark (Australian Genomics), 2 May 2020
Sources: Expert Review, Literature
Cholestasis v1.61 GALM Ivone Leong Classified gene: GALM as Amber List (moderate evidence)
Cholestasis v1.61 GALM Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with an appropriate phenotype in OMIM but not in Gene2Phenotype. There is enough evidence for this gene to be Green. The gene has been given an Amber rating and will be promoted to Green at the next review.
Cholestasis v1.61 GALM Ivone Leong Gene: galm has been classified as Amber List (Moderate Evidence).
Cholestasis v1.60 GALM Ivone Leong Tag for-review tag was added to gene: GALM.
Extreme early-onset hypertension v1.14 MTX2 Ivone Leong Classified gene: MTX2 as Green List (high evidence)
Extreme early-onset hypertension v1.14 MTX2 Ivone Leong Gene: mtx2 has been classified as Green List (High Evidence).
Extreme early-onset hypertension v1.13 MTX2 Ivone Leong gene: MTX2 was added
gene: MTX2 was added to Extreme early-onset hypertension. Sources: Expert Review,Literature
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification; severe hypertension
Review for gene: MTX2 was set to GREEN
Added comment: The Genomics England Clinical Team suggested that this gene should be added to this panel as severe hypertension is a phenotype. Therefore, this gene has been given a Green rating.

Review from Zornitza Stark on the Lipodystrophy - childhood onset:
"Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"
Sources: Literature, Expert Review
Created: 13 Nov 2020, 1:32 p.m.
Sources: Expert Review, Literature
Skeletal dysplasia v2.32 MTX2 Ivone Leong Classified gene: MTX2 as Amber List (moderate evidence)
Skeletal dysplasia v2.32 MTX2 Ivone Leong Gene: mtx2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.31 MTX2 Ivone Leong gene: MTX2 was added
gene: MTX2 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: MTX2.
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Skeletal dysplasia; Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Review for gene: MTX2 was set to GREEN
Added comment: The Genomics England Clinical Team suggested that this gene should be added to this panel as there are enough skeletal features for it to be here. Therefore, this gene has been given an Amber rating and will be promoted to Green at the next review.

Review from Zornitza Stark on the Lipodystrophy - childhood onset:
"Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"
Sources: Literature
Intellectual disability v3.532 CEP120 Arina Puzriakova Tag for-review tag was added to gene: CEP120.
Intellectual disability v3.532 CEP120 Arina Puzriakova Classified gene: CEP120 as Amber List (moderate evidence)
Intellectual disability v3.532 CEP120 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the evidence provided, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)

4 unrelated individuals with distinct variants in the CEP120 gene and Joubert syndrome, including a neurological phenotype in all consisting of hypotonia, developmental delay and cognitive impairment (PMID:27208211).
Intellectual disability v3.532 CEP120 Arina Puzriakova Gene: cep120 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.211 NUS1 Eleanor Williams Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa, 617082; Mental retardation, autosomal dominant 55, with seizures, 617831; Abnormality of extrapyramidal motor function to ?Congenital disorder of glycosylation, type 1aa OMIM:617082; Mental retardation, autosomal dominant 55, with seizures OMIM:617831; Abnormality of extrapyramidal motor function
Early onset or syndromic epilepsy v2.210 NUS1 Eleanor Williams Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Early onset or syndromic epilepsy v2.209 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: 2 further heterozygous cases reported by Den et al 2019 (PMID: 31656175). 2 unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. The variant c.691 + 1C > A, creates a new splice donor site resulting in a 91 bp deletion in exon 3.; Changed publications: 25066056, 29100083, 24824130, 30348779, 31656175
Intellectual disability v3.531 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: As reported by reviewer Konstantinos Varvagiannis another 2 cases now reported by Den et al 2019 (PMID: 31656175). 2 unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. The variant c.691 + 1C > A, creates a new splice donor site resulting in a 91 bp deletion in exon 3.

This now gives a total of 5 families with heterozygous variants in NUS1 and a presentation of developmental delay and epileptic encephalopathy.; Changed publications: 31656175
Intellectual disability v3.531 PET100 Eleanor Williams Classified gene: PET100 as Amber List (moderate evidence)
Intellectual disability v3.531 PET100 Eleanor Williams Added comment: Comment on list classification: Leaving this gene rating as amber until the next GMS review, but as reviewer Zornitza Stark notes there are 8 Lebanese familes with the same variant, plus an Asian British family with a similar phenotype and a different variant, plus functional data to support the disease causation, so would recommend Green rating.
Intellectual disability v3.531 PET100 Eleanor Williams Gene: pet100 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.530 PET100 Eleanor Williams Tag for-review tag was added to gene: PET100.
Intellectual disability v3.530 PET100 Eleanor Williams Added comment: Comment on phenotypes: Removing MIM# 220110 as this is associated with variants in SURF1
Intellectual disability v3.530 PET100 Eleanor Williams Phenotypes for gene: PET100 were changed from Mitochondrial complex IV deficiency,220110; Intellectual disability; Complex IV-deficient Leigh syndrome to Intellectual disability; Complex IV-deficient Leigh syndrome; Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055
Intellectual disability v3.529 PET100 Eleanor Williams Publications for gene: PET100 were set to 26425749; 24462369; 25293719
Intellectual disability v3.528 PET100 Eleanor Williams reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12 OMIM:619055, Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.528 PIGH Eleanor Williams Phenotypes for gene: PIGH were changed from Glycosylphosphatidylinositol biosynthesis defect, 17; 618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures to Glycosylphosphatidylinositol biosynthesis defect, 17 OMIM:618010; Hypotonia, moderate developmental delay, and autism, two episodes of febrile seizures
Intellectual disability v3.527 PIGH Eleanor Williams Classified gene: PIGH as Amber List (moderate evidence)
Intellectual disability v3.527 PIGH Eleanor Williams Added comment: Comment on list classification: Leaving as amber for now, but this gene should be reviewed at the next GMS update. It is borderline green as there are 5 families reported with DD/ID but only two without epilepsy.
Intellectual disability v3.527 PIGH Eleanor Williams Gene: pigh has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.526 PIGH Eleanor Williams Tag for-review tag was added to gene: PIGH.
Intellectual disability v3.526 PIGH Eleanor Williams reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: None; Publications: 33156547, 29573052, 29603516; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17 OMIM:618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.209 PIGH Eleanor Williams Publications for gene: PIGH were set to 29603516; 29573052
Early onset or syndromic epilepsy v2.208 PIGH Eleanor Williams commented on gene: PIGH
Hereditary ataxia, adult onset v2.17 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16 OMIM:617964 to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Intellectual disability v3.526 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16 (MIM #617964) to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Early onset or syndromic epilepsy v2.208 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16 (MIM #617964) to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Inherited white matter disorders v1.86 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating 16, MIM#617964 to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Ataxia and cerebellar anomalies - childhood onset v2.28 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16, MIM# 617964 to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
White matter disorders and cerebral calcification - childhood onset v1.23 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating 16, MIM#617964 to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Early onset or syndromic epilepsy v2.207 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Hereditary ataxia, adult onset v2.16 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Green List (high evidence)
Hereditary ataxia, adult onset v2.16 TMEM106B Arina Puzriakova Added comment: Comment on list classification: This gene has been flagged for review at the next GMS panel update (added 'for-review tag) as there is only enough evidence for TMEM106B to be rated AMBER on this panel.

Only 2/6 cases present ataxia, which is mild in one individual. Cases are more likely to be recognised for the leukodystrophy feature of this disease presentation; however, this could be reviewed if evidence emerges of a more prominent ataxic phenotype.
Hereditary ataxia, adult onset v2.16 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Green List (High Evidence).
Hereditary ataxia, adult onset v2.15 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Tag for-review tag was added to gene: TMEM106B.
Hereditary ataxia, adult onset v2.15 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - childhood onset v2.27 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Ataxia and cerebellar anomalies - childhood onset v2.27 TMEM106B Arina Puzriakova Mode of pathogenicity for gene: TMEM106B 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
Ataxia and cerebellar anomalies - childhood onset v2.26 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371; 29444210
Ataxia and cerebellar anomalies - childhood onset v2.25 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.25 TMEM106B Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2/6 cases present ataxia, which is mild in one individual. Cases are more likely to be recognised for the leukodystrophy feature of this disease presentation; however, this may be reviewed if evidence emerges of a more prominent ataxic phenotype.
Ataxia and cerebellar anomalies - childhood onset v2.25 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.24 TMEM106B Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'TMEM106B related hypomyelinating leukodystrophy' in Gene2Phenotype.

Recurrent variant c.754G>A p.(Asp252Asn) identified in 6 unrelated families from different ethnicities. Clinical characteristics include hypomyelinating leukodystrophy (6/6), nystagmus (6/6), hypotonia (5/6), cognitive impairment (5/6), movement disorder (3/6) and seizures (2/6).

Only 2 individuals present gait ataxia and intention tremor (mild/minimal in one case), with no prominent cerebellar atrophy on brain MRI.; to: Associated with relevant phenotype in OMIM, and is a 'probable' gene for 'TMEM106B related hypomyelinating leukodystrophy' in Gene2Phenotype.

Recurrent variant c.754G>A p.(Asp252Asn) identified in 6 unrelated families from different ethnicities. Clinical characteristics include hypomyelinating leukodystrophy (6/6), nystagmus (6/6), hypotonia (5/6), cognitive impairment (5/6), movement disorder (3/6) and seizures (2/6).

Only 2 individuals present gait ataxia and intention tremor (mild/minimal in one case), with only mild cerebellar atrophy identified in one patient on brain MRI.
Ataxia and cerebellar anomalies - childhood onset v2.24 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited white matter disorders v1.85 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Inherited white matter disorders v1.85 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371, 29444210
Inherited white matter disorders v1.84 TMEM106B Arina Puzriakova Mode of pathogenicity for gene: TMEM106B 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
Inherited white matter disorders v1.83 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Green List (high evidence)
Inherited white matter disorders v1.83 TMEM106B Arina Puzriakova Added comment: Comment on list classification: Promoting from Red to Green - sufficient unrelated cases (6), hypomyelinating leukodystrophy is the predominant feature of the disease presentation.
Inherited white matter disorders v1.83 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Green List (High Evidence).
Inherited white matter disorders v1.82 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
White matter disorders and cerebral calcification - childhood onset v1.22 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
White matter disorders and cerebral calcification - childhood onset v1.22 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371, 29444210
White matter disorders and cerebral calcification - childhood onset v1.21 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.21 TMEM106B Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases (6) to promote the rating to Green at the next GMS panel update - hypomyelinating leukodystrophy is the predominant feature of the disease presentation.
White matter disorders and cerebral calcification - childhood onset v1.21 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.20 TMEM106B Arina Puzriakova Tag for-review tag was added to gene: TMEM106B.
White matter disorders and cerebral calcification - childhood onset v1.20 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.525 PRKAR1B Ivone Leong Tag watchlist tag was added to gene: PRKAR1B.
Intellectual disability v3.525 PRKAR1B Ivone Leong Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability v3.525 PRKAR1B Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the provided evidence this gene has been given an Amber rating.
Intellectual disability v3.525 PRKAR1B Ivone Leong Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Early onset or syndromic epilepsy v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to
Intellectual disability v3.524 KCNC3 Catherine Snow Tag for-review tag was added to gene: KCNC3.
Intellectual disability v3.524 KCNC3 Catherine Snow Phenotypes for gene: KCNC3 were changed from Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529 to Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529
Intellectual disability v3.523 KCNC3 Catherine Snow Phenotypes for gene: KCNC3 were changed from SPINOCEREBELLAR ATAXIA TYPE 13 (SCA13) to Spinocerebellar ataxia 13, OMIM:605259; MONDO:0011529
Intellectual disability v3.523 KCNC3 Catherine Snow Publications for gene: KCNC3 were set to 32655623; 25756792
Intellectual disability v3.523 KCNC3 Catherine Snow Publications for gene: KCNC3 were set to 0
Intellectual disability v3.522 KCNC3 Catherine Snow reviewed gene: KCNC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 32655623; Phenotypes: Spinocerebellar ataxia 13, OMIM:605259, MONDO:0011529; Mode of inheritance: None
Intellectual disability v3.522 LSS Eleanor Williams commented on gene: LSS
Hereditary ataxia, adult onset v2.15 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Hypomyelinating leukodystrophy 16, 617964 to Leukodystrophy, hypomyelinating, 16 OMIM:617964
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2 individuals with seizures (both early-onset, before age 6 months) reported at present
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.205 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: Rating: ; 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.522 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Intellectual disability v3.522 TMEM106B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag) in view of 6 cases with the same variant and phenotype, supported by some evidence of altered gene function.

Inclusion on this panel would also cover the hypotonia feature exhibited by most cases in the neonatal period (as ID is a sub-panel of the Hypotonic Infant super panel)
Intellectual disability v3.522 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.521 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
CAKUT v1.155 ZMYM2 Ivone Leong Classified gene: ZMYM2 as Green List (high evidence)
CAKUT v1.155 ZMYM2 Ivone Leong Gene: zmym2 has been classified as Green List (High Evidence).
CAKUT v1.154 ZMYM2 Ivone Leong gene: ZMYM2 was added
gene: ZMYM2 was added to CAKUT. Sources: Expert Review
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to CAKUT; Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Review for gene: ZMYM2 was set to GREEN
Added comment: Review by Konstantinos Varvagiannis on the Intellectual disability panel:
"Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Created: 19 Sep 2020, 1:07 a.m."

Based on the expert review and evidence, there is enough evidence to support a gene-disease association. Therefore, this gene has been given a Green rating.
Sources: Expert Review
Intellectual disability v3.520 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Intellectual disability v3.520 TMEM106B Arina Puzriakova Tag for-review tag was added to gene: TMEM106B.
Intellectual disability v3.520 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.520 AFF3 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models; to: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models. If the preprint is peer reviewed and the evidence is relevant, then this gene could be rated green at the next major review (as of 12/11/2020).
Intellectual disability v3.520 ZMYM2 Ivone Leong Classified gene: ZMYM2 as Amber List (moderate evidence)
Intellectual disability v3.520 ZMYM2 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is probably associated with a phenotype on Gene2Phenotype. This gene has been given an Amber rating based on the expert review and the evidence provided. As ID is not an identifying part of the phenotype and not all affected individuals had ID, this gene has been given an Amber rating.
Intellectual disability v3.520 ZMYM2 Ivone Leong Gene: zmym2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.519 AFF3 Sarah Leigh Tag for-review tag was added to gene: AFF3.
Intellectual disability v3.519 AFF3 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are confvincing aminal models; to: Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models
Distal myopathies v1.22 Catherine Snow Panel version has been signed off
Distal myopathies v1.21 Catherine Snow Panel types changed to Rare Disease 100K; Component Of Super Panel; GMS signed-off
Neurological ciliopathies v1.10 Catherine Snow Panel types changed to Component Of Super Panel; GMS signed-off
Renal ciliopathies v1.31 Catherine Snow Panel types changed to Component Of Super Panel; GMS signed-off
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.5 Catherine Snow Panel version has been signed off
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.4 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Autosomal recessive primary hypertrophic osteoarthropathy v1.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Panel version has been signed off
Possible mitochondrial disorder, nuclear genes v1.18 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version has been signed off
Intellectual disability v3.519 WNT5A Arina Puzriakova commented on gene: WNT5A
Intellectual disability v3.519 WFS1 Arina Puzriakova Phenotypes for gene: WFS1 were changed from to Wolfram syndrome 1, 222300; Wolfram-like syndrome, autosomal dominant, 614296
Intellectual disability v3.518 WFS1 Arina Puzriakova Mode of inheritance for gene: WFS1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.517 WFS1 Arina Puzriakova commented on gene: WFS1
Structural eye disease v1.15 MAPRE2 Arina Puzriakova Phenotypes for gene: MAPRE2 were changed from Skin Creases, Congenital Symmetric Circumferential, 2, CSCSC2, 616734 to Symmetric circumferential skin creases, congenital, 2, 616734
Structural eye disease v1.14 MAPRE2 Arina Puzriakova Publications for gene: MAPRE2 were set to 26637975
Structural eye disease v1.13 MAPRE2 Arina Puzriakova Mode of inheritance for gene: MAPRE2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.111 MAPRE2 Arina Puzriakova Phenotypes for gene: MAPRE2 were changed from Circumferential Skin Creases Kunze Type to Symmetric circumferential skin creases, congenital, 2, 616734
Fetal anomalies v1.110 MAPRE2 Arina Puzriakova Publications for gene: MAPRE2 were set to
Fetal anomalies v1.109 MAPRE2 Arina Puzriakova Mode of inheritance for gene: MAPRE2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting v2.8 MAPRE2 Arina Puzriakova Phenotypes for gene: MAPRE2 were changed from SKIN CREASES, CONGENITAL SYMMETRIC CIRCUMFERENTIAL, 2; CSCSC2 to Symmetric circumferential skin creases, congenital, 2, 616734
Clefting v2.7 MAPRE2 Arina Puzriakova Publications for gene: MAPRE2 were set to
Clefting v2.6 MAPRE2 Arina Puzriakova Mode of inheritance for gene: MAPRE2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.517 MAPRE2 Arina Puzriakova Phenotypes for gene: MAPRE2 were changed from Circumferential Skin Creases Kunze Type to Symmetric circumferential skin creases, congenital, 2, 616734
Intellectual disability v3.516 MAPRE2 Arina Puzriakova Publications for gene: MAPRE2 were set to
Intellectual disability v3.515 MAPRE2 Arina Puzriakova Mode of inheritance for gene: MAPRE2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.514 MAPRE2 Arina Puzriakova Classified gene: MAPRE2 as Amber List (moderate evidence)
Intellectual disability v3.514 MAPRE2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases to promote this gene rating to Green at the next GMS panel update (added 'for-review' tag). Also not all patients present other associated features for which this gene is on a panel (e.g. Clefting, Structural eye disease) and so ID should be a sufficient indication for detecting these cases.
Intellectual disability v3.514 MAPRE2 Arina Puzriakova Gene: mapre2 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.14 ALPK3 Ivone Leong Added comment: Comment on mode of inheritance: MOI has been changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BIALLELIC, autosomal or pseudoautosomal".

All the published cases of affected individuals have homozygous variants in this gene. However, family members who are heterozygous for the ALPK3 variants either show no cardiac phenotype or have later-onset cardiomyopathy or an atypical distribution of hypertrophy (PMID: 26846950, 30046096, 2710685, 32480058). PMID: 32480058 found that some individuals with heterozygous variants in ALPK3 are diagnosed with HCM when they are adults. The paper suggests that LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy.

More evidence is needed for heterozygous variants in ALPK3 contributing to disease, so therefore the change of MOI. The inclusion of heterozygous variants of ALPK3 will be reviewed at the next panel review.
Hypertrophic cardiomyopathy v2.14 ALPK3 Ivone Leong Mode of inheritance for gene: ALPK3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.513 MAPRE2 Arina Puzriakova edited their review of gene: MAPRE2: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.513 MAPRE2 Arina Puzriakova edited their review of gene: MAPRE2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.513 MAPRE2 Arina Puzriakova Tag for-review tag was added to gene: MAPRE2.
Intellectual disability v3.513 MAPRE2 Arina Puzriakova reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26637975, 31903734, 31502381; Phenotypes: Symmetric circumferential skin creases, congenital, 2, 616734; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.380 MAP1B Arina Puzriakova Classified gene: MAP1B as Red List (low evidence)
Hereditary neuropathy v1.380 MAP1B Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single family reported with a homozygous MAP1B variant and polyneuropathy. Furthermore, the article identified by the expert reviewer is currently not published in PubMed. Additional cases required to support this gene-disease association.
Hereditary neuropathy v1.380 MAP1B Arina Puzriakova Gene: map1b has been classified as Red List (Low Evidence).
Intellectual disability v3.513 MAP1B Arina Puzriakova Deleted their comment
Malformations of cortical development v2.15 MAP1B Arina Puzriakova Classified gene: MAP1B as Amber List (moderate evidence)
Malformations of cortical development v2.15 MAP1B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag). Multiple unrelated families with different variants in the MAP1B gene and brain malformations, particularly PVNH
Malformations of cortical development v2.15 MAP1B Arina Puzriakova Gene: map1b has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.14 MAP1B Arina Puzriakova Tag for-review tag was added to gene: MAP1B.
Malformations of cortical development v2.14 MAP1B Arina Puzriakova reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30150678, 29738522, 31317654; Phenotypes: Periventricular nodular heterotopia 9, 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.513 MAP1B Arina Puzriakova Classified gene: MAP1B as Amber List (moderate evidence)
Intellectual disability v3.513 MAP1B Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as although cognitive impairment is reported in multiple (but not all) cases, often this is mild and not sufficient for a clinical diagnosis of ID. Affected individuals are more likely to be assessed in view of the brain malformations - MAP1B will be added to the 'Malformations of cortical development' panel.
Intellectual disability v3.513 MAP1B Arina Puzriakova Gene: map1b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.512 MAP1B Arina Puzriakova Phenotypes for gene: MAP1B were changed from Intellectual disability; No OMIM number to Periventricular nodular heterotopia 9, 618918
Intellectual disability v3.511 MAP1B Arina Puzriakova Publications for gene: MAP1B were set to 30150678; 29738522
Intellectual disability v3.510 MAP1B Arina Puzriakova commented on gene: MAP1B: Only one homozygous case identified in a screening study of a congenital microcephaly cohort. Other features included hypochromic microcytic anaemia, lymphocytic colitis, retinal coloboma, dysmorphic features, and normal brain MRI. As this is only considered a candidate variant and the phenotype is not compatible with other monoallelic reports, the evidence is currently insufficient for a disease association with biallelic variants (PMID:30214071)
Intellectual disability v3.510 MAP1B Arina Puzriakova reviewed gene: MAP1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 30150678, 29738522, 30214071, 31317654; Phenotypes: Periventricular nodular heterotopia 9, 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.108 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Monogenic hearing loss v2.108 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as degree of the deafness phenotype is unclear in 2/4 individuals reported with auditory impairment. Animal model supports association with this presentation but additional congenital/early-onset cases required before inclusion on a diagnostic hearing loss panel (added 'watchlist' tag)
Monogenic hearing loss v2.108 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.107 SPTBN4 Arina Puzriakova Tag watchlist tag was added to gene: SPTBN4.
Monogenic hearing loss v2.107 SPTBN4 Arina Puzriakova gene: SPTBN4 was added
gene: SPTBN4 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 29861105; 31230720; 32672909
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519
Review for gene: SPTBN4 was set to AMBER
Added comment: At least 11 individuals from 9 unrelated families with biallelic variants in SPTBN4 reported at present. Of these, two unrelated patients presented early-onset deafness (PMID:28540413, 31230720) and two further unrelated individuals displayed abnormal auditory brain stem responses consistent with auditory neuropathy but no further details regarding the deafness phenotype are provided (PMID:29861105). Furthermore, loss of Sptbn4 in mice causes deafness and auditory neuropathy.
Sources: Literature
Hereditary neuropathy or pain disorder v1.17 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.17 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it has been agreed to add this gene as Amber, awaiting review by the GMS specialist group (added 'for-review' tag).

Although neuropathy is reported in at least 5 unrelated cases with biallelic SPTBN4 variants, the phenotype relevance requires review due to the more limited scope of this panel.
Hereditary neuropathy or pain disorder v1.17 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.16 SPTBN4 Arina Puzriakova gene: SPTBN4 was added
gene: SPTBN4 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
for-review tags were added to gene: SPTBN4.
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255; 32672909
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519
Review for gene: SPTBN4 was set to AMBER
Added comment: At least 11 individuals from 9 unrelated families with biallelic variants in SPTBN4 reported at present. Motor neuronopathy/axonopathy was reported in 5 unrelated families. A formal evaluation by EMG/NCS was not conducted in the rest but phenotypes did include hypotonia and hyporeflexia which could be suggestive of neuropathy.
Sources: Literature
Hereditary neuropathy v1.379 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Green List (high evidence)
Hereditary neuropathy v1.379 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: New gene added as Green - sufficient number of unrelated cases (at least 5) presenting neuropathy in association with biallelic variants in the SPTBN4 gene.
Hereditary neuropathy v1.379 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Green List (High Evidence).
Hereditary neuropathy v1.378 SPTBN4 Arina Puzriakova gene: SPTBN4 was added
gene: SPTBN4 was added to Hereditary neuropathy. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255; 32672909
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519
Review for gene: SPTBN4 was set to GREEN
Added comment: At least 11 individuals from 9 unrelated families with biallelic variants in SPTBN4 reported at present. Motor neuronopathy/axonopathy was reported in 5 unrelated families. A formal evaluation by EMG/NCS was not conducted in the rest but phenotypes did include hypotonia and hyporeflexia which could be suggestive of neuropathy.
Sources: Literature
Intellectual disability v3.510 SPTBN4 Arina Puzriakova commented on gene: SPTBN4: Review by Helen Brittain (Genomics England Clinical Team): the phenotype is characterised by marked hypotonia in infancy and developmental delay / ID. Adding as Green to the ID panel would therefore cover both of these GMS indications (as the Hypotonic Infant super panel has the ID panel as a sub-panel).
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: New gene identified and reviewed by Konstantinos Varvagiannis. Following discussion with Helen Brittain (Genomics England Clinical Team) it has been agreed that this gene should be added as Amber.

Although number of unrelated cases (3) reaches threshold for inclusion, only 2 patients presented severe intractable seizures (could not find any evidence of epilepsy in the case from Pehlivan et al, as stated by external expert review). Furthermore, epilepsy was not a consistent finding (total 11 individuals from 9 families). Rating set to Amber, awaiting further cases.
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.510 HDAC4 Sarah Leigh changed review comment from: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such this gene should be rated as amber.; to: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS.
This gene should be rated as amber at the next major review.
Intellectual disability v3.510 HDAC4 Sarah Leigh Tag for-review tag was added to gene: HDAC4.
Intellectual disability v3.510 HDAC4 Sarah Leigh changed review comment from: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such the this gene should be rated as amber.; to: There are many cases of 2q37.3 terminal region (includes HDAC4) loss in PMID 30848064, however, there are only two intragenic variants in HDAC4, with a rating of VUS and as such this gene should be rated as amber.
Intellectual disability v3.510 HDAC4 Sarah Leigh reviewed gene: HDAC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 30848064; Phenotypes: Chromosome 2q37 deletion syndrome 600430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.510 ISCA-37394-Loss Sarah Leigh reviewed Region: ISCA-37394-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: 30848064; Phenotypes: Chromosome 2q37 deletion syndrome 600430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.30 SCUBE3 Arina Puzriakova Classified gene: SCUBE3 as Red List (low evidence)
Skeletal dysplasia v2.30 SCUBE3 Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently only one case reported with a potentially pathogenic variant associated with skeletal dysplasia. Additional cases required to corroborate causality.
Skeletal dysplasia v2.30 SCUBE3 Arina Puzriakova Gene: scube3 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.204 DMXL2 Arina Puzriakova Tag for-review tag was added to gene: DMXL2.
Fetal anomalies v1.108 ASXL3 Arina Puzriakova commented on gene: ASXL3
Monogenic hearing loss v2.106 PPIP5K2 Eleanor Williams Classified gene: PPIP5K2 as Amber List (moderate evidence)
Monogenic hearing loss v2.106 PPIP5K2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. 2 cases (but with same variant, likely founder effect) plus mouse model replicating disease.
Monogenic hearing loss v2.106 PPIP5K2 Eleanor Williams Gene: ppip5k2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.105 PPIP5K2 Eleanor Williams Phenotypes for gene: PPIP5K2 were changed from Deafness, autosomal recessive 100, MIM#618422 to Deafness, autosomal recessive 100, MIM#618422; deafness, autosomal recessive 100 MONDO:0032740
Monogenic hearing loss v2.104 PPIP5K2 Eleanor Williams edited their review of gene: PPIP5K2: Changed rating: AMBER; Changed publications: 29590114; Changed phenotypes: Deafness, autosomal recessive 100, 618422, deafness, autosomal recessive 100 MONDO:0032740; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.104 PPIP5K2 Eleanor Williams commented on gene: PPIP5K2
Monogenic hearing loss v2.104 ROR1 Eleanor Williams Phenotypes for gene: ROR1 were changed from Deafness, autosomal recessive 108, MIM#617654 to Deafness, autosomal recessive 108, MIM#617654; deafness, autosomal recessive 108 MONDO:0033200
Monogenic hearing loss v2.103 ROR1 Eleanor Williams Classified gene: ROR1 as Amber List (moderate evidence)
Monogenic hearing loss v2.103 ROR1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber as there is 1 familial case plus a mouse model that replicates the disease.
Monogenic hearing loss v2.103 ROR1 Eleanor Williams Gene: ror1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.102 ROR1 Eleanor Williams reviewed gene: ROR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27162350; Phenotypes: ?Deafness, autosomal recessive 108, 617654, deafness, autosomal recessive 108 MONDO:0033200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.102 SNAI2 Eleanor Williams Tag for-review tag was added to gene: SNAI2.
Monogenic hearing loss v2.102 SNAI2 Eleanor Williams Classified gene: SNAI2 as Green List (high evidence)
Monogenic hearing loss v2.102 SNAI2 Eleanor Williams Added comment: Comment on list classification: Leaving this gene as green for now, but it should be reviewed by the GMS due to the fact that only two cases have been reported of homozygous deletions in patients with Waardenburg syndrome, type 2D. Those reported with heterozygous variants either have no hearing loss or the variants have an allele frequency > 0.001 in the ExAC_EAS database.
Monogenic hearing loss v2.102 SNAI2 Eleanor Williams Gene: snai2 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.101 SNAI2 Eleanor Williams changed review comment from: Associated with Waardenburg syndrome, type 2D #608890 (AR) in OMIM, and Waardenburg syndrome (MONDO_0018094) in ClinGen (limited, assessed in 2017). This syndrome is characterized by deafness and pigmentary abnormalities.
SNAI2 is also know has SLUG.

Some reports of heterozgous variants associated with piebaldism (PMID: 12955764, PMID: 24443330) but no hearing loss.

PMID: 30936914 - Li et al 2019 - screened 90 patients with WS by NGS and found 2 patients with WS type 2 with de novo SNAI2 variants (c.230C>G, p. S77C and c.365C>T, p.A122V), however these variants were found at a frequency >1/10000 in the Exac population database (0.0045 and 0.0015 respectively). Presume these variants are heterozygous as they are de novo.

PMID: 12444107 - Sanchez-Martin et al 2002 - screened 38 unrelated patients with features of WS for SLUG genomic rearrangements, deletions or point mutations and found two unrelated (Bangladeshi and Dutch origin) patients with WS2 that have homozygous deletions spanning the entire SLUG coding region.; to: Associated with Waardenburg syndrome, type 2D #608890 (AR) in OMIM, and Waardenburg syndrome (MONDO_0018094) in ClinGen (limited, assessed in 2017). This syndrome is characterized by deafness and pigmentary abnormalities.
SNAI2 is also know has SLUG.

Some reports of heterozygous variants associated with piebaldism (PMID: 12955764, PMID: 24443330) but no hearing loss.

PMID: 30936914 - Li et al 2019 - screened 90 patients with WS by NGS and found 2 patients with WS type 2 with de novo SNAI2 variants (c.230C>G, p. S77C and c.365C>T, p.A122V), however these variants were found at a frequency >1/10000 in the Exac population database (0.0045 and 0.0015 respectively). Presume these variants are heterozygous as they are de novo.

PMID: 12444107 - Sanchez-Martin et al 2002 - screened 38 unrelated patients with features of WS for SLUG genomic rearrangements, deletions or point mutations and found two unrelated (Bangladeshi and Dutch origin) patients with WS2 that have homozygous deletions spanning the entire SLUG coding region.
Monogenic hearing loss v2.101 SNAI2 Eleanor Williams edited their review of gene: SNAI2: Changed rating: AMBER; Changed publications: 30936914, 12444107; Changed phenotypes: Waardenburg syndrome, type 2D, Waardenburg syndrome type 2 MONDO_0019517; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.101 SNAI2 Eleanor Williams commented on gene: SNAI2
Monogenic hearing loss v2.101 SLITRK6 Eleanor Williams Tag for-review tag was added to gene: SLITRK6.
Monogenic hearing loss v2.101 SLITRK6 Eleanor Williams Classified gene: SLITRK6 as Amber List (moderate evidence)
Monogenic hearing loss v2.101 SLITRK6 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber but with a recommendation for a green rating following GMS review.
Monogenic hearing loss v2.101 SLITRK6 Eleanor Williams Gene: slitrk6 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.100 SLITRK6 Eleanor Williams Phenotypes for gene: SLITRK6 were changed from Deafness and myopia, 221200 to Deafness and myopia, 221200; high myopia-sensorineural deafness syndrome MONDO:0009082
Monogenic hearing loss v2.99 SLITRK6 Eleanor Williams Publications for gene: SLITRK6 were set to
Monogenic hearing loss v2.98 SLITRK6 Eleanor Williams edited their review of gene: SLITRK6: Changed rating: GREEN; Changed publications: 29551497, 23946138, 23543054; Changed phenotypes: Deafness and myopia, 221200, high myopia-sensorineural deafness syndrome MONDO:0009082; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.98 SLITRK6 Eleanor Williams changed review comment from: Associated with Deafness and myopia #221200 (AR) in OMIM.

PMID: 29551497 - Salime et al 2018 - report a consanguineous Moroccan family with 2 children diagnosed for deafness and myopia in infancy. The SLITRK6 was sequenced and a homozygous 1 bp deletion leading to a premature stop codon p.Trp232Cysfs*10 was found. The parents were heterozygous for the variant as were 3 unaffected siblings.

PMID: 23946138 - Morlet et al 2014 - report 9 Old Order Amish individuals who were homozygous for a nonsense mutation of SLITRK6 (c.1240C>T, p.Gln414Ter) and suffered progressive cochlear and auditory nerve dysfunction

PMID: 23543054 - Tekin et al 2013 - report 3 families (1 old-order Amish family, 1 consanguineous Turkish and 1 Greek).
The Amish and Turkish families had members with congenital myopia and prelingual sensorineural hearing loss, while the affected Greek family had hearing loss only. Homozygous nonsense variants were found in SLITRK6 in all 3 families (Amish p.Q414X, Turkish p.S297X, Greek p.R181X). WES was performed on the Turkish family, targeted sequencing in a region of autozygosity in the Amish family, and targeted SLITRK6 sequencing in the Greek family in which affected members had the same haplotype in that region. Mouse Slitrk6 KO show a hearing loss phenotype.

Summary: founder mutation in SLITRK6 in several Amish families, plus 3 other variants reported in families of other ethnicities.; to: Associated with Deafness and myopia #221200 (AR) in OMIM.

PMID: 29551497 - Salime et al 2018 - report a consanguineous Moroccan family with 2 children diagnosed for deafness and myopia in infancy. The SLITRK6 was sequenced and a homozygous 1 bp deletion leading to a premature stop codon p.Trp232Cysfs*10 was found. The parents were heterozygous for the variant as were 3 unaffected siblings.

PMID: 23946138 - Morlet et al 2014 - report 9 Old Order Amish individuals who were homozygous for a nonsense mutation of SLITRK6 (c.1240C>T, p.Gln414Ter) and suffered progressive cochlear and auditory nerve dysfunction

PMID: 23543054 - Tekin et al 2013 - report 3 families (1 old-order Amish family, 1 consanguineous Turkish and 1 Greek).
The Amish and Turkish families had members with congenital myopia and prelingual sensorineural hearing loss, while the affected Greek family had hearing loss only. Homozygous nonsense variants were found in SLITRK6 in all 3 families (Amish p.Q414X, Turkish p.S297X, Greek p.R181X). WES was performed on the Turkish family, targeted sequencing in a region of autozygosity in the Amish family, and targeted SLITRK6 sequencing in the Greek family in which affected members had the same haplotype in that region. Mouse Slitrk6 KO show a hearing loss phenotype.

Summary: founder mutation in SLITRK6 in several Amish families, plus 3 other variants reported in families of other ethnicities. Mouse model shows hearing loss phenotype.
Monogenic hearing loss v2.98 SLITRK6 Eleanor Williams commented on gene: SLITRK6
Monogenic hearing loss v2.98 SIX5 Eleanor Williams Classified gene: SIX5 as Red List (low evidence)
Monogenic hearing loss v2.98 SIX5 Eleanor Williams Added comment: Comment on list classification: Demoting from amber to red in view of ClinGen DISPUTED rating and no further reports of variants in SIX5 associated with hearing loss.
Monogenic hearing loss v2.98 SIX5 Eleanor Williams Gene: six5 has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.97 EYA1 Eleanor Williams Publications for gene: EYA1 were set to PMID:10072433; 10471511; 10655545; 10991693; 11409867; 11703923; 11734542; 12404110; 14517553; 14628042; 14628052; 14628053; 15146463; 15226428; 15479196; 15493068; 16441263; 16691597; 16990542; 18177466; 18220287; 19206155; 19234442; 21280147; 2773990; 5365063; 9006082; 9020840; 9342347; 9359046; 9361030; 9603436
Monogenic hearing loss v2.96 EYA1 Eleanor Williams changed review comment from: PMID: 23840632 - Song et al 2013 - analysed EYA1, SIX1 and SIX5 in 7 families (10 patients) with typical BOR/BO syndrome, while one patient exhibited only mixed type of hearing loss and inner ear anomalies. One missense and three splice site mutations were identified in EYA1, while no mutations were found in either SIX1 or SIX5 gene; to: PMID: 23840632 - Song et al 2013 - analysed EYA1, SIX1 and SIX5 in 7 families (10 patients) - all with typical BOR/BO syndrome, except for one patient who exhibited only mixed type of hearing loss and inner ear anomalies. One missense and three splice site mutations were identified in EYA1, while no mutations were found in either SIX1 or SIX5 gene
Monogenic hearing loss v2.96 EYA1 Eleanor Williams reviewed gene: EYA1: Rating: ; Mode of pathogenicity: None; Publications: 23840632; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.96 PMP22 Eleanor Williams changed review comment from: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified. No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. A point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants.; to: Associated with Charcot-Marie-Tooth disease, type 1E #118300 (AD) in which hearing loss is listed as a clinical feature

PMID: 12578939 - Sambuughin et al 2003 - report deafness associated with a demyelinating neuropathy in three individuals of a family in whom a novel 12bp deletion resulting in the deletion of four-amino acid deletion (115-118) in the PMP22 gene was identified (targeted sequencing of PMP22). No asymptomatic family members had the deletion nor was it detected in 55 healthy controls.

PMID: 11835375 - Boerkoel et al 2002 - screened PMP22, GJB1, and MPZ contained 159 unrelated patients with primary peripheral demyelinating neuropathy or a primary peripheral axonal neuropathy and report 5 which have heterozygous variants in PMP22, 1 of which had a clinical diagnosis of CMT1 + deafness (variant 82T>C W28R). An affected sibling had the same variant.

PMID: 10330345 - Kovach et al 1999 - analysis of a 7 generation family from central Illinois with autosomal dominant CMT and deafness. In the 31 affected family members, hearing loss ranged from borderline normal to profound hearing loss, with all having at least mild bilateral hearing loss by adulthood. Following haplotype analysis they sequenced PMP22 and a point mutation was found in affected individuals G->C at position 248 in exon 4 in the heterozygous state (p.Ala67Pro).

PMID: 8355122 - Hamiel et al 1993 - Abstract only accessed. Describe a family with hereditary motor-sensory neuropathy with sensorineural deafness is described; the neurologic features and deafness were apparent in early childhood and infancy.

Summary: 3 cases in which hearing loss is reported in CMT patients with PMP22 variants. In all cases a limited number of genes were sequenced.
Monogenic hearing loss v2.96 PMP22 Eleanor Williams edited their review of gene: PMP22: Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.96 PMP22 Eleanor Williams commented on gene: PMP22
Osteogenesis imperfecta v2.10 KDELR2 Eleanor Williams Publications for gene: KDELR2 were set to PMID: 33053334
Skeletal dysplasia v2.29 KDELR2 Eleanor Williams Tag for-review tag was added to gene: KDELR2.
Skeletal dysplasia v2.29 KDELR2 Eleanor Williams Phenotypes for gene: KDELR2 were changed from Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms; Osteogenesis imperfecta
Skeletal dysplasia v2.28 KDELR2 Eleanor Williams Publications for gene: KDELR2 were set to PMID: 33053334
Skeletal dysplasia v2.27 KDELR2 Eleanor Williams Classified gene: KDELR2 as Amber List (moderate evidence)
Skeletal dysplasia v2.27 KDELR2 Eleanor Williams Added comment: Comment on list classification: Changing the status from grey to amber, but with a recommendation for a green rating following GMS review.
Skeletal dysplasia v2.27 KDELR2 Eleanor Williams Gene: kdelr2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.26 KDELR2 Eleanor Williams edited their review of gene: KDELR2: Changed rating: GREEN; Changed publications: 33053334; Changed phenotypes: Osteogenesis imperfecta; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.26 KDELR2 Eleanor Williams commented on gene: KDELR2
Osteogenesis imperfecta v2.9 KDELR2 Eleanor Williams Tag for-review tag was added to gene: KDELR2.
Osteogenesis imperfecta v2.9 KDELR2 Eleanor Williams Phenotypes for gene: KDELR2 were changed from Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms; Osteogenesis imperfecta
Osteogenesis imperfecta v2.8 KDELR2 Eleanor Williams Classified gene: KDELR2 as Amber List (moderate evidence)
Osteogenesis imperfecta v2.8 KDELR2 Eleanor Williams Added comment: Comment on list classification: Changing the status from grey to amber, but with a recommendation for a green rating following GMS review.
Osteogenesis imperfecta v2.8 KDELR2 Eleanor Williams Gene: kdelr2 has been classified as Amber List (Moderate Evidence).
Osteogenesis imperfecta v2.7 KDELR2 Eleanor Williams reviewed gene: KDELR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33053334; Phenotypes: Osteogenesis imperfecta; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 UBA1 Zornitza Stark gene: UBA1 was added
gene: UBA1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: UBA1 was set to Other
Publications for gene: UBA1 were set to 33108101
Phenotypes for gene: UBA1 were set to Autoinflammatory disease, adult onset; VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
Review for gene: UBA1 was set to GREEN
Added comment: 25 men reported with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation, and an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopaenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis.
Sources: Literature
Intellectual disability v3.510 ZFHX4 Zornitza Stark edited their review of gene: ZFHX4: Changed rating: GREEN
Intellectual disability v3.510 ZFHX4 Zornitza Stark reviewed gene: ZFHX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194, 24038936; Phenotypes: Developmental disorders, intellectual disability, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.510 UPF1 Zornitza Stark gene: UPF1 was added
gene: UPF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 U2AF2 Zornitza Stark gene: U2AF2 was added
gene: U2AF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 TCF7L2 Zornitza Stark gene: TCF7L2 was added
gene: TCF7L2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TCF7L2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF7L2 were set to 33057194
Phenotypes for gene: TCF7L2 were set to Developmental disorders
Review for gene: TCF7L2 was set to AMBER
Added comment: A diabetes susceptibility locus associated with common SNVs, see OMIM for details.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo variants (2 frameshift, 6 missense, 1 splice acceptor, 2 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SRRM2 Zornitza Stark gene: SRRM2 was added
gene: SRRM2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SPEN Zornitza Stark gene: SPEN was added
gene: SPEN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 SATB1 Zornitza Stark reviewed gene: SATB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Developmental disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.510 RAB14 Zornitza Stark gene: RAB14 was added
gene: RAB14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 PSMC5 Zornitza Stark gene: PSMC5 was added
gene: PSMC5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 MSL2 Zornitza Stark gene: MSL2 was added
gene: MSL2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 31332282; 33057194
Phenotypes for gene: MSL2 were set to Developmental disorders; autism
Review for gene: MSL2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model
Sources: Literature
Intellectual disability v3.510 MMGT1 Zornitza Stark gene: MMGT1 was added
gene: MMGT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 HNRNPD Zornitza Stark gene: HNRNPD was added
gene: HNRNPD was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 GIGYF1 Zornitza Stark gene: GIGYF1 was added
gene: GIGYF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
Sources: Literature
Intellectual disability v3.510 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel?

Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here.
Sources: Literature
Intellectual disability v3.510 DHX32 Zornitza Stark gene: DHX32 was added
gene: DHX32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX32 were set to 32989326
Phenotypes for gene: DHX32 were set to Intellectual disability, spastic diplegia, dystonia, brain abnormalities
Review for gene: DHX32 was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two unrelated patients with intellectual disability, one with spastic diplegia, and the other characterised as generalised dystonia. Brain abnormalities were identified also.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.19 ALK Zornitza Stark gene: ALK was added
gene: ALK was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALK were set to 32989326
Phenotypes for gene: ALK were set to Spastic-dystonic diplegia
Review for gene: ALK was set to AMBER
Added comment: Variants in this gene are linked to susceptibility to neuroblastoma.

PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two patients with spastic diplegia with mild tremor, scattered subcortical hyperintensities and an atrial septal defect; and spastic-dystonic diplegia, white matter abnormalities and epilepsy, respectively, with no evidence of neuroblastoma in either patient.
Sources: Literature
Hereditary spastic paraplegia, childhood onset v2.19 RHOB Zornitza Stark gene: RHOB was added
gene: RHOB was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: RHOB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RHOB were set to 32989326
Phenotypes for gene: RHOB were set to Cerebral palsy
Review for gene: RHOB was set to AMBER
Added comment: Recurrent de novo missense variant reported in 2 unrelated families from a 'cerebral palsy' cohort with supporting functional studies.
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.20 STN1 Zornitza Stark gene: STN1 was added
gene: STN1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2, MIM# 617341
Review for gene: STN1 was set to GREEN
Added comment: Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Hereditary neuropathy or pain disorder v1.15 ITPR3 Zornitza Stark gene: ITPR3 was added
gene: ITPR3 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITPR3 were set to 32949214
Phenotypes for gene: ITPR3 were set to Charcot-Marie-Tooth disease
Review for gene: ITPR3 was set to AMBER
Added comment: Two unrelated families reported: variant segregated in four affected individuals in one family and was de novo in the second family where there was a single affected person. Some evidence for dominant-negative effect.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 SOCS1 Zornitza Stark edited their review of gene: SOCS1: Added comment: PMID 33087723: Ten individuals from 5 unrelated families with LOF variants in this gene and early-onset autoimmunity. Functional data indicates cytokine hypersensitivity of immune cells.; Changed publications: 32499645, 10490099, 10490100, 33087723; Changed phenotypes: Common variable immunodeficiency, Early-onset autoimmunity
Intellectual disability v3.510 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Changed phenotypes: Mental retardation, autosomal recessive 45, MIM#615979, Intellectual disability, spasticity, autosomal dominant
Intellectual disability v3.510 FBXO31 Zornitza Stark gene: FBXO31 was added
gene: FBXO31 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO31 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FBXO31 were set to 24623383; 32989326
Phenotypes for gene: FBXO31 were set to Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant
Review for gene: FBXO31 was set to AMBER
Added comment: Bi-allelic variants: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.

Mono-allelic variants: 2 unrelated probands reported as part of a 'cerebral palsy' cohort harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Sources: Literature
Clefting v2.5 AMOTL1 Zornitza Stark gene: AMOTL1 was added
gene: AMOTL1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 33026150
Phenotypes for gene: AMOTL1 were set to Cleft lip and palate; imperforate anus; dysmorphism
Review for gene: AMOTL1 was set to RED
Added comment: Two unrelated families reported. In one, the variant was identified in parent and child who had orofacial cleft and cardiac abnormalities. Second report in PMID 33026150, de novo missense variant and cleft lip/palate, imperforate anus and dysmorphism. Mouse model does not recapitulate phenotype.
Sources: Literature
Proteinuric renal disease v2.33 KIRREL1 Zornitza Stark gene: KIRREL1 was added
gene: KIRREL1 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: KIRREL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIRREL1 were set to 31472902
Phenotypes for gene: KIRREL1 were set to Steroid-resistant nephrotic syndrome
Review for gene: KIRREL1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic variants and limited functional data.
Sources: Literature
Fetal anomalies v1.108 GFRA1 Zornitza Stark gene: GFRA1 was added
gene: GFRA1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GFRA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFRA1 were set to 33020172
Phenotypes for gene: GFRA1 were set to Renal agenesis
Review for gene: GFRA1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic LOF variants identified in individuals with bilateral renal agenesis. GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system. Also relevant to the CAKUT panel.
Sources: Literature
Intellectual disability v3.510 AP2S1 Zornitza Stark gene: AP2S1 was added
gene: AP2S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AP2S1 were set to 33057194
Phenotypes for gene: AP2S1 were set to Developmental disorder
Review for gene: AP2S1 was set to AMBER
Added comment: Established hypercalcaemia gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 ARHGAP35 Zornitza Stark gene: ARHGAP35 was added
gene: ARHGAP35 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Intellectual disability v3.510 ATP6V0A1 Zornitza Stark gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Intellectual disability v3.510 DDX23 Zornitza Stark gene: DDX23 was added
gene: DDX23 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders (rated Amber as no other phenotype info provided).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 FAAP24 Eleanor Williams edited their review of gene: FAAP24: Added comment: Not associated with a phenotype in OMIM.

PMID: 17289582 - Ciccia et al 2007 - report that FAAP24 (C19ORF40) is a component of the Fanconi anemia (FA) core complex and interacts with the C-terminal region of FANCM. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage.

PMID: 27473539 - Daschkey et al 2016 - report a homozygous missense mutation in FAAP24 (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.; Changed rating: RED; Changed phenotypes: EBV-associated lymphoproliferative disease; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 AP3D1 Eleanor Williams Classified gene: AP3D1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 AP3D1 Eleanor Williams Added comment: Comment on list classification: Changing the rating from red to amber. Two cases now reported.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 AP3D1 Eleanor Williams Gene: ap3d1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 AP3D1 Eleanor Williams edited their review of gene: AP3D1: Added comment: Provisionally associated with Hermansky-Pudlak syndrome 10 #617050 (AR) in OMIM.

PMID: 30472485 - Mohammad et al 2019 - 1 family with parents who were first cousins with three affected children who presented similarly with severe seizures, developmental delay, albinism, and immunodeficiency. Whole exome sequencing identified homozygosity for AP3D1 deleterious sequence variant (NM_001261826.3:c.1978delG: p.Ala660Argfs*54) which co-segregated with the phenotype. The variant is not found in the gnomAD database or in an in-house database of 284 exome or Middle Eastern population specific database.

PMID: 26744459 - Ammann et al 2016 - report a patient with consanguineous Turkish parents presenting with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing. Whole exome sequencing identified a homozygous mutation in AP3D1 (c.3565_3566delGT) that leads to destabilization of the adaptor protein 3 (AP3) complex.; Changed rating: AMBER; Changed phenotypes: Hermansky-Pudlak syndrome 10, 617050; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.15 NUDT2 Arina Puzriakova Classified gene: NUDT2 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.15 NUDT2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2 unrelated cases harbouring the same variant reported at present
Hereditary neuropathy or pain disorder v1.15 NUDT2 Arina Puzriakova Gene: nudt2 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.14 NUDT2 Arina Puzriakova commented on gene: NUDT2: Comment on tags: added 'founder-effect' tag - although authors state that they do not believe p.Ala63GlnfsTer3 to be a founder variant (one family of Mexican descent while the other of Cajun descent), this was not confirmed by haplotype analysis. Also added 'watchlist' tag in anticipation of further publications/clinical evidence to support association with this phenotype.
Hereditary neuropathy or pain disorder v1.14 NUDT2 Arina Puzriakova Publications for gene: NUDT2 were set to 27431290; 30059600; 33058507
Hereditary neuropathy or pain disorder v1.13 NUDT2 Arina Puzriakova gene: NUDT2 was added
gene: NUDT2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
watchlist, founder-effect tags were added to gene: NUDT2.
Mode of inheritance for gene: NUDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDT2 were set to 27431290; 30059600; 33058507
Phenotypes for gene: NUDT2 were set to Sensorimotor polyneuropathy; Muscular hypotonia; Intellectual disability; no OMIM number
Review for gene: NUDT2 was set to AMBER
Added comment: - PMID: 33058507 (2020) - Three patients from two families harbouring the same homozygous variant (c.186del, p.Ala63GlnfsTer3). Affected individuals present distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.
----------
A further 4 Saudi families (7 affected individuals) with a different homozygous NUDT2 variant (c.34C> T, p.Arg12) have been published elsewhere (PMID: 27431290, 30059600), however neuropathy was not reported in these cases.
Sources: Literature
Intellectual disability v3.510 NUDT2 Arina Puzriakova Classified gene: NUDT2 as Amber List (moderate evidence)
Intellectual disability v3.510 NUDT2 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (added 'for-review' tag). There are now at least 2 biallelic variants reported in 6 families - 3 of which present GDD and ID, while the remaining had delay but borderline intelligence.
Intellectual disability v3.510 NUDT2 Arina Puzriakova Gene: nudt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.509 NUDT2 Arina Puzriakova Tag founder-effect was removed from gene: NUDT2.
Tag for-review tag was added to gene: NUDT2.
Intellectual disability v3.509 NUDT2 Arina Puzriakova Phenotypes for gene: NUDT2 were changed from Muscular hypotonia; Global developmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Global developmental delay; Intellectual disability; Polyneuropathy; no OMIM number
Intellectual disability v3.508 NUDT2 Arina Puzriakova Publications for gene: NUDT2 were set to 27431290; 30059600
Intellectual disability v3.507 NUDT2 Arina Puzriakova commented on gene: NUDT2
Hereditary neuropathy or pain disorder v1.12 NEMF Arina Puzriakova Classified gene: NEMF as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.12 NEMF Arina Puzriakova Added comment: Comment on list classification: Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) - axonal neuropathy reported in all formally assessed cases (at least 4 with biallelic variants)
Hereditary neuropathy or pain disorder v1.12 NEMF Arina Puzriakova Gene: nemf has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.11 NEMF Arina Puzriakova Added comment: Comment on mode of inheritance: Set MOI to 'Biallelic' as only 1 case with a monoallelic variant described at present. The 'watchlist' tag has been added while further evidence is gathered to establish whether or not there is a wider association with monoallelic variants and disease.
Hereditary neuropathy or pain disorder v1.11 NEMF Arina Puzriakova Mode of inheritance for gene: NEMF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.10 NEMF Arina Puzriakova edited their review of gene: NEMF: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.10 NEMF Arina Puzriakova gene: NEMF was added
gene: NEMF was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
watchlist, for-review tags were added to gene: NEMF.
Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225; 33048237
Phenotypes for gene: NEMF were set to Hypotonia; Axonal neuropathy; Ataxia; Abnormal brain imaging; Global developmental delay; Intellectual disability; Kyphosis; Scoliosis; Tremor; Respiratory distress
Review for gene: NEMF was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on 04/01/2017) or Gene2Phenotype.

Gene added and expert reviewed on Intellectual Disability panel:
https://panelapp.genomicsengland.co.uk/panels/285/gene/NEMF/


- PMID: 32934225 (2020) - 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M)), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M). The authors provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration.


- PMID: 33048237 (2020) - 13 affected individuals from 5 unrelated families presenting with a spectrum of central and peripheral neurological involvement. Peripheral systemic neurological manifestations such as impaired eye movements, limb weakness, and axonal polyneuropathy were found in families 1, 2 and 5 - however, only 2 sibs from family 2 had a precise diagnosis for polyneuropathies. Knockdown studies in cultured mouse primary cortical neurons showed a significant decrease in axon length and impaired synapse development.
Sources: Literature
Intellectual disability v3.507 NEMF Arina Puzriakova Classified gene: NEMF as Amber List (moderate evidence)
Intellectual disability v3.507 NEMF Arina Puzriakova Added comment: Comment on list classification: Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.507 NEMF Arina Puzriakova Gene: nemf has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.506 NEMF Arina Puzriakova Publications for gene: NEMF were set to 32934225
Intellectual disability v3.505 NEMF Arina Puzriakova Added comment: Comment on mode of inheritance: Set MOI to 'Biallelic' as currently only 1 case (total 14) with a monoallelic variant described but with normal intellectual development.
Intellectual disability v3.505 NEMF Arina Puzriakova Mode of inheritance for gene: NEMF was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.504 NEMF Arina Puzriakova Tag for-review tag was added to gene: NEMF.
Intellectual disability v3.504 NEMF Arina Puzriakova commented on gene: NEMF: At least 14 unrelated families reported with variants in NEMF (13 biallelic, 1 monoallelic). GDD/ID is reported in all but 2 cases (USA1 and USA3 in PMID: 32934225) albeit mostly within the mild range. Nonetheless, there are sufficient cases with moderate-severe ID to warrant a Green rating on this panel. Some cases also do not present all other features associated with NEMF variants (e.g. neuropathy) providing further support for inclusion.
Intellectual disability v3.504 NEMF Arina Puzriakova reviewed gene: NEMF: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 33048237; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.204 SETD1A Arina Puzriakova Phenotypes for gene: SETD1A were changed from Epilepsy to Epilepsy, early-onset, with or without developmental delay, 618832
Intellectual disability v3.504 SETD1A Arina Puzriakova Phenotypes for gene: SETD1A were changed from Schizophrenia; developmental disorder; Intellectual disability to Neurodevelopmental disorder with speech impairment and dysmorphic facies, 619056; Epilepsy, early-onset, with or without developmental delay, 618832
Intellectual disability v3.503 SETD1A Arina Puzriakova Publications for gene: SETD1A were set to 28135719; 26974950; 31197650
Intellectual disability v3.502 SETD1A Arina Puzriakova Tag watchlist was removed from gene: SETD1A.
Intellectual disability v3.502 SETD1A Arina Puzriakova commented on gene: SETD1A
Intellectual disability v3.502 SETD1A Arina Puzriakova Tag for-review tag was added to gene: SETD1A.
Skeletal dysplasia v2.26 PRKG2 Arina Puzriakova Classified gene: PRKG2 as Amber List (moderate evidence)
Skeletal dysplasia v2.26 PRKG2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review tag). Two unrelated cases exhibiting a consistent phenotype, supported by functional characterisation of harboured variants and concordant animal models.
Skeletal dysplasia v2.26 PRKG2 Arina Puzriakova Gene: prkg2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.25 PRKG2 Arina Puzriakova Tag watchlist was removed from gene: PRKG2.
Tag for-review tag was added to gene: PRKG2.
Skeletal dysplasia v2.25 PRKG2 Arina Puzriakova edited their review of gene: PRKG2: Changed rating: GREEN
Skeletal dysplasia v2.25 PRKG2 Arina Puzriakova gene: PRKG2 was added
gene: PRKG2 was added to Skeletal dysplasia. Sources: Literature
watchlist tags were added to gene: PRKG2.
Mode of inheritance for gene: PRKG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKG2 were set to 33106379
Phenotypes for gene: PRKG2 were set to Acromesomelic dysplasia
Review for gene: PRKG2 was set to AMBER
Added comment: - PMID: 33106379 (2020) - Distinct homozygous variants in PRKG2 identified in two unrelated individuals, both with a skeletal dysplasia associated with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones.

Functional studies showed both variants result in NMD and disrupt the downstream MAPK signalling pathway in response to FGF2. The role of cGKII, encoded by PRKG2, in skeletal growth has been established in several animal models (references provided in paper).
Sources: Literature
Intellectual disability v3.502 JARID2 Konstantinos Varvagiannis reviewed gene: JARID2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arrhythmogenic right ventricular cardiomyopathy v2.12 TTN Arina Puzriakova commented on gene: TTN: This gene will been flagged for review at the next GMS panel update, in the context of newly published data (added 'for-review' tag). High occurrence of arrhythmias has been associated with TTN-related DCM, which often precedes a DCM diagnosis. Therefore, there may be value in considering inclusion on this panel.
Arrhythmogenic right ventricular cardiomyopathy v2.12 TTN Arina Puzriakova changed review comment from: Recent 2020 paper (PMID: 33106378) reports a high burden of ventricular arrhythmias associated with TTNtv-related DCM. From a total of 115 patients, 43% had atrial fibrillation and 23% had ventricular arrhythmias. In 20% an arrhythmia preceded the DCM diagnosis.; to: Recent 2020 paper (PMID: 33106378) reports a high burden of arrhythmias associated with TTNtv-related DCM. From a total of 115 patients, 43% had atrial fibrillation, 23% had ventricular arrhythmias, and 13% had other supraventricular arrhythmias. In 20% an arrhythmia preceded the DCM diagnosis.
Arrhythmogenic right ventricular cardiomyopathy v2.12 TTN Arina Puzriakova Publications for gene: TTN were set to 30535219; 31251381
Arrhythmogenic right ventricular cardiomyopathy v2.11 TTN Arina Puzriakova Tag for-review tag was added to gene: TTN.
Arrhythmogenic right ventricular cardiomyopathy v2.11 TTN Arina Puzriakova reviewed gene: TTN: Rating: ; Mode of pathogenicity: None; Publications: 33106378; Phenotypes: Cardiomyopathy, dilated, 1G, 604145; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.502 ARID2 Arina Puzriakova Added comment: Comment on publications: Added new publication (Kang et al. 2020) reviewing phenotypes of patients with ARID2 variants, and supporting the current Green rating on this panel.
Intellectual disability v3.502 ARID2 Arina Puzriakova Publications for gene: ARID2 were set to 28124119; 26238514
Intellectual disability v3.501 ARID2 Arina Puzriakova Phenotypes for gene: ARID2 were changed from Coffin-Siris syndrome-like phenotype to Coffin-Siris syndrome 6, 617808; ARID2-Coffin-Siris like disorder
Congenital disorders of glycosylation v2.18 SLC37A4 Zornitza Stark gene: SLC37A4 was added
gene: SLC37A4 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: SLC37A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC37A4 were set to 32884905
Phenotypes for gene: SLC37A4 were set to Congenital disorder of glycosylation
Review for gene: SLC37A4 was set to RED
Added comment: Bi-allelic LOF variants in this gene cause glycogen storage disorder.

Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease.
Sources: Literature
Skeletal ciliopathies v1.3 PRKACA Zornitza Stark gene: PRKACA was added
gene: PRKACA was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRKACA were set to 33058759; 31130284
Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth
Review for gene: PRKACA was set to GREEN
Added comment: This gene is difficult to place but this seems like the most appropriate panel.

Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia.

The phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polydactyly, AVSD).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlies the developmental defects observed in affected individuals.

The authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Hydrocephalus v2.5 SMARCC1 Zornitza Stark gene: SMARCC1 was added
gene: SMARCC1 was added to Hydrocephalus. Sources: Literature
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCC1 were set to 33077954; 24170322
Phenotypes for gene: SMARCC1 were set to Congenital hydrocephalus
Review for gene: SMARCC1 was set to GREEN
gene: SMARCC1 was marked as current diagnostic
Added comment: Three de novo variants, two LOF, one missense, reported in this hydrocephalus cohort. Supportive mouse model.
Sources: Literature
Congenital myaesthenic syndrome v2.5 SYT2 Zornitza Stark reviewed gene: SYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25192047, 32776697, 32250532, 30533528; Phenotypes: Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.500 JARID2 Zornitza Stark gene: JARID2 was added
gene: JARID2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JARID2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JARID2 were set to 23294540; 33077894
Phenotypes for gene: JARID2 were set to Intellectual disability
Review for gene: JARID2 was set to GREEN
gene: JARID2 was marked as current diagnostic
Added comment: 13 individuals reported recently, note CNVs common but LOF sequence variants identified too.
Sources: Literature
Intellectual disability v3.500 NUDT2 Zornitza Stark reviewed gene: NUDT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 30059600, 33058507; Phenotypes: Muscular hypotonia, Global developmental delay, Intellectual disability, Polyneuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Bilateral congenital or childhood onset cataracts v2.17 SREBF1 Zornitza Stark gene: SREBF1 was added
gene: SREBF1 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SREBF1 were set to 32497488; 31790666; 32902915
Phenotypes for gene: SREBF1 were set to Mucoepithelial dysplasia, hereditary, MIM#158310
Review for gene: SREBF1 was set to GREEN
Added comment: HMD phenotype: 5 unrelated families reported with heterozygous variants at same residue (p.Arg557Cys and p.Arg557His) and a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Individuals developed cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses.

Needs to be added to skin panels, in addition to the already described IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016 phenotype.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.62 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to RED
Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.62 VPS16 Zornitza Stark gene: VPS16 was added
gene: VPS16 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS16 were set to 32808683
Phenotypes for gene: VPS16 were set to Dystonia
Review for gene: VPS16 was set to GREEN
Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood.

Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: Literature
Early onset or syndromic epilepsy v2.203 SATB2 Zornitza Stark gene: SATB2 was added
gene: SATB2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SATB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB2 were set to 32446642
Phenotypes for gene: SATB2 were set to Glass syndrome, MIM# 612313
gene: SATB2 was marked as current diagnostic
Added comment: In a cohort of 101 individuals with SATB2-associated syndrome, 41 had at least one prior abnormal EEG. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six individuals with definite clinical seizures needed polytherapy (35%).
Sources: Literature
Paroxysmal central nervous system disorders v1.4 ATP1A4 Zornitza Stark gene: ATP1A4 was added
gene: ATP1A4 was added to Paroxysmal central nervous system disorders. Sources: Literature
Mode of inheritance for gene: ATP1A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A4 were set to 32549268
Phenotypes for gene: ATP1A4 were set to Hemiplegic migraine
Review for gene: ATP1A4 was set to RED
Added comment: Single family reported where missense variant segregated with hemiplegic migraine in four affected individuals.
Sources: Literature
Intellectual disability v3.500 AGAP1 Zornitza Stark gene: AGAP1 was added
gene: AGAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGAP1 were set to 31700678; 25666757; 30472483
Phenotypes for gene: AGAP1 were set to Cerebral palsy
Review for gene: AGAP1 was set to AMBER
Added comment: Two individuals reported with de novo variants in this gene and a CP phenotype. Rare variants over-represented in a case-control study. Supportive zebrafish model. Another individual with a deletion (+1 other gene) reported with ID and autism. This seems the most appropriate panel?
Sources: Literature
Primary ovarian insufficiency v1.19 BUB1B Zornitza Stark gene: BUB1B was added
gene: BUB1B was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: BUB1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BUB1B were set to 32716490
Phenotypes for gene: BUB1B were set to Premature ovarian failure
Review for gene: BUB1B was set to AMBER
Added comment: The association between bi-allelic variants and mosaic variegated aneuploidy syndrome, MIM#257300 is well established.

Moderate evidence for association between mono-allelic variants and POF, PMID 32716490
Sources: Literature
White matter disorders and cerebral calcification - childhood onset v1.20 ACER3 Zornitza Stark gene: ACER3 was added
gene: ACER3 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 32816236; 26792856
Phenotypes for gene: ACER3 were set to Leukodystrophy
Review for gene: ACER3 was set to AMBER
Added comment: Two families reported with bi-allelic variants, and paediatric onset progressive leukodystorphy. Functional data demonstrating ACER3 deficiency.
Sources: Literature
Intellectual disability v3.500 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Intellectual disability v3.500 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous tests not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro).

All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK, p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO mice display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Fetal anomalies v1.108 TRAPPC12 Rhiannon Mellis reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32347653; Phenotypes: Hydrocephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.500 CEP120 Ivone Leong Phenotypes for gene: CEP120 were changed from Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) to Joubert syndrome 31 (617761); Short-rib thoracic dysplasia 13 with or without polydactyly (616300)
Cholestasis v1.60 NBAS Ivone Leong commented on gene: NBAS: After consultation with the Genomics Clinical Team this gene has been left on this panel for the following reason:
"Helen Brittain (Genomics England):
Infantile liver failure: the evidence for this seems good. It doesn't clearly map to any of our panels or the GMS indications. The closest would probably be cholestasis. I think it is worth adding there as amber, for expert phenotypic review in the next GMS iteration."
Cholestasis v1.60 NBAS Ivone Leong changed review comment from: There are >3 unrelated cases of patients with variants in NBAS with infantile liver failure. Variants in this gene causes a wide range of symptoms that affect the liver, skeletal system and eyes. This gene has been given an Amber review and tagged with "for-review" for the next major update of this panel.
Sources: Literature; to: There are >3 unrelated cases of patients with variants in NBAS with infantile liver failure. Variants in this gene causes a wide range of symptoms that affect the liver, skeletal system and eyes. This gene has been given an Amber review and tagged with "for-review" for the next major update of this panel.
Sources: Literature
Cholestasis v1.60 COG7 Ivone Leong Classified gene: COG7 as Amber List (moderate evidence)
Cholestasis v1.60 COG7 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is Green on the Neonatal cholestasis panel (v1.4) with the following review:
"Sarah Leigh (Genomics England Curator)

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 2 variants reported in 3 unrelated families, together with supportive in vitro studies (PMID 19577670)."

This gene has been given an Amber rating and will be made Green at the next review.
Cholestasis v1.60 COG7 Ivone Leong Gene: cog7 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.59 COG7 Ivone Leong Tag for-review tag was added to gene: COG7.
Cholestasis v1.59 ATP7B Ivone Leong Publications for gene: ATP7B were set to
Cholestasis v1.58 ATP7B Ivone Leong Phenotypes for gene: ATP7B were changed from Wilson disease, MIM# 277900 to Wilson disease, 277900
Cholestasis v1.57 ATP7B Ivone Leong Classified gene: ATP7B as Amber List (moderate evidence)
Cholestasis v1.57 ATP7B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is Green on the Neonatal cholestasis panel (v1.4) with the following review:
"Sarah Leigh (Genomics England Curator)

Comment on list classification: Based on comments by Helen Britain, Genomics England Clinical Fellow
Created: 3 Sep 2018, 11:31 a.m.

Associated with phenotype in OMIM and not in Gen2Phen. Numerous variants identified in unrelated cases, however, seldom reported in young children.

Comments of Helen Britain, Genomics England Clinical Fellow "the age of onset is often later than the target range of this panel, however when there is a juvenile onset, the presentation is often primarily hepatic. There are treatment options for affected individuals and confirmatory biochemical tests. Therefore, even though this is not a classical phenotypic fit, I think on balance it worth including."
Created: 14 Aug 2018, 9:33 a.m."

Therefore, this Gene has been given an Amber gene rating and will be promoted to Green status at next review.
Cholestasis v1.57 ATP7B Ivone Leong Gene: atp7b has been classified as Amber List (Moderate Evidence).
Cholestasis v1.56 ATP7B Ivone Leong Tag for-review tag was added to gene: ATP7B.
Cholestasis v1.56 COG7 Ivone Leong Phenotypes for gene: COG7 were changed from Congenital disorder of glycosylation, type IIe , MIM#608779 to Congenital disorder of glycosylation, type IIe , 608779
Cholestasis v1.55 CYP7A1 Ivone Leong Tag for-review tag was added to gene: CYP7A1.
Cholestasis v1.55 CYP7A1 Ivone Leong commented on gene: CYP7A1: CYP7A1 is not associated with a relevant phenotype in OMIM or Gene2Phenotype. PMID: 9802883 describes a patient with severe cholestasis, cirrhosis, and liver synthetic failure and variants were found in CYP7B1. There were no variants found in CYP7A1. CYP7A1 is associated with Hypercholesterolemia on Orphanet.

Therefore, this gene should be demoted from Green to Red.
Cholestasis v1.55 CYP7A1 Ivone Leong edited their review of gene: CYP7A1: Changed rating: GREEN
Cholestasis v1.55 CYP7A1 Ivone Leong Deleted their comment
Cholestasis v1.55 CYP7A1 Ivone Leong changed review comment from: CYP7A1 is not associated with a relevant phenotype in OMIM or Gene2Phenotype. PMID: 9802883 describes a patient with severe cholestasis, cirrhosis, and liver synthetic failure and variants were found in CYP7B1. There were no variants found in CYP7A1. CYP7A1 is associated with Hypercholesterolemia on Orphanet.; to: CYP7A1 is not associated with a relevant phenotype in OMIM or Gene2Phenotype. PMID: 9802883 describes a patient with severe cholestasis, cirrhosis, and liver synthetic failure and variants were found in CYP7B1. There were no variants found in CYP7A1. CYP7A1 is associated with Hypercholesterolemia on Orphanet.
Cholestasis v1.55 CYP7A1 Ivone Leong edited their review of gene: CYP7A1: Added comment: CYP7A1 is not associated with a relevant phenotype in OMIM or Gene2Phenotype. PMID: 9802883 describes a patient with severe cholestasis, cirrhosis, and liver synthetic failure and variants were found in CYP7B1. There were no variants found in CYP7A1. CYP7A1 is associated with Hypercholesterolemia on Orphanet.; Changed rating: RED
Neonatal cholestasis v1.7 CYP7B1 Ivone Leong Phenotypes for gene: CYP7B1 were changed from Neonatal and Adult Cholestasis; Bile acid synthesis defect, congenital, 3 to Bile acid synthesis defect, congenital, 3, 613812; Neonatal and Adult Cholestasis
Neonatal cholestasis v1.6 CYP7B1 Ivone Leong Publications for gene: CYP7B1 were set to 9802883
Neonatal cholestasis v1.5 CYP7B1 Ivone Leong Classified gene: CYP7B1 as Green List (high evidence)
Neonatal cholestasis v1.5 CYP7B1 Ivone Leong Added comment: Comment on list classification: The case described in PMID: 9802883 has already been reviewed by Ellen McDonagh (Genomics England Curator), 25 Jul 2018. Variant is CYP7B1 (R388X/R388X) and the individual is of Hispanic ancestry.

PMID: 18367963 and 31337596 describe 4 unrelated cases from Taiwan who all had the same variant (R112X/R112X). PMID: 31337596 found that the allele frequency of p.R112X is 0.16% in the Taiwanese populatio, compared with the allele frequency of the worldwide population (0.014%). All 4 had neonatal cholestasis.

PMID: 21567895 describes a Japanese patient with R112X/R417C with progressive cholestatic liver disease.

PMID: 24658845 describes a patient from a consanguineous Pakistani family with cholestatic liver disease with R417C/R417C.

There is enough evidence to support gene-disease association. This gene has been promoted from Amber to Green.
Neonatal cholestasis v1.5 CYP7B1 Ivone Leong Gene: cyp7b1 has been classified as Green List (High Evidence).
Cholestasis v1.55 CYP7B1 Ivone Leong Publications for gene: CYP7B1 were set to 9802883; 31337596; 30366773; 18367963
Cholestasis v1.54 CYP7B1 Ivone Leong Tag for-review tag was added to gene: CYP7B1.
Cholestasis v1.54 CYP7B1 Ivone Leong Classified gene: CYP7B1 as Amber List (moderate evidence)
Cholestasis v1.54 CYP7B1 Ivone Leong Added comment: Comment on list classification: The case described in PMID: 9802883 has already been reviewed by Ellen McDonagh (Genomics England Curator), 25 Jul 2018. Variant is CYP7B1 (R388X/R388X) and the individual is of Hispanic ancestry.

PMID: 18367963 and 31337596 describe 4 unrelated cases from Taiwan who all had the same variant (R112X/R112X). PMID: 31337596 found that the allele frequency of p.R112X is 0.16% in the Taiwanese populatio, compared with the allele frequency of the worldwide population (0.014%). All 4 had neonatal cholestasis.

PMID: 21567895 describes a Japanese patient with R112X/R417C with progressive cholestatic liver disease.

PMID: 24658845 describes a patient from a consanguineous Pakistani family with cholestatic liver disease with R417C/R417C.

There is enough evidence to support gene-disease association. This gene will be promoted to Green status at the next review.
Cholestasis v1.54 CYP7B1 Ivone Leong Gene: cyp7b1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.53 CYP7B1 Ivone Leong Publications for gene: CYP7B1 were set to 9802883; 31337596; 30366773
Cholestasis v1.52 CYP7B1 Ivone Leong Phenotypes for gene: CYP7B1 were changed from Bile acid synthesis defect, congenital, 3; Neonatal and Adult Cholestasis to Bile acid synthesis defect, congenital, 3, 613812; Neonatal and Adult Cholestasis
Cholestasis v1.51 CYP7B1 Ivone Leong Publications for gene: CYP7B1 were set to 9802883
Cholestasis v1.50 DGUOK Ivone Leong Classified gene: DGUOK as Amber List (moderate evidence)
Cholestasis v1.50 DGUOK Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. This gene has been given an Amber rating and will be promoted to Green status at the next review.

This gene is also Green on Mitochondrial liver disease (v1.3), Mitochondrial DNA maintenance disorder (1.3), Inborn errors of metabolism (v2.24) and Possible mitochondrial disorder - nuclear genes (v1.17), Mitochondrial disorders (v2.8). It is also a Green gene on the Neonatal cholestasis panel (v1.4).
Cholestasis v1.50 DGUOK Ivone Leong Gene: dguok has been classified as Amber List (Moderate Evidence).
Cholestasis v1.49 DGUOK Ivone Leong Tag for-review tag was added to gene: DGUOK.
Osteogenesis imperfecta v2.7 KDELR2 Dmitrijs Rots gene: KDELR2 was added
gene: KDELR2 was added to Osteogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KDELR2 were set to PMID: 33053334
Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Penetrance for gene: KDELR2 were set to Complete
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies reported in PMID: 33053334
Sources: Literature
Skeletal dysplasia v2.24 KDELR2 Dmitrijs Rots gene: KDELR2 was added
gene: KDELR2 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KDELR2 were set to PMID: 33053334
Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Penetrance for gene: KDELR2 were set to Complete
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies reported in PMID: 33053334
Sources: Literature
Cholestasis v1.49 DGUOK Ivone Leong Phenotypes for gene: DGUOK were changed from Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880 to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), 251880
Cholestasis v1.48 GBA Ivone Leong Classified gene: GBA as Amber List (moderate evidence)
Cholestasis v1.48 GBA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. This gene has been given an Amber review and will be promoted to a Green gene at the next review.

This gene is also Green on the Neonatal cholestasis panel (v1.4) with the following review:
"Comment when marking as ready: Associated with relevant phenotype in OMIM and as both DD and IF Gen2Phen gene. At least 40 variants reported.
Sarah Leigh (Genomics England Curator), 14 Aug 2018"
Cholestasis v1.48 GBA Ivone Leong Gene: gba has been classified as Amber List (Moderate Evidence).
Cholestasis v1.47 GBA Ivone Leong Tag for-review tag was added to gene: GBA.
Cholestasis v1.47 IARS Ivone Leong commented on gene: IARS: "New gene name" tag added, the new gene name is IARS1.
Cholestasis v1.47 IARS Ivone Leong Tag new-gene-name tag was added to gene: IARS.
Cholestasis v1.47 IARS Ivone Leong Classified gene: IARS as Amber List (moderate evidence)
Cholestasis v1.47 IARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. Based on the available evidence there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.

This gene is also Amber on the Neonatal cholestasis panel (v1.4) with the following review:
"Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 8 variants reported in 4 unrelated cases. Cholestasis was only evident in 2 of these cases and one of these cases also carried a heterozygous ABCB11 variant, which may contribute to the manifestation of cholestasis.
Created: 15 Aug 2018, 1:13 p.m."
Cholestasis v1.47 IARS Ivone Leong Gene: iars has been classified as Amber List (Moderate Evidence).
Cholestasis v1.46 IARS Ivone Leong Phenotypes for gene: IARS were changed from Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093 to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, 617093
Cholestasis v1.45 NPHP3 Ivone Leong Classified gene: NPHP3 as Amber List (moderate evidence)
Cholestasis v1.45 NPHP3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association; however, as cholestasis is not a prominant feature of Renal-hepatic-pancreatic dysplasia and there does not appear to be any cases with isolated cholestasis phenotype. Therefore, this gene has been given an Amber rating.

This gene is Green on Cystic kidney disease (v2.19), Unexplained paediatric onset end-stage renal disease (v1.11), Fetal anomalies (v1.92) and Renal ciliopathies (v1.30).

It is also Amber on Neonatal cholestasis (v1.4) with the following review:
"Comment on list classification: Cholestasis is not a major feature of Nephronophthisis 3. Biallelic variants in this gene have been reported in Caroli syndrome and renal-hepatic-pancreatic dysplasia; only a small number of cases have been reported and features vary. It would be less likely for variants in this gene to present with isolated cholestasis; NPHP3 is on a number of other panels including rare multisystem ciliopathies and cystic kidneys.
Anna de Burca (Genomics England Curator), 25 Jul 2018"
Cholestasis v1.45 NPHP3 Ivone Leong Gene: nphp3 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.44 NPHP3 Ivone Leong Publications for gene: NPHP3 were set to 18371931; 20007846; 32341812
Severe microcephaly v2.40 METTL5 Arina Puzriakova Classified gene: METTL5 as Amber List (moderate evidence)
Severe microcephaly v2.40 METTL5 Arina Puzriakova Added comment: Comment on list classification: Borderline Green/Amber gene. Sufficient unrelated cases (3) from literature and supportive animal models, but uncertain functional significance of one variant. Thus METTL5 will be flagged for review of evidence at the next GMS panel update (added 'for-review' tag)
Severe microcephaly v2.40 METTL5 Arina Puzriakova Gene: mettl5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.39 METTL5 Arina Puzriakova gene: METTL5 was added
gene: METTL5 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: METTL5.
Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL5 were set to 29302074; 31564433; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Phenotypes for gene: METTL5 were set to Intellectual developmental disorder, autosomal recessive 72, 618665
Added comment: Associated with 'Intellectual developmental disorder' in OMIM, and is a 'probable' gene for 'Autosomal-Recessive Intellectual Disability and Microcephaly' in DD-G2P.

Gene added and expert reviewed on Intellectual Disability panel: https://panelapp.genomicsengland.co.uk/panels/285/gene/METTL5/

Distinct biallelic variants reported in 3 unrelated families (total 9 individuals) with severe microcephaly (OFC -2.8 to -8 SD) and intellectual disability. Mouse and zebrafish models appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation).

However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classified VUS as localisation and expression studies failed to demonstrate a functional impact on the encoded protein.
Sources: Literature
Intellectual disability v3.499 METTL5 Arina Puzriakova Phenotypes for gene: METTL5 were changed from Autosomal-Recessive Intellectual Disability and Microcephaly; Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality to Intellectual developmental disorder, autosomal recessive 72, 618665
Intellectual disability v3.498 METTL5 Arina Puzriakova Tag for-review tag was added to gene: METTL5.
Intellectual disability v3.498 METTL5 Arina Puzriakova reviewed gene: METTL5: Rating: ; Mode of pathogenicity: None; Publications: 29302074, 31564433; Phenotypes: Intellectual developmental disorder, autosomal recessive 72, 618665; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.11 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from MICROCEPHALY 15, PRIMARY, AUTOSOMAL RECESSIVE 616486 to Microcephaly 15, primary, autosomal recessive, 616486
Fetal anomalies v1.108 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from MICROCEPHALY 15, PRIMARY, AUTOSOMAL RECESSIVE to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486
Cholestasis v1.43 GBA Ivone Leong Phenotypes for gene: GBA were changed from Gaucher disease to Gaucher disease, perinatal lethal 608013; Gaucher disease, type I 230800; Gaucher disease, type II 230900; Gaucher disease, type III 231000; Gaucher disease, type IIIC 231005
Cholestasis v1.42 HNF1B Ivone Leong Classified gene: HNF1B as Amber List (moderate evidence)
Cholestasis v1.42 HNF1B Ivone Leong Added comment: Comment on list classification: Comment on list classification: New gene added by Zornitiza Stark. Based on the available evidence there is enough evidence to support a gene-disease association. Therefore, this gene is rated Amber and will be promoted to Green in the next review.

This gene is also Green on the Neonatal Cholestasis panel (v1.4)
Cholestasis v1.42 HNF1B Ivone Leong Gene: hnf1b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.38 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from Microcephaly 15, primary, autosomal recessive, 616486 to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486
Severe microcephaly v2.37 MFSD2A Arina Puzriakova Added comment: Comment on publications: Added publications to support this gene-disease association
Severe microcephaly v2.37 MFSD2A Arina Puzriakova Publications for gene: MFSD2A were set to 12046007
Cholestasis v1.41 HNF1B Ivone Leong Tag for-review tag was added to gene: HNF1B.
Intellectual disability v3.498 MFSD2A Arina Puzriakova Classified gene: MFSD2A as Amber List (moderate evidence)
Intellectual disability v3.498 MFSD2A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated Green at the next GMS panel update.
Intellectual disability v3.498 MFSD2A Arina Puzriakova Gene: mfsd2a has been classified as Amber List (Moderate Evidence).
Cholestasis v1.41 HNF1B Ivone Leong Phenotypes for gene: HNF1B were changed from Renal cysts and diabetes syndrome, MIM# 137920 to Renal cysts and diabetes syndrome, 137920
Intellectual disability v3.497 MFSD2A Arina Puzriakova Phenotypes for gene: MFSD2A were changed from NA to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486
Intellectual disability v3.496 MFSD2A Arina Puzriakova Publications for gene: MFSD2A were set to
Intellectual disability v3.495 MFSD2A Arina Puzriakova Mode of inheritance for gene: MFSD2A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.494 MFSD2A Arina Puzriakova Tag for-review tag was added to gene: MFSD2A.
Intellectual disability v3.494 MFSD2A Arina Puzriakova reviewed gene: MFSD2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 26005868, 26005865, 29302074, 30043326, 32572202; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities, 616486; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.40 MPV17 Ivone Leong Classified gene: MPV17 as Amber List (moderate evidence)
Cholestasis v1.40 MPV17 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitiza Stark. Based on the available evidence there is enough evidence to support a gene-disease association. Therefore, this gene is rated Amber and will be promoted to Green in the next review.

This gene is also Green on the Neonatal Cholestasis panel (v1.4)
Cholestasis v1.40 MPV17 Ivone Leong Gene: mpv17 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.39 MPV17 Ivone Leong Tag for-review tag was added to gene: MPV17.
Intellectual disability v3.494 NPHP3 Arina Puzriakova Publications for gene: NPHP3 were set to
Intellectual disability v3.493 NPHP3 Arina Puzriakova Classified gene: NPHP3 as Amber List (moderate evidence)
Intellectual disability v3.493 NPHP3 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as affected individuals are more likely to be assessed under renal and ciliopathy panels, for which this gene is already Green.
Intellectual disability v3.493 NPHP3 Arina Puzriakova Gene: nphp3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.492 NPHP3 Arina Puzriakova reviewed gene: NPHP3: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 3, 604387, Renal-hepatic-pancreatic dysplasia 1, 208540, Meckel syndrome 7, 267010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.12 ZIC1 Arina Puzriakova Phenotypes for gene: ZIC1 were changed from Craniosynostosis 6 616602; 616602 to ?Craniosynostosis 6, 616602; Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.11 ZIC1 Arina Puzriakova Added comment: Comment on publications: Added publications to support gene-disease association
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.11 ZIC1 Arina Puzriakova Publications for gene: ZIC1 were set to 26340333
Intellectual disability v3.492 ZIC1 Arina Puzriakova Publications for gene: ZIC1 were set to
Intellectual disability v3.491 ZIC1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

; to: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

Predicted that both gain- and loss-of-function variants can be deleterious.
Intellectual disability v3.491 ZIC1 Arina Puzriakova changed review comment from: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with craniosynostosis and associated variable intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe); to: Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.
Intellectual disability v3.491 ZIC1 Arina Puzriakova Phenotypes for gene: ZIC1 were changed from CRANIOSYNOSTOSIS 6 to Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; ?Craniosynostosis 6, 616602
Intellectual disability v3.490 ZIC1 Arina Puzriakova Classified gene: ZIC1 as Amber List (moderate evidence)
Intellectual disability v3.490 ZIC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.490 ZIC1 Arina Puzriakova Gene: zic1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.489 ZIC1 Arina Puzriakova Tag for-review tag was added to gene: ZIC1.
Intellectual disability v3.489 ZIC1 Arina Puzriakova reviewed gene: ZIC1: 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: 26340333, 30391508; Phenotypes: ?Craniosynostosis 6, 616602, Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited ovarian cancer (without breast cancer) v2.5 PALB2 Arina Puzriakova Publications for gene: PALB2 were set to
Inherited ovarian cancer (without breast cancer) v2.4 PALB2 Arina Puzriakova Classified gene: PALB2 as Red List (low evidence)
Inherited ovarian cancer (without breast cancer) v2.4 PALB2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Red, as it remains unclear whether the risk is sufficiently high to warrant the inclusion of PALB2 in the ovarian cancer gene panel.
Inherited ovarian cancer (without breast cancer) v2.4 PALB2 Arina Puzriakova Gene: palb2 has been classified as Red List (Low Evidence).
Inherited ovarian cancer (without breast cancer) v2.3 PALB2 Arina Puzriakova reviewed gene: PALB2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult solid tumours cancer susceptibility v2.6 PALB2 Arina Puzriakova Phenotypes for gene: PALB2 were changed from breast, pancreas to Fanconi anemia, complementation group N, 610832; {Breast cancer, susceptibility to}, 114480; {Pancreatic cancer, susceptibility to, 3}, 613348; High Risk Breast Cancer; Breast and Ovarian Cancer
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag) as there are sufficient unrelated cases to support a gene-disease association.
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.202 ZNF335 Arina Puzriakova gene: ZNF335 was added
gene: ZNF335 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: ZNF335.
Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087; 30500859; 31187448
Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive, 615095
Review for gene: ZNF335 was set to GREEN
Added comment: At least 6 unrelated families reported in literature with different biallelic variants in ZNF335. Microcephaly is the primary feature, but also commonly in association with a variable epilepsy phenotype.

Stouffs et al. (PMID:29652087) report 2 unrelated cases: patient A, demonstrating refractory seizures leading to death at age 5 days, whereas patient B lacked any clinical seizures, but had frequent spasms that have yet to be recorded by EEG. The proband in Sato et al. (PMID:27540107) had rare focal seizures controlled by treatment. Although not noted by Yang et al. (PMID:231781260), affected individuals in that family had seizures described as paroxysmal myoclonic jerks (personal communication with Stouffs et al). The case by Rana et al. (PMID:31187448) presented multifocal drug-resistant epilepsy, and while details were limited in McSherry et al. (PMID:30500859), authors did also note seizures.
Sources: Literature
Severe microcephaly v2.36 ZNF335 Arina Puzriakova Publications for gene: ZNF335 were set to 25951892; 25548773; 23178126
Severe microcephaly v2.35 ZNF335 Arina Puzriakova Phenotypes for gene: ZNF335 were changed from Autosomal recessive primary microcephaly (MCPH) ; ?Microcephaly 10, primary, autosomal recessive, 615095 to Microcephaly 10, primary, autosomal recessive, 615095
Severe microcephaly v2.34 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Severe microcephaly v2.34 ZNF335 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag).
Severe microcephaly v2.34 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.33 ZNF335 Arina Puzriakova Tag for-review tag was added to gene: ZNF335.
Severe microcephaly v2.33 ZNF335 Arina Puzriakova reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087, 30500859, 31187448; Phenotypes: Microcephaly 10, primary, autosomal recessive, 615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.489 ZNF335 Arina Puzriakova Publications for gene: ZNF335 were set to 23178126
Intellectual disability v3.488 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Intellectual disability v3.488 ZNF335 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.488 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.487 ZNF335 Arina Puzriakova Tag watchlist was removed from gene: ZNF335.
Tag for-review tag was added to gene: ZNF335.
Intellectual disability v3.487 ZNF335 Arina Puzriakova commented on gene: ZNF335: Removed 'watchlist' tag as there are now sufficient cases to support a gene-disease association, and for this gene to be rated Green.
Intellectual disability v3.487 ZNF335 Arina Puzriakova reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087, 30500859, 31187448; Phenotypes: Microcephaly 10, primary, autosomal recessive, 615095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.487 ZNF335 Arina Puzriakova Phenotypes for gene: ZNF335 were changed from ?Microcephaly 10, primary, autosomal recessive, 615095; developmental delay; intellectual disability to Microcephaly 10, primary, autosomal recessive, 615095
Intellectual disability v3.486 ZNF335 Arina Puzriakova Mode of inheritance for gene: ZNF335 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.485 ZNF148 Arina Puzriakova reviewed gene: ZNF148: Rating: AMBER; Mode of pathogenicity: None; Publications: 27964749; Phenotypes: Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies, 617260; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.201 SLC5A6 Sarah Leigh commented on gene: SLC5A6: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene.
Early onset or syndromic epilepsy v2.201 SLC5A6 Sarah Leigh Tag for-review tag was added to gene: SLC5A6.
Likely inborn error of metabolism v2.24 SLC5A6 Sarah Leigh changed review comment from: Comment on list classification: Based on five variants in three unrelated cases, together with supportive aminal model studies.; to: Comment on list classification: Based on five variants in three unrelated cases, together with supportive animal model studies.
Severe microcephaly v2.33 TTC5 Sarah Leigh Deleted their comment
Intellectual disability v3.485 KIF21B Arina Puzriakova Classified gene: KIF21B as Amber List (moderate evidence)
Intellectual disability v3.485 KIF21B Arina Puzriakova Added comment: Comment on list classification: Rating Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.485 KIF21B Arina Puzriakova Gene: kif21b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.484 KIF21B Arina Puzriakova Tag for-review tag was added to gene: KIF21B.
Intellectual disability v3.484 KIF21B Arina Puzriakova commented on gene: KIF21B
Paediatric or syndromic cardiomyopathy v1.9 COX14 Zornitza Stark reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 10, MIM# 619053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.9 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: RED; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: RED; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.484 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB 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: PRKACB was set to AMBER
Added comment: ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.

Please consider inclusion of PRKACB (and PRKACA) in other relevant gene panels e.g. for polydactyly, congenital heart defects. The disorder may be considered in the DD of ciliopathies.

-----


Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Fetal anomalies v1.107 NEK9 Rhiannon Mellis edited their review of gene: NEK9: Added comment: Deden et al (2020) report a further family with two consecutive prenatal presentations with compound heterozygous NEK9 variants. Both fetuses had arthrogryposis.

Both variants were reported as VUS when detected in the first fetus, which initially presented with 'short long bones, bowed femur, micrognathia, talipes and deviated hand' but re-evaluated after the phenotype progressed to arthrogryposis and then the next pregnancy showed the same ultrasound abnormalities and the same compound het variants. At this point the authors felt this represented a conclusive diagnosis.; Changed rating: GREEN; Changed publications: PMID: 26908619, 26633546, 32333414; Changed phenotypes: Arthrogryposis, short long bones
Intellectual disability v3.484 FA2H Sarah Leigh Tag for-review tag was added to gene: FA2H.
Intellectual disability v3.484 FA2H Sarah Leigh reviewed gene: FA2H: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.484 CDH2 Sarah Leigh Phenotypes for gene: CDH2 were changed from Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929
Intellectual disability v3.483 CDH2 Sarah Leigh Tag for-review tag was added to gene: CDH2.
Intellectual disability v3.483 CDH2 Sarah Leigh reviewed gene: CDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dilated Cardiomyopathy and conduction defects v1.65 RAB3GAP2 Dmitrijs Rots reviewed gene: RAB3GAP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.43 ISCU Arina Puzriakova changed review comment from: Added 'for-review' tag as the MOI has changed since previous sign-off of this panel and requires review by the Specialist Test Group.; to: Added 'for-review' tag as the MOI has changed since previous sign-off of this panel (version 1.34) and requires review by the Specialist Test Group.
Intellectual disability v3.483 SCN8A Arina Puzriakova Tag for-review tag was added to gene: SCN8A.
Intellectual disability v3.483 SCN8A Arina Puzriakova commented on gene: SCN8A
Early onset or syndromic epilepsy v2.201 SCN8A Arina Puzriakova Tag for-review tag was added to gene: SCN8A.
Early onset or syndromic epilepsy v2.201 SCN8A Arina Puzriakova commented on gene: SCN8A
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 STAT5B Arina Puzriakova Tag for-review tag was added to gene: STAT5B.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 STAT5B Arina Puzriakova commented on gene: STAT5B
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 TCF3 Arina Puzriakova Tag for-review tag was added to gene: TCF3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 TCF3 Arina Puzriakova commented on gene: TCF3
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 PIK3CD Arina Puzriakova Tag for-review tag was added to gene: PIK3CD.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 PIK3CD Arina Puzriakova commented on gene: PIK3CD
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 RIPK1 Arina Puzriakova commented on gene: RIPK1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 RIPK1 Arina Puzriakova Tag for-review tag was added to gene: RIPK1.
Rhabdomyolysis and metabolic muscle disorders v1.43 ISCU Arina Puzriakova commented on gene: ISCU
Rhabdomyolysis and metabolic muscle disorders v1.43 ISCU Arina Puzriakova Tag for-review tag was added to gene: ISCU.
Rare multisystem ciliopathy disorders v1.130 IFT27 Arina Puzriakova changed review comment from: Comment on list classification: With the addition of recent publications, there are now at least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to GREEN at the next major review.; to: Comment on list classification: With the addition of recent publications, there are now at least four unrelated cases reported, and therefore enough evidence for a rating upgrade from Amber to Green.
Rare multisystem ciliopathy disorders v1.130 IFT27 Arina Puzriakova Classified gene: IFT27 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.130 IFT27 Arina Puzriakova Gene: ift27 has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.129 IFT27 Arina Puzriakova Tag for-review was removed from gene: IFT27.
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Classified gene: PIGP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Gene: pigp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.200 PIGP Arina Puzriakova Tag for-review tag was added to gene: PIGP.
Intellectual disability v3.483 PIGP Arina Puzriakova Tag for-review tag was added to gene: PIGP.
Intellectual disability v3.483 PIGP Arina Puzriakova Classified gene: PIGP as Amber List (moderate evidence)
Intellectual disability v3.483 PIGP Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.483 PIGP Arina Puzriakova Gene: pigp has been classified as Amber List (Moderate Evidence).
Tubulointerstitial kidney disease v1.11 SEC61A1 Arina Puzriakova Classified gene: SEC61A1 as Amber List (moderate evidence)
Tubulointerstitial kidney disease v1.11 SEC61A1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Tubulointerstitial kidney disease v1.11 SEC61A1 Arina Puzriakova Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.199 PUM1 Arina Puzriakova Tag for-review tag was added to gene: PUM1.
Intellectual disability v3.482 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Intellectual disability v3.482 PUM1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.482 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.481 PUM1 Arina Puzriakova Tag for-review tag was added to gene: PUM1.
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Classified gene: RALGAPA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Gene: ralgapa1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.198 RALGAPA1 Arina Puzriakova Tag for-review tag was added to gene: RALGAPA1.
Intellectual disability v3.481 RALGAPA1 Arina Puzriakova Classified gene: RALGAPA1 as Amber List (moderate evidence)
Intellectual disability v3.481 RALGAPA1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.481 RALGAPA1 Arina Puzriakova Gene: ralgapa1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.480 RALGAPA1 Arina Puzriakova Tag for-review tag was added to gene: RALGAPA1.
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.197 RARS Arina Puzriakova Tag for-review tag was added to gene: RARS.
Intellectual disability v3.480 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Intellectual disability v3.480 RARS Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.480 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.479 RARS Arina Puzriakova Tag for-review tag was added to gene: RARS.
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Tag for-review tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.479 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Intellectual disability v3.479 RNF113A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.479 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.478 RNF113A Arina Puzriakova Tag for-review tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Classified gene: RNF13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.195 RNF13 Arina Puzriakova Tag for-review tag was added to gene: RNF13.
Intellectual disability v3.478 RNF13 Arina Puzriakova Classified gene: RNF13 as Amber List (moderate evidence)
Intellectual disability v3.478 RNF13 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.478 RNF13 Arina Puzriakova Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.477 RNF13 Arina Puzriakova Tag for-review tag was added to gene: RNF13.
Renal tubulopathies v2.24 VPS33B Arina Puzriakova Tag for-review tag was added to gene: VPS33B.
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Classified gene: SERPINI1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Gene: serpini1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.194 SERPINI1 Arina Puzriakova Tag for-review tag was added to gene: SERPINI1.
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Classified gene: SETD1A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Gene: setd1a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.193 SETD1A Arina Puzriakova Tag for-review tag was added to gene: SETD1A.
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Classified gene: SETD1B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Gene: setd1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.192 SETD1B Arina Puzriakova Tag for-review tag was added to gene: SETD1B.
Skeletal dysplasia v2.24 NXN Arina Puzriakova Classified gene: NXN as Amber List (moderate evidence)
Skeletal dysplasia v2.24 NXN Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Skeletal dysplasia v2.24 NXN Arina Puzriakova Gene: nxn has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.23 NXN Arina Puzriakova Tag for-review tag was added to gene: NXN.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 SNORA31 Arina Puzriakova Classified gene: SNORA31 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 SNORA31 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 SNORA31 Arina Puzriakova Gene: snora31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.367 SNORA31 Arina Puzriakova Tag for-review tag was added to gene: SNORA31.
Intellectual disability v3.477 GAD1 Arina Puzriakova Classified gene: GAD1 as Amber List (moderate evidence)
Intellectual disability v3.477 GAD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.477 GAD1 Arina Puzriakova Gene: gad1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.476 GAD1 Arina Puzriakova Tag for-review tag was added to gene: GAD1.
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Classified gene: GAD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Gene: gad1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.191 GAD1 Arina Puzriakova Tag for-review tag was added to gene: GAD1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.367 BCL10 Arina Puzriakova Classified gene: BCL10 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.367 BCL10 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.367 BCL10 Arina Puzriakova Gene: bcl10 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.366 BCL10 Arina Puzriakova Tag for-review tag was added to gene: BCL10.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.366 ZNF341 Arina Puzriakova Classified gene: ZNF341 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.366 ZNF341 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.366 ZNF341 Arina Puzriakova Gene: znf341 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.365 ZNF341 Arina Puzriakova Tag for-review tag was added to gene: ZNF341.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.365 WDR1 Arina Puzriakova Classified gene: WDR1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.365 WDR1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.365 WDR1 Arina Puzriakova Gene: wdr1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.364 WDR1 Arina Puzriakova Tag for-review tag was added to gene: WDR1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.364 USP18 Arina Puzriakova Classified gene: USP18 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.364 USP18 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.364 USP18 Arina Puzriakova Gene: usp18 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.363 USP18 Arina Puzriakova Tag for-review tag was added to gene: USP18.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.363 TRIM22 Arina Puzriakova Classified gene: TRIM22 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.363 TRIM22 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.363 TRIM22 Arina Puzriakova Gene: trim22 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.362 TRIM22 Arina Puzriakova Tag for-review tag was added to gene: TRIM22.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.362 TOP2B Arina Puzriakova Classified gene: TOP2B as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.362 TOP2B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.362 TOP2B Arina Puzriakova Gene: top2b has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.361 TOP2B Arina Puzriakova Tag for-review tag was added to gene: TOP2B.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.361 TNFRSF9 Arina Puzriakova Classified gene: TNFRSF9 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.361 TNFRSF9 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.361 TNFRSF9 Arina Puzriakova Gene: tnfrsf9 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.360 TNFRSF9 Arina Puzriakova Tag for-review tag was added to gene: TNFRSF9.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.360 NFE2L2 Arina Puzriakova Classified gene: NFE2L2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.360 NFE2L2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.360 NFE2L2 Arina Puzriakova Gene: nfe2l2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.359 NFE2L2 Arina Puzriakova Tag for-review tag was added to gene: NFE2L2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.359 SRP54 Arina Puzriakova Classified gene: SRP54 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.359 SRP54 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.359 SRP54 Arina Puzriakova Gene: srp54 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.358 SRP54 Arina Puzriakova Tag for-review tag was added to gene: SRP54.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.358 SMARCD2 Arina Puzriakova Classified gene: SMARCD2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.358 SMARCD2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.358 SMARCD2 Arina Puzriakova Gene: smarcd2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.357 SMARCD2 Arina Puzriakova Tag for-review tag was added to gene: SMARCD2.
Arthrogryposis v3.15 LMX1B Arina Puzriakova Classified gene: LMX1B as Amber List (moderate evidence)
Arthrogryposis v3.15 LMX1B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Arthrogryposis v3.15 LMX1B Arina Puzriakova Gene: lmx1b has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.14 LMX1B Arina Puzriakova Tag for-review tag was added to gene: LMX1B.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.357 RECQL4 Arina Puzriakova Classified gene: RECQL4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.357 RECQL4 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.357 RECQL4 Arina Puzriakova Gene: recql4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.356 RECQL4 Arina Puzriakova Tag for-review tag was added to gene: RECQL4.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.356 SLC39A7 Arina Puzriakova Classified gene: SLC39A7 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.356 SLC39A7 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.356 SLC39A7 Arina Puzriakova Gene: slc39a7 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.355 SLC39A7 Arina Puzriakova Tag for-review tag was added to gene: SLC39A7.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.355 RAC2 Arina Puzriakova Classified gene: RAC2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.355 RAC2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.355 RAC2 Arina Puzriakova Gene: rac2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.354 RAC2 Arina Puzriakova Tag for-review tag was added to gene: RAC2.
Severe microcephaly v2.33 CEP55 Arina Puzriakova Classified gene: CEP55 as Amber List (moderate evidence)
Severe microcephaly v2.33 CEP55 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Severe microcephaly v2.33 CEP55 Arina Puzriakova Gene: cep55 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.32 CEP55 Arina Puzriakova Tag for-review tag was added to gene: CEP55.
Intellectual disability v3.476 CEP55 Arina Puzriakova Classified gene: CEP55 as Amber List (moderate evidence)
Intellectual disability v3.476 CEP55 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.476 CEP55 Arina Puzriakova Gene: cep55 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.475 CEP55 Arina Puzriakova Tag for-review tag was added to gene: CEP55.
Limb disorders v2.16 CEP55 Arina Puzriakova Classified gene: CEP55 as Amber List (moderate evidence)
Limb disorders v2.16 CEP55 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Limb disorders v2.16 CEP55 Arina Puzriakova Gene: cep55 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.15 CEP55 Arina Puzriakova Tag for-review tag was added to gene: CEP55.
Unexplained young onset end-stage renal disease v1.11 VIPAS39 Arina Puzriakova Classified gene: VIPAS39 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v1.11 VIPAS39 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Unexplained young onset end-stage renal disease v1.11 VIPAS39 Arina Puzriakova Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v1.10 VIPAS39 Arina Puzriakova Tag for-review tag was added to gene: VIPAS39.
Nephrocalcinosis or nephrolithiasis v2.16 VIPAS39 Arina Puzriakova Classified gene: VIPAS39 as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.16 VIPAS39 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Nephrocalcinosis or nephrolithiasis v2.16 VIPAS39 Arina Puzriakova Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.15 VIPAS39 Arina Puzriakova Tag for-review tag was added to gene: VIPAS39.
Nephrocalcinosis or nephrolithiasis v2.15 VPS33B Arina Puzriakova Classified gene: VPS33B as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.15 VPS33B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Nephrocalcinosis or nephrolithiasis v2.15 VPS33B Arina Puzriakova Gene: vps33b has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.14 VPS33B Arina Puzriakova Tag for-review tag was added to gene: VPS33B.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.354 SLC7A7 Arina Puzriakova Classified gene: SLC7A7 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.354 SLC7A7 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.354 SLC7A7 Arina Puzriakova Gene: slc7a7 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.353 SLC7A7 Arina Puzriakova Tag for-review tag was added to gene: SLC7A7.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.353 CIB1 Arina Puzriakova Classified gene: CIB1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.353 CIB1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.353 CIB1 Arina Puzriakova Gene: cib1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.352 CIB1 Arina Puzriakova Tag for-review tag was added to gene: CIB1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.352 C17orf62 Arina Puzriakova Classified gene: C17orf62 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.352 C17orf62 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.352 C17orf62 Arina Puzriakova Gene: c17orf62 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.351 C17orf62 Arina Puzriakova Tag for-review tag was added to gene: C17orf62.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.351 ADAM17 Arina Puzriakova Classified gene: ADAM17 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.351 ADAM17 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.351 ADAM17 Arina Puzriakova Gene: adam17 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.350 ADAM17 Arina Puzriakova Tag for-review tag was added to gene: ADAM17.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.350 EFL1 Arina Puzriakova Classified gene: EFL1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.350 EFL1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.350 EFL1 Arina Puzriakova Gene: efl1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.349 EFL1 Arina Puzriakova Tag for-review tag was added to gene: EFL1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.349 DBR1 Arina Puzriakova Classified gene: DBR1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.349 DBR1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.349 DBR1 Arina Puzriakova Gene: dbr1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.348 DBR1 Arina Puzriakova Tag for-review tag was added to gene: DBR1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.348 DNASE1L3 Arina Puzriakova Classified gene: DNASE1L3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.348 DNASE1L3 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.348 DNASE1L3 Arina Puzriakova Gene: dnase1l3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.347 DNASE1L3 Arina Puzriakova Tag for-review tag was added to gene: DNASE1L3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.347 POLE Arina Puzriakova Classified gene: POLE as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.347 POLE Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.347 POLE Arina Puzriakova Gene: pole has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.346 POLE Arina Puzriakova Tag for-review tag was added to gene: POLE.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.346 PAX1 Arina Puzriakova Classified gene: PAX1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.346 PAX1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.346 PAX1 Arina Puzriakova Gene: pax1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.345 PAX1 Arina Puzriakova Tag for-review tag was added to gene: PAX1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.345 LIG1 Arina Puzriakova Classified gene: LIG1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.345 LIG1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.345 LIG1 Arina Puzriakova Gene: lig1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.344 LIG1 Arina Puzriakova Tag for-review tag was added to gene: LIG1.
Intellectual disability v3.475 CTU2 Arina Puzriakova Classified gene: CTU2 as Amber List (moderate evidence)
Intellectual disability v3.475 CTU2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.475 CTU2 Arina Puzriakova Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.474 CTU2 Arina Puzriakova Tag for-review tag was added to gene: CTU2.
Primary ciliary disorders v1.26 GAS2L2 Arina Puzriakova Deleted their review
Primary ciliary disorders v1.26 GAS2L2 Arina Puzriakova Classified gene: GAS2L2 as Green List (high evidence)
Primary ciliary disorders v1.26 GAS2L2 Arina Puzriakova Gene: gas2l2 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.25 GAS2L2 Arina Puzriakova Tag for-review was removed from gene: GAS2L2.
Primary ciliary disorders v1.25 GAS2L2 Arina Puzriakova Classified gene: GAS2L2 as Amber List (moderate evidence)
Primary ciliary disorders v1.25 GAS2L2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary ciliary disorders v1.25 GAS2L2 Arina Puzriakova Gene: gas2l2 has been classified as Amber List (Moderate Evidence).
Primary ciliary disorders v1.24 GAS2L2 Arina Puzriakova Tag for-review tag was added to gene: GAS2L2.
Respiratory ciliopathies including non-CF bronchiectasis v1.8 GAS2L2 Arina Puzriakova Classified gene: GAS2L2 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.8 GAS2L2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Respiratory ciliopathies including non-CF bronchiectasis v1.8 GAS2L2 Arina Puzriakova Gene: gas2l2 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.7 GAS2L2 Arina Puzriakova Tag for-review tag was added to gene: GAS2L2.
Hyperthyroidism v2.7 TTR Arina Puzriakova Classified gene: TTR as Amber List (moderate evidence)
Hyperthyroidism v2.7 TTR Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Hyperthyroidism v2.7 TTR Arina Puzriakova Gene: ttr has been classified as Amber List (Moderate Evidence).
Hyperthyroidism v2.6 TTR Arina Puzriakova Tag for-review tag was added to gene: TTR.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.344 PIK3CG Arina Puzriakova Tag for-review tag was added to gene: PIK3CG.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.344 PIK3CG Arina Puzriakova Classified gene: PIK3CG as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.344 PIK3CG Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.344 PIK3CG Arina Puzriakova Gene: pik3cg has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.43 TANGO2 Arina Puzriakova Classified gene: TANGO2 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v1.43 TANGO2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Rhabdomyolysis and metabolic muscle disorders v1.43 TANGO2 Arina Puzriakova Gene: tango2 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.42 TANGO2 Arina Puzriakova Tag for-review tag was added to gene: TANGO2.
Cardiac arrhythmias - additional genes v1.11 TANGO2 Arina Puzriakova Classified gene: TANGO2 as Amber List (moderate evidence)
Cardiac arrhythmias - additional genes v1.11 TANGO2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Cardiac arrhythmias - additional genes v1.11 TANGO2 Arina Puzriakova Gene: tango2 has been classified as Amber List (Moderate Evidence).
Cardiac arrhythmias - additional genes v1.10 TANGO2 Arina Puzriakova Tag for-review tag was added to gene: TANGO2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.343 CDC42 Arina Puzriakova Classified gene: CDC42 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.343 CDC42 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.343 CDC42 Arina Puzriakova Gene: cdc42 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.342 CDC42 Arina Puzriakova Tag for-review tag was added to gene: CDC42.
Retinal disorders v2.21 DRAM2 Arina Puzriakova Classified gene: DRAM2 as Amber List (moderate evidence)
Retinal disorders v2.21 DRAM2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Retinal disorders v2.21 DRAM2 Arina Puzriakova Gene: dram2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.20 DRAM2 Arina Puzriakova Tag for-review tag was added to gene: DRAM2.
Hypogonadotropic hypogonadism (GMS) v1.10 NDNF Arina Puzriakova Classified gene: NDNF as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v1.10 NDNF Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Hypogonadotropic hypogonadism (GMS) v1.10 NDNF Arina Puzriakova Gene: ndnf has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v1.9 NDNF Arina Puzriakova Tag for-review tag was added to gene: NDNF.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.342 IL6ST Arina Puzriakova Classified gene: IL6ST as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.342 IL6ST Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.342 IL6ST Arina Puzriakova Gene: il6st has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.341 IL6ST Arina Puzriakova Tag for-review tag was added to gene: IL6ST.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.341 FCHO1 Arina Puzriakova Classified gene: FCHO1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.341 FCHO1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.341 FCHO1 Arina Puzriakova Gene: fcho1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.340 FCHO1 Arina Puzriakova Tag for-review tag was added to gene: FCHO1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.340 IL6R Arina Puzriakova Classified gene: IL6R as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.340 IL6R Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.340 IL6R Arina Puzriakova Gene: il6r has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.339 IL6R Arina Puzriakova Tag for-review tag was added to gene: IL6R.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.339 IL2RB Arina Puzriakova Classified gene: IL2RB as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.339 IL2RB Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.339 IL2RB Arina Puzriakova Gene: il2rb has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.338 IL2RB Arina Puzriakova Tag for-review tag was added to gene: IL2RB.
Intellectual disability v3.474 ALG9 Arina Puzriakova Classified gene: ALG9 as Amber List (moderate evidence)
Intellectual disability v3.474 ALG9 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.474 ALG9 Arina Puzriakova Gene: alg9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.473 ALG9 Arina Puzriakova Tag for-review tag was added to gene: ALG9.
Cystic kidney disease v2.19 ALG9 Arina Puzriakova Classified gene: ALG9 as Amber List (moderate evidence)
Cystic kidney disease v2.19 ALG9 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Cystic kidney disease v2.19 ALG9 Arina Puzriakova Gene: alg9 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.18 ALG9 Arina Puzriakova Tag for-review tag was added to gene: ALG9.
Cystic kidney disease v2.18 ALG8 Arina Puzriakova Classified gene: ALG8 as Amber List (moderate evidence)
Cystic kidney disease v2.18 ALG8 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Cystic kidney disease v2.18 ALG8 Arina Puzriakova Gene: alg8 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.17 ALG8 Arina Puzriakova Tag for-review tag was added to gene: ALG8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.338 HAVCR2 Arina Puzriakova Classified gene: HAVCR2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.338 HAVCR2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.338 HAVCR2 Arina Puzriakova Gene: havcr2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.337 HAVCR2 Arina Puzriakova Tag for-review tag was added to gene: HAVCR2.
Intellectual disability v3.473 EXT2 Arina Puzriakova Classified gene: EXT2 as Amber List (moderate evidence)
Intellectual disability v3.473 EXT2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.473 EXT2 Arina Puzriakova Gene: ext2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.472 EXT2 Arina Puzriakova Tag for-review tag was added to gene: EXT2.
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Classified gene: PCYT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Gene: pcyt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.190 PCYT2 Arina Puzriakova Tag for-review tag was added to gene: PCYT2.
Paediatric disorders - additional genes v1.60 ACTG2 Arina Puzriakova Classified gene: ACTG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.60 ACTG2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Paediatric disorders - additional genes v1.60 ACTG2 Arina Puzriakova Gene: actg2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.59 GREB1L Arina Puzriakova Classified gene: GREB1L as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.59 GREB1L Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Paediatric disorders - additional genes v1.59 GREB1L Arina Puzriakova Gene: greb1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.472 PTRHD1 Arina Puzriakova Classified gene: PTRHD1 as Amber List (moderate evidence)
Intellectual disability v3.472 PTRHD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.472 PTRHD1 Arina Puzriakova Gene: ptrhd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.471 PTRHD1 Arina Puzriakova Tag for-review tag was added to gene: PTRHD1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.337 OAS1 Arina Puzriakova Classified gene: OAS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.337 OAS1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.337 OAS1 Arina Puzriakova Gene: oas1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.336 OAS1 Arina Puzriakova Tag for-review tag was added to gene: OAS1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.10 SOX6 Arina Puzriakova Classified gene: SOX6 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.10 SOX6 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.10 SOX6 Arina Puzriakova Gene: sox6 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SOX6 Arina Puzriakova Tag for-review tag was added to gene: SOX6.
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Classified gene: ANKRD11 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Gene: ankrd11 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.189 ANKRD11 Arina Puzriakova Tag for-review tag was added to gene: ANKRD11.
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.188 UGP2 Arina Puzriakova Tag for-review tag was added to gene: UGP2.
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Classified gene: TRAPPC4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Gene: trappc4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.187 TRAPPC4 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC4.
Intellectual disability v3.471 TRAPPC4 Arina Puzriakova Classified gene: TRAPPC4 as Amber List (moderate evidence)
Intellectual disability v3.471 TRAPPC4 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.471 TRAPPC4 Arina Puzriakova Gene: trappc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.470 TRAPPC4 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC4.
Intellectual disability v3.470 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Intellectual disability v3.470 UGP2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.470 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.469 CXorf56 Arina Puzriakova Classified gene: CXorf56 as Amber List (moderate evidence)
Intellectual disability v3.469 CXorf56 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.469 CXorf56 Arina Puzriakova Gene: cxorf56 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.468 KAT8 Arina Puzriakova Classified gene: KAT8 as Amber List (moderate evidence)
Intellectual disability v3.468 KAT8 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.468 KAT8 Arina Puzriakova Gene: kat8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Classified gene: KAT8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Gene: kat8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Classified gene: SEMA6B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Gene: sema6b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.185 SETD5 Arina Puzriakova Classified gene: SETD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.185 SETD5 Arina Puzriakova Gene: setd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Classified gene: SETD5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Gene: setd5 has been classified as Green List (High Evidence).
Intellectual disability v3.467 SLC5A6 Arina Puzriakova Classified gene: SLC5A6 as Amber List (moderate evidence)
Intellectual disability v3.467 SLC5A6 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.467 SLC5A6 Arina Puzriakova Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.24 SLC5A6 Arina Puzriakova Classified gene: SLC5A6 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.24 SLC5A6 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Likely inborn error of metabolism v2.24 SLC5A6 Arina Puzriakova Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.466 SNX27 Arina Puzriakova Classified gene: SNX27 as Amber List (moderate evidence)
Intellectual disability v3.466 SNX27 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.466 SNX27 Arina Puzriakova Gene: snx27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Classified gene: SNX27 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Gene: snx27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.32 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Severe microcephaly v2.32 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Severe microcephaly v2.32 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.14 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Malformations of cortical development v2.14 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Malformations of cortical development v2.14 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.336 CD247 Arina Puzriakova Classified gene: CD247 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.336 CD247 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.336 CD247 Arina Puzriakova Gene: cd247 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.335 CD247 Arina Puzriakova Tag for-review tag was added to gene: CD247.
Intellectual disability v3.465 UGP2 Arina Puzriakova Tag for-review tag was added to gene: UGP2.
Intellectual disability v3.465 CXorf56 Arina Puzriakova Tag for-review tag was added to gene: CXorf56.
Early onset or syndromic epilepsy v2.181 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Early onset or syndromic epilepsy v2.181 KAT8 Arina Puzriakova Tag for-review tag was added to gene: KAT8.
Intellectual disability v3.465 KAT8 Arina Puzriakova Tag for-review tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.181 SEMA6B Arina Puzriakova Tag for-review tag was added to gene: SEMA6B.
Early onset or syndromic epilepsy v2.181 SETD5 Arina Puzriakova Tag for-review tag was added to gene: SETD5.
Intellectual disability v3.465 SLC5A6 Arina Puzriakova Tag for-review tag was added to gene: SLC5A6.
Likely inborn error of metabolism v2.23 SLC5A6 Arina Puzriakova Tag for-review tag was added to gene: SLC5A6.
Intellectual disability v3.465 SNX27 Arina Puzriakova Tag for-review tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.181 SNX27 Arina Puzriakova Tag for-review tag was added to gene: SNX27.
Intellectual disability v3.465 WNT1 Arina Puzriakova Classified gene: WNT1 as Amber List (moderate evidence)
Intellectual disability v3.465 WNT1 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.465 WNT1 Arina Puzriakova Gene: wnt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.464 WNT1 Arina Puzriakova Tag for-review tag was added to gene: WNT1.
Malformations of cortical development v2.13 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Severe microcephaly v2.31 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Intellectual disability v3.464 PIGK Arina Puzriakova Classified gene: PIGK as Amber List (moderate evidence)
Intellectual disability v3.464 PIGK Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.464 PIGK Arina Puzriakova Gene: pigk has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.463 PIGK Arina Puzriakova Tag for-review tag was added to gene: PIGK.
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Classified gene: PIGK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Gene: pigk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.180 PIGK Arina Puzriakova Tag for-review tag was added to gene: PIGK.
Intellectual disability v3.463 HSPG2 Ivone Leong Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800; Dyssegmental dysplasia, Silverman-Handmaker type, 224410 to Schwartz-Jampel syndrome, type 1, 255800
Fetal anomalies v1.107 TMEM94 Arina Puzriakova Deleted their review
Fetal anomalies v1.107 TMEM94 Arina Puzriakova Deleted their comment
Fetal anomalies v1.107 TMEM94 Arina Puzriakova Tag for-review was removed from gene: TMEM94.
Fetal anomalies v1.107 TMEM94 Arina Puzriakova Classified gene: TMEM94 as Green List (high evidence)
Fetal anomalies v1.107 TMEM94 Arina Puzriakova Gene: tmem94 has been classified as Green List (High Evidence).
Fetal anomalies v1.106 TMEM94 Arina Puzriakova Classified gene: TMEM94 as Amber List (moderate evidence)
Fetal anomalies v1.106 TMEM94 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.106 TMEM94 Arina Puzriakova Gene: tmem94 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.105 TMEM94 Arina Puzriakova Tag for-review tag was added to gene: TMEM94.
Haematological malignancies cancer susceptibility v2.5 TSR2 Arina Puzriakova changed review comment from: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red.; to: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined. This indicates that there is NOT sufficient evidence for a Green rating and this gene should be downgraded to Amber/Red - will be flagged for review at the next GMS panel update (added 'for-review' tag)
Haematological malignancies cancer susceptibility v2.5 TSR2 Arina Puzriakova Tag for-review tag was added to gene: TSR2.
Cytopenia - NOT Fanconi anaemia v1.30 RPL9 Arina Puzriakova changed review comment from: Comment on list classification: Current Green rating is based on consensus from GLHs, so will remain Green. However, the 'for-review' tag has been added in view of the recent Red review by Zornitza Stark on this Green gene. ; to: Comment on list classification: Current Green rating is based on consensus from GLHs, so will remain Green. Excluding the VUS, only two unrelated cases published with the same variant, but including functional data. The 'for-review' tag has been added in view of this evidence and recent Red review by Zornitza Stark on a Green gene.
Cytopenia - NOT Fanconi anaemia v1.30 RPL9 Arina Puzriakova Tag for-review tag was added to gene: RPL9.
Cytopenia - NOT Fanconi anaemia v1.30 RPL9 Arina Puzriakova changed review comment from: Comment on list classification: Current Green rating is based on consensus from GLHs, so will remain Green.; to: Comment on list classification: Current Green rating is based on consensus from GLHs, so will remain Green. However, the 'for-review' tag has been added in view of the recent Red review by Zornitza Stark on this Green gene.
Unexplained kidney failure in young people v1.92 VIPAS39 Arina Puzriakova Tag for-review was removed from gene: VIPAS39.
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Classified gene: TIMM50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Gene: timm50 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.96 SLC52A3 Arina Puzriakova Classified gene: SLC52A3 as Amber List (moderate evidence)
Monogenic hearing loss v2.96 SLC52A3 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Monogenic hearing loss v2.96 SLC52A3 Arina Puzriakova Gene: slc52a3 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.95 SLC52A2 Arina Puzriakova Classified gene: SLC52A2 as Amber List (moderate evidence)
Monogenic hearing loss v2.95 SLC52A2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Monogenic hearing loss v2.95 SLC52A2 Arina Puzriakova Gene: slc52a2 has been classified as Amber List (Moderate Evidence).
Unexplained kidney failure in young people v1.92 SARS2 Arina Puzriakova Classified gene: SARS2 as Green List (high evidence)
Unexplained kidney failure in young people v1.92 SARS2 Arina Puzriakova Gene: sars2 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.91 SARS2 Arina Puzriakova Tag for-review was removed from gene: SARS2.
Hereditary spastic paraplegia, childhood onset v2.19 PCYT2 Arina Puzriakova changed review comment from: Comment on list classification: The rating of this gene should be reviewed at the next GMS panel update. Based on the review by Rebecca Foulger, there is sufficient evidence to rate this gene Green.; to: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Hereditary spastic paraplegia, adult onset v1.13 PCYT2 Arina Puzriakova changed review comment from: Comment on list classification: The rating of this gene should be reviewed at the next GMS panel update. Based on the review by Rebecca Foulger, there is sufficient evidence to rate this gene Green.; to: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Hereditary systemic amyloidosis v1.8 NLRP3 Arina Puzriakova Classified gene: NLRP3 as Amber List (moderate evidence)
Hereditary systemic amyloidosis v1.8 NLRP3 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Hereditary systemic amyloidosis v1.8 NLRP3 Arina Puzriakova Gene: nlrp3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.462 KDM3B Ivone Leong commented on gene: KDM3B
Intellectual disability v3.462 KCNMA1 Ivone Leong Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911
Intellectual disability v3.461 KCNK4 Ivone Leong Tag watchlist tag was added to gene: KCNK4.
Intellectual disability v3.461 KCNK4 Ivone Leong commented on gene: KCNK4: As the 2 unrelated patients who have the same de novo variants have severe ID/DD and 3rd patient has low average ID, this gene will be kept as Amber until further evidence is available. Watchlist tag has been added as well.
Intellectual disability v3.461 IQSEC1 Ivone Leong Tag watchlist tag was added to gene: IQSEC1.
Osteogenesis imperfecta v2.7 MESD Arina Puzriakova Classified gene: MESD as Amber List (moderate evidence)
Osteogenesis imperfecta v2.7 MESD Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Osteogenesis imperfecta v2.7 MESD Arina Puzriakova Gene: mesd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.179 LMBRD2 Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber but there is a sufficient number of unrelated cases with the relevant phenotype to rate this gene GREEN at the next major review.
Intellectual disability v3.461 LMBRD2 Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber but there is a sufficient number of unrelated cases with the relevant phenotype to rate this gene GREEN at the next major review.
Limb disorders v2.15 KYNU Arina Puzriakova Classified gene: KYNU as Amber List (moderate evidence)
Limb disorders v2.15 KYNU Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Limb disorders v2.15 KYNU Arina Puzriakova Gene: kynu has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.461 KCNK4 Ivone Leong Phenotypes for gene: KCNK4 were changed from Neurodevelopmental delay; Intellectual disability; Seizures; Gingival overgrowth; Hypertrichosis to Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome, 618381
Intellectual disability v3.460 IQSEC1 Ivone Leong commented on gene: IQSEC1
Renal ciliopathies v1.30 IFT172 Arina Puzriakova Classified gene: IFT172 as Amber List (moderate evidence)
Renal ciliopathies v1.30 IFT172 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Renal ciliopathies v1.30 IFT172 Arina Puzriakova Gene: ift172 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.29 IFT140 Arina Puzriakova Classified gene: IFT140 as Amber List (moderate evidence)
Renal ciliopathies v1.29 IFT140 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Renal ciliopathies v1.29 IFT140 Arina Puzriakova Gene: ift140 has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.14 HNF4A Arina Puzriakova Classified gene: HNF4A as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.14 HNF4A Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Nephrocalcinosis or nephrolithiasis v2.14 HNF4A Arina Puzriakova Gene: hnf4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.460 IQSEC1 Ivone Leong Phenotypes for gene: IQSEC1 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature; Intellectual developmental disorder with short stature and behavioral abnormalities, 618687
Paediatric disorders - additional genes v1.58 GATA3 Arina Puzriakova Classified gene: GATA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.58 GATA3 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Paediatric disorders - additional genes v1.58 GATA3 Arina Puzriakova Gene: gata3 has been classified as Amber List (Moderate Evidence).
Inherited white matter disorders v1.82 GALNT2 Arina Puzriakova Tag for-review was removed from gene: GALNT2.
Tubulointerstitial kidney disease v1.10 DNAJB11 Arina Puzriakova Classified gene: DNAJB11 as Amber List (moderate evidence)
Tubulointerstitial kidney disease v1.10 DNAJB11 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Tubulointerstitial kidney disease v1.10 DNAJB11 Arina Puzriakova Gene: dnajb11 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.57 CHRNA3 Arina Puzriakova Classified gene: CHRNA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.57 CHRNA3 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Paediatric disorders - additional genes v1.57 CHRNA3 Arina Puzriakova Gene: chrna3 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v1.6 BLOC1S6 Arina Puzriakova Classified gene: BLOC1S6 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.6 BLOC1S6 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Albinism or congenital nystagmus v1.6 BLOC1S6 Arina Puzriakova Gene: bloc1s6 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.56 ANOS1 Arina Puzriakova Classified gene: ANOS1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.56 ANOS1 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Paediatric disorders - additional genes v1.56 ANOS1 Arina Puzriakova Gene: anos1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.459 ALG14 Arina Puzriakova Classified gene: ALG14 as Amber List (moderate evidence)
Intellectual disability v3.459 ALG14 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Intellectual disability v3.459 ALG14 Arina Puzriakova Gene: alg14 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.425 ALG14 Arina Puzriakova Classified gene: ALG14 as Green List (high evidence)
Undiagnosed metabolic disorders v1.425 ALG14 Arina Puzriakova Gene: alg14 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.424 ALG14 Arina Puzriakova Tag for-review was removed from gene: ALG14.
Undiagnosed metabolic disorders v1.424 AHCY Arina Puzriakova Classified gene: AHCY as Green List (high evidence)
Undiagnosed metabolic disorders v1.424 AHCY Arina Puzriakova Added comment: Comment on list classification: Promoted from Red to Green - multiple unrelated families with this neurometabolic disorder caused by biallelic variants in AHCY.
Undiagnosed metabolic disorders v1.424 AHCY Arina Puzriakova Gene: ahcy has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.423 AHCY Arina Puzriakova Tag for-review was removed from gene: AHCY.
Undiagnosed metabolic disorders v1.423 AHCY Arina Puzriakova Deleted their comment
Early onset or syndromic epilepsy v2.179 UBE3A Sarah Leigh Phenotypes for gene: UBE3A were changed from Angelman syndrome to Angelman syndrome 105830
Skeletal dysplasia v2.23 XYLT1 Arina Puzriakova Phenotypes for gene: XYLT1 were changed from Desbuquois dysplasia 2 615777; Desbuquois dysplasia 2 615777 to Desbuquois dysplasia 2, 615777
Likely inborn error of metabolism v2.23 XYLT1 Arina Puzriakova Phenotypes for gene: XYLT1 were changed from Desbuquois dysplasia 2 to Desbuquois dysplasia 2, 615777
Severe microcephaly v2.31 UBE3A Sarah Leigh Phenotypes for gene: UBE3A were changed from Angelman syndrome MIM#105830 to Angelman syndrome 105830
Severe microcephaly v2.30 UBE3A Sarah Leigh Publications for gene: UBE3A were set to
Undiagnosed metabolic disorders v1.423 XYLT1 Arina Puzriakova Phenotypes for gene: XYLT1 were changed from Desbuquois dysplasia 2 to Desbuquois dysplasia 2, 615777
Severe microcephaly v2.29 UBE3A Sarah Leigh Classified gene: UBE3A as Amber List (moderate evidence)
Severe microcephaly v2.29 UBE3A Sarah Leigh Gene: ube3a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.28 UBE3A Sarah Leigh Tag for-review tag was added to gene: UBE3A.
Intellectual disability v3.458 XYLT1 Arina Puzriakova Publications for gene: XYLT1 were set to
Severe microcephaly v2.28 UBE3A Sarah Leigh edited their review of gene: UBE3A: Added comment: Postnatal microcephaly has been reported in Angelman syndrome patients, mostly amonst those with deletions rather than UPD of 15q.; Changed rating: AMBER; Changed publications: 2012134, 9182785, 10861661, 10861661; Changed phenotypes: Angelman syndrome 105830; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Intellectual disability v3.457 XYLT1 Arina Puzriakova Phenotypes for gene: XYLT1 were changed from {Pseudoxanthoma elasticum, modifier of severity of}, 264800; Desbuquois dysplasia 2, 615777 to Desbuquois dysplasia 2, 615777
Intellectual disability v3.456 XYLT1 Arina Puzriakova reviewed gene: XYLT1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Desbuquois dysplasia 2, 615777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.28 UBE3A Sarah Leigh Added comment: Comment on mode of inheritance: In accordance with http://igc.otago.ac.nz/home.html
Severe microcephaly v2.28 UBE3A Sarah Leigh Mode of inheritance for gene: UBE3A was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Intellectual disability v3.456 XYLT1 Arina Puzriakova Tag for-review tag was added to gene: XYLT1.
Paediatric or syndromic cardiomyopathy v1.9 PDLIM3 Zornitza Stark changed review comment from: PMID: 30681346 assessed as LIMITED by ClinGen working group.

PMID: 26455666; 1x proband with multi-exon deletion PMID: 20801532; 1x proband het for a missense; to: PMID: 30681346 assessed as LIMITED by ClinGen working group. Note gene is rated RED on multiple other panels.

PMID: 26455666; 1x proband with multi-exon deletion PMID: 20801532; 1x proband het for a missense
Paediatric or syndromic cardiomyopathy v1.9 PDLIM3 Zornitza Stark reviewed gene: PDLIM3: Rating: RED; Mode of pathogenicity: None; Publications: 30681346, 26455666, 20801532; Phenotypes: Hypertrophic cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.456 CSNK1G1 Konstantinos Varvagiannis reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33009664; Phenotypes: Global developmental delay, Intellectual disability, Autism, Seizures, Abnormality of the face, Abnormality of limbs; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.27 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB2 were set to Complete
Mode of pathogenicity for gene: LMNB2 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: LMNB2 was set to GREEN
Added comment: Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) apart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occurred at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Severe microcephaly v2.27 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 33033404
Phenotypes for gene: LMNB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB1 were set to Complete
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to GREEN
Added comment: Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) apart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occurred at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability v3.456 LMNB2 Konstantinos Varvagiannis gene: LMNB2 was added
gene: LMNB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Congenital microcephaly; Global developmental delay; Intellectual disability
Penetrance for gene: LMNB2 were set to Complete
Mode of pathogenicity for gene: LMNB2 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: LMNB2 was set to GREEN
Added comment: Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) apart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occurred at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]
Sources: Literature
Intellectual disability v3.456 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: Added comment: There is an additional report on LMBN1/2-associated phenotypes supporting green rating of the gene in the current panel.

Parry et al (2020 - PMID: 33033404) in a study to identify novel microcephaly genes using the DDD and 100k genomes project (100kGP) patient cohort, report on the phenotype of 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6).

LMNB1 : The authors identified 3 recurrent variants (c.97A>G - p.Lys33Glu (3), c.97_99del - p.Lys33del (2) , c.269G>C - p.Arg90Pro (2) / NM_005573.4) in seven individuals (3 from the DDD study, 4 from the 100kGP). In all cases were segregation studies were possible, the variant had occurred as a de novo event.

LMNB2 : 4 individuals from the DDD cohort and 1 from the 100kGP were found to harbor the same missense SNV (NM_032737.4:c.1192G>A, p.Glu398Lys). The variant had occurred de novo in 3 subjects and was inherited from a mosaic - unaffected - parent in a further case. Another individual was found to harbor c.160A>C - p.Asn54His.

LMNB1/2 common phenotypes :
All cases had congenital microcephaly (OFC -5.85 +/- 1.14 SD) appart from one individual, without history of IUGR or postnatally abnormal height (the latter in most).

Neuroimaging suggested structurally normal brain without abnormal migration. Gyral simplification / global reduction in white matter / increased extra axial spaces / enlarged ventricles were reported in 2.

LMNB1 - Global developmental delay was a feature in all (mild to severe) with some having occasional words at 7y (P3), absent speech (P9 - age category 5-10y) or ID not further specified (P13).

LMNB2 - DD was a feature in all 6 subjects (5/6 moderate to severe - 1/6 GDD). 5/6 were 10y or older with language (in 3 language not achieved) and motor deficits (walking not achieved in 1/6 - occured at the age of 6y in 1/6).

Facial features were not consistent nor suggestive of a syndromic diagnosis (sloping forehead in some).

Overall, as the authors comment, the phenotype corresponded to a severe nonsyndromic microcephaly (although additional features were reported in some).

Animal model:
Microcephaly is supported by Lmnb1 ko mouse model. Lmnb1/2 ko mice however display migration defects, while Lmnb2 ko mice do not have reduced size at birth. Heterozygous Lmnb1 mice do not present microcephaly. It is suggested that while animal models support a similar (to the human) phenotype the underlying mechanism is different.

Variant effect :
variants were shown to affect highly conserved residues within the lamin a-helical rod-domain. As affected residues are conserved in LMNA, modelling with available LMNA PDB structures, suggested disrupted interactions required for higher-order assembly of lamin filaments.

Recurrence of specific variants at specific residues, absence of pLoF ones, the htz mouse Lmnb1 phenotype (absence of microcephaly) and the proposed mechanism (perturbation of complex formation) suggest a gain-of-function/dominant-negative effect rather than happloinsufficiency.

[Please also note the additional OMIM phenotypes for LMNB1 / LMNB2 - not here reviewed]; Changed publications: 32910914, 33033404
Intellectual disability v3.456 CNPY3 Arina Puzriakova Classified gene: CNPY3 as Amber List (moderate evidence)
Intellectual disability v3.456 CNPY3 Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed by Konstantinos Varvagiannis. Although there are sufficient cases to support a gene-disease association, this disorder is mainly characterised by severe epileptic encephalopathy and ID manifests secondarily to seizures.

Rating Amber, but this may be reviewed if new evidence emerges indicating that neurodevelopmental impairment precedes onset of seizures.
Intellectual disability v3.456 CNPY3 Arina Puzriakova Gene: cnpy3 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.24 Arina Puzriakova Panel version has been signed off
Renal tubulopathies v2.22 SLC2A2 Arina Puzriakova Classified gene: SLC2A2 as Amber List (moderate evidence)
Renal tubulopathies v2.22 SLC2A2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version, will be examined at next panel review.
Renal tubulopathies v2.22 SLC2A2 Arina Puzriakova Gene: slc2a2 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.21 SLC5A2 Ivone Leong Tag for-review tag was added to gene: SLC5A2.
Intellectual disability v3.455 HSPG2 Ivone Leong Publications for gene: HSPG2 were set to
Renal tubulopathies v2.21 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Renal tubulopathies v2.20 VIPAS39 Catherine Snow Tag for-review tag was added to gene: VIPAS39.
Renal tubulopathies v2.20 VPS33B Catherine Snow Classified gene: VPS33B as Amber List (moderate evidence)
Renal tubulopathies v2.20 VPS33B Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Renal tubulopathies v2.20 VPS33B Catherine Snow Gene: vps33b has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.19 VIPAS39 Catherine Snow Classified gene: VIPAS39 as Amber List (moderate evidence)
Renal tubulopathies v2.19 VIPAS39 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Renal tubulopathies v2.19 VIPAS39 Catherine Snow Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.18 SLC5A2 Catherine Snow Classified gene: SLC5A2 as Amber List (moderate evidence)
Renal tubulopathies v2.18 SLC5A2 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Renal tubulopathies v2.18 SLC5A2 Catherine Snow Gene: slc5a2 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.17 HNF4A Catherine Snow Classified gene: HNF4A as Amber List (moderate evidence)
Renal tubulopathies v2.17 HNF4A Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Renal tubulopathies v2.17 HNF4A Catherine Snow Gene: hnf4a has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v2.16 CLDN10 Catherine Snow Classified gene: CLDN10 as Amber List (moderate evidence)
Renal tubulopathies v2.16 CLDN10 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Renal tubulopathies v2.16 CLDN10 Catherine Snow Gene: cldn10 has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.14 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Hypogonadotropic hypogonadism (GMS) v1.9 TCF12 Ivone Leong Phenotypes for gene: TCF12 were changed from Craniosynostosis 3, MIM# 615314; Kallman syndrome to Craniosynostosis 3, 615314; Kallman syndrome
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFI Catherine Snow Tag for-review tag was added to gene: CFI.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFB Catherine Snow Classified gene: CFB as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFB Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.13 CFB Catherine Snow Gene: cfb has been classified as Green List (High Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.12 CFI Catherine Snow Classified gene: CFI as Green List (high evidence)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.12 CFI Catherine Snow Added comment: Comment on list classification: Changed rating to Green to reflect NHS signed-off rating, will be examined at next panel review.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.12 CFI Catherine Snow Gene: cfi has been classified as Green List (High Evidence).
Proteinuric renal disease v2.33 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Proteinuric renal disease v2.32 TPRKB Catherine Snow Classified gene: TPRKB as Amber List (moderate evidence)
Proteinuric renal disease v2.32 TPRKB Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Proteinuric renal disease v2.32 TPRKB Catherine Snow Gene: tprkb has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.31 FN1 Catherine Snow Classified gene: FN1 as Amber List (moderate evidence)
Proteinuric renal disease v2.31 FN1 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Proteinuric renal disease v2.31 FN1 Catherine Snow Gene: fn1 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.30 DGKE Catherine Snow Classified gene: DGKE as Amber List (moderate evidence)
Proteinuric renal disease v2.30 DGKE Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Proteinuric renal disease v2.30 DGKE Catherine Snow Gene: dgke has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.29 CD151 Catherine Snow Classified gene: CD151 as Amber List (moderate evidence)
Proteinuric renal disease v2.29 CD151 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Proteinuric renal disease v2.29 CD151 Catherine Snow Gene: cd151 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.28 APOE Catherine Snow Classified gene: APOE as Amber List (moderate evidence)
Proteinuric renal disease v2.28 APOE Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Proteinuric renal disease v2.28 APOE Catherine Snow Gene: apoe has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.27 AMN Catherine Snow Classified gene: AMN as Amber List (moderate evidence)
Proteinuric renal disease v2.27 AMN Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.
Proteinuric renal disease v2.27 AMN Catherine Snow Gene: amn has been classified as Amber List (Moderate Evidence).
Fanconi anaemia or Bloom syndrome v1.8 Catherine Snow List of related panels changed from R229 to R229; R258
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Cytopenia - NOT Fanconi anaemia v1.30 Catherine Snow List of related panels changed from R91; R258 to R91
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Cytopenia - NOT Fanconi anaemia v1.29 EFL1 Catherine Snow Classified gene: EFL1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.29 EFL1 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be reviewed at next major review.
Cytopenia - NOT Fanconi anaemia v1.29 EFL1 Catherine Snow Gene: efl1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.28 EFL1 Catherine Snow Tag for-review tag was added to gene: EFL1.
Palmoplantar keratodermas v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Epidermolysis bullosa and congenital skin fragility v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Ichthyosis and erythrokeratoderma v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Mosaic skin disorders - Deep sequencing v1.4 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
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Vascular skin disorders v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Epidermodysplasia verruciformis v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Cutaneous photosensitivity with a likely genetic cause v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Multiple monogenic benign skin tumours v1.4 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
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Pigmentary skin disorders v1.5 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Rare genetic inflammatory skin disorders v1.7 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Ectodermal dysplasia v1.11 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Endocrine neoplasia v1.4 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
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Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.8 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Autosomal recessive primary hypertrophic osteoarthropathy v1.5 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
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Autosomal recessive primary hypertrophic osteoarthropathy v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
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Laterality disorders and isomerism v1.20 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Haematuria v2.5 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Leukodystrophy, adult onset v1.7 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Hereditary spastic paraplegia, adult onset v1.13 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Dystonia, chorea or related movement disorder, adult onset v1.15 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Possible mitochondrial disorder, nuclear genes v1.17 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Neuronal ceroid lipofuscinosis v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Familial Chylomicronaemia Syndrome v1.4 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Non-acute porphyrias v1.5 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Sporadic aniridia v2.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Fanconi anaemia or Bloom syndrome v1.7 Catherine Snow Panel version has been signed off
Fanconi anaemia or Bloom syndrome v1.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Sudden unexplained death or survivors of a cardiac event v9.84 Catherine Snow Panel version has been signed off
Arrhythmogenic right ventricular cardiomyopathy v2.11 Catherine Snow Panel version has been signed off
Arrhythmogenic right ventricular cardiomyopathy v2.10 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
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Early onset or syndromic epilepsy v2.178 USP7 Arina Puzriakova Publications for gene: USP7 were set to 26365382; 19946331
Intellectual disability v3.454 USP7 Arina Puzriakova Publications for gene: USP7 were set to 30679821; 26365382; 19946331
Early onset or syndromic epilepsy v2.177 USP7 Arina Puzriakova Phenotypes for gene: USP7 were changed from Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism to Hao-Fountain syndrome, 616863
Intellectual disability v3.453 USP7 Arina Puzriakova Phenotypes for gene: USP7 were changed from Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism to Hao-Fountain syndrome, 616863
Intellectual disability v3.452 USP7 Arina Puzriakova Classified gene: USP7 as Amber List (moderate evidence)
Intellectual disability v3.452 USP7 Arina Puzriakova Added comment: Comment on list classification: Based on published evidence and expert reviews, this gene should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.452 USP7 Arina Puzriakova Gene: usp7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.451 USP7 Arina Puzriakova Tag for-review tag was added to gene: USP7.
Intellectual disability v3.451 USP7 Arina Puzriakova reviewed gene: USP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365382, 30679821, 33012787; Phenotypes: Hao-Fountain syndrome, 616863; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated and arrhythmogenic cardiomyopathy v1.7 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
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Hypertrophic cardiomyopathy v2.12 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
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Congenital disorders of glycosylation v2.18 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from ?Congenital disorder of glycosylation, type Iw 615596 to Congenital disorder of glycosylation, type Iw, 615596
Congenital disorders of glycosylation v2.17 STT3A Arina Puzriakova Publications for gene: STT3A were set to 23842455
Congenital disorders of glycosylation v2.16 STT3A Arina Puzriakova Classified gene: STT3A as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.16 STT3A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association, and so STT3A should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).

At least 7 individuals from 3 unrelated families reported in literature, with 2 different homozygous variants in STT3A, as well as an additional case indicated by expert reviewer.
Congenital disorders of glycosylation v2.16 STT3A Arina Puzriakova Gene: stt3a has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v2.15 STT3A Arina Puzriakova Tag for-review tag was added to gene: STT3A.
Intellectual disability v3.451 STT3A Arina Puzriakova Classified gene: STT3A as Amber List (moderate evidence)
Intellectual disability v3.451 STT3A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association, and so STT3A should be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).

ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A)
Intellectual disability v3.451 STT3A Arina Puzriakova Gene: stt3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.450 STT3A Arina Puzriakova commented on gene: STT3A
Intellectual disability v3.450 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from ?Congenital disorder of glycosylation, type Iw, 615596; developmental delay; intellectual disability to Congenital disorder of glycosylation, type Iw, 615596
Intellectual disability v3.449 STT3A Arina Puzriakova Publications for gene: STT3A were set to 28424003; 23842455
Intellectual disability v3.448 STT3A Arina Puzriakova Tag watchlist was removed from gene: STT3A.
Tag for-review tag was added to gene: STT3A.
Intellectual disability v3.448 CARS2 Arina Puzriakova changed review comment from: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Inborn errors of metabolism (v2.2) panel, a component the Epilepsy super panel, which should be a sufficient route for detecting these cases.; to: Comment on list classification: Kept rating Amber as developmental regression and progressive cognitive decline appear secondary to seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on Inborn errors of metabolism (v2.3) and has been added to the Genetic epilepsy syndromes (v2.176) panel, which should be sufficient routes for detecting these cases.
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association. This gene has been added with an Amber rating but should be promoted to Green at the GMS panel update (added 'for-review' tag).

Note this is a metabolic gene and is already Green on the Inborn errors of metabolism (v2.3) panel.
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.175 CARS2 Arina Puzriakova gene: CARS2 was added
gene: CARS2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CARS2.
Mode of inheritance for gene: CARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARS2 were set to 25361775; 25787132; 30139652; 32571458; 32348839
Phenotypes for gene: CARS2 were set to Combined oxidative phosphorylation deficiency 27, 616672
Review for gene: CARS2 was set to GREEN
Added comment: Associated with phenotype in OMIM and as a probable gene for Epileptic encephalopathy with complex movement disorder and regression in Gen2Phen.

At least 6 individuals from 5 unrelated families, all with different biallelic variants in CARS2 and a neurodegenerative disorder which includes early-onset seizures.
Sources: Literature
Early onset or syndromic epilepsy v2.174 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393; 29156220
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Classified gene: TRPM3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the next GMS panel update, in view of recently published functional data and expert reviews.
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.172 TRPM3 Arina Puzriakova reviewed gene: TRPM3: Rating: ; 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: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.448 TRPM3 Arina Puzriakova Classified gene: TRPM3 as Amber List (moderate evidence)
Intellectual disability v3.448 TRPM3 Arina Puzriakova Added comment: Comment on list classification: Excluding the individual harbouring a VUS, 8 unrelated individuals with ID and the same p.Val837Met variant have been reported (PMID:31278393, 32439617). Also now available is functional data demonstrating variants render the channel overactive.

With addition of the recent publications, there is enough evidence to support a Green rating on this panel. Therefore added 'for-review' tag, for reassessment at next GMS panel update.