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Primary immunodeficiency 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 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 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
Hearing loss v2.129 PMP22 Eleanor Williams Classified gene: PMP22 as Amber List (moderate evidence)
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.
Hearing loss v2.129 PMP22 Eleanor Williams Gene: pmp22 has been classified as Amber List (Moderate Evidence).
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
Hearing loss v2.127 PMP22 Eleanor Williams Publications for gene: PMP22 were set to
Hearing loss v2.126 PMP22 Eleanor Williams Mode of inheritance for gene: PMP22 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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.
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.
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
Hearing loss v2.124 COCH Eleanor Williams edited their review of gene: COCH: Changed publications: 29449721, 31126177, 32562050, 32939038
Hearing loss v2.124 COCH Eleanor Williams edited their review of gene: COCH: Changed publications: 31126177
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
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
Hearing loss v2.122 COCH Eleanor Williams Tag for-review tag was added to gene: COCH.
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
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
Hearing loss v2.121 THOC1 Eleanor Williams Classified gene: THOC1 as Amber List (moderate evidence)
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.
Hearing loss v2.121 THOC1 Eleanor Williams Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.120 LMX1A Eleanor Williams Tag watchlist tag was added to gene: LMX1A.
Tag for-review tag was added to gene: LMX1A.
Hearing loss v2.120 LMX1A Eleanor Williams Classified gene: LMX1A as Amber List (moderate evidence)
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.
Hearing loss v2.120 LMX1A Eleanor Williams Gene: lmx1a has been classified as Amber List (Moderate Evidence).
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.
Hearing loss v2.119 LMX1A Eleanor Williams Mode of inheritance for gene: LMX1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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
Hearing loss v2.117 LMX1A Eleanor Williams Publications for gene: LMX1A were set to
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
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.
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.
Hearing loss v2.116 NARS2 Eleanor Williams Tag for-review tag was added to gene: NARS2.
Hearing loss v2.116 NARS2 Eleanor Williams Classified gene: NARS2 as Amber List (moderate evidence)
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.
Hearing loss v2.116 NARS2 Eleanor Williams Gene: nars2 has been classified as Amber List (Moderate Evidence).
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.
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
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.
Severe Paediatric Disorders v1.20 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
Severe Paediatric Disorders v1.20 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 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 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 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 v2.378 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Primary immunodeficiency 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 v2.378 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.377 CNBP Arina Puzriakova Publications for gene: CNBP were set to
Primary immunodeficiency 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 v2.375 UBA1 Arina Puzriakova Classified gene: UBA1 as Red List (low evidence)
Primary immunodeficiency v2.375 UBA1 Arina Puzriakova Gene: uba1 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.374 UBA1 Arina Puzriakova Classified gene: UBA1 as No list
Primary immunodeficiency 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 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
Genetic epilepsy syndromes v2.225 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: RED; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency 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 v2.372 UBA1 Arina Puzriakova Tag somatic tag was added to gene: UBA1.
Genetic epilepsy syndromes v2.225 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 16826530
Primary immunodeficiency v2.372 SOCS1 Arina Puzriakova Phenotypes for gene: SOCS1 were changed from Common variable immunodeficiency to Common variable immunodeficiency; Early-onset autoimmunity
Primary immunodeficiency v2.371 SOCS1 Arina Puzriakova Publications for gene: SOCS1 were set to 32499645; 10490099; 10490100
Primary immunodeficiency v2.370 SOCS1 Arina Puzriakova Tag for-review tag was added to gene: SOCS1.
Primary immunodeficiency v2.370 SOCS1 Arina Puzriakova Classified gene: SOCS1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.370 SOCS1 Arina Puzriakova Gene: socs1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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 v2.369 CNBP Boaz Palterer Deleted their review
Primary immunodeficiency 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
Childhood onset dystonia or chorea or related movement disorder v1.64 DDC Arina Puzriakova Publications for gene: DDC were set to 27830117; 27604308; 24816252
Severe Paediatric Disorders v1.19 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
Childhood onset dystonia or chorea or related movement disorder 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
Adult onset movement disorder 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
Genetic epilepsy syndromes 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
Inborn errors 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).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.222 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Genetic epilepsy syndromes v2.221 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.221 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Craniosynostosis v2.15 PJA1 Arina Puzriakova Classified gene: PJA1 as Amber List (moderate evidence)
Craniosynostosis v2.15 PJA1 Arina Puzriakova Gene: pja1 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.14 PJA1 Arina Puzriakova Classified gene: PJA1 as Red List (low evidence)
Craniosynostosis 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.
Craniosynostosis v2.14 PJA1 Arina Puzriakova Gene: pja1 has been classified as Red List (Low Evidence).
Craniosynostosis 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).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.219 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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).
Hearing loss v2.113 MPZL2 Eleanor Williams Tag for-review tag was added to gene: MPZL2.
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
Hearing loss v2.112 MPZL2 Eleanor Williams Publications for gene: MPZL2 were set to 29982980; 29961571
Hearing loss v2.111 MPZL2 Eleanor Williams Classified gene: MPZL2 as Amber List (moderate evidence)
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.
Hearing loss v2.111 MPZL2 Eleanor Williams Gene: mpzl2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.110 MPZL2 Eleanor Williams edited their review of gene: MPZL2: Changed rating: GREEN
Hearing loss v2.110 MPZL2 Eleanor Williams edited their review of gene: MPZL2: Changed publications: 29982980, 29961571, 32203226
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
Hearing loss v2.110 PLS1 Eleanor Williams Tag for-review tag was added to gene: PLS1.
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
Hearing loss v2.109 PLS1 Eleanor Williams Classified gene: PLS1 as Amber List (moderate evidence)
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.
Hearing loss v2.109 PLS1 Eleanor Williams Gene: pls1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.108 PLS1 Eleanor Williams edited their review of gene: PLS1: Changed rating: GREEN
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
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 - narrow panel 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 - narrow panel v1.26 STN1 Sarah Leigh Tag for-review tag was added to gene: STN1.
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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 - narrow panel v1.26 STN1 Sarah Leigh Classified gene: STN1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel 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 - narrow panel v1.26 STN1 Sarah Leigh Gene: stn1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel 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
Inborn errors 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
Cardiomyopathies - including childhood onset v1.12 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to
Inborn errors 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
Cardiomyopathies - including childhood onset 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
Severe Paediatric Disorders v1.18 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
Severe Paediatric Disorders v1.17 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 30847515
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
Genetic epilepsy syndromes 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.
Severe Paediatric Disorders v1.16 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 30847515
Severe Paediatric Disorders v1.15 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
Cardiomyopathies - including childhood onset 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
Genetic epilepsy syndromes 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
Inborn errors 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
Inborn errors of metabolism v2.29 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 27604308
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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 - narrow panel 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).
Genetic epilepsy syndromes v2.214 TBC1D2B Arina Puzriakova Tag for-review tag was added to gene: TBC1D2B.
Genetic epilepsy syndromes v2.214 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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 - narrow panel 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 - narrow panel v2.30 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel 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 - narrow panel v2.30 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel 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
Genetic epilepsy syndromes v2.212 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.212 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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
Inborn errors 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
Inborn errors of metabolism v2.27 GALM Ivone Leong Phenotypes for gene: GALM were changed from Galactosemia IV, 618881 to Galactosemia IV, OMIM:618881; MONDO:0030105
Inborn errors of metabolism v2.26 GALM Ivone Leong Classified gene: GALM as Amber List (moderate evidence)
Inborn errors 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
Inborn errors 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
Growth failure in early childhood v1.16 MTX2 Ivone Leong Classified gene: MTX2 as Amber List (moderate evidence)
Growth failure in early childhood v1.16 MTX2 Ivone Leong Gene: mtx2 has been classified as Amber List (Moderate Evidence).
Growth failure in early childhood v1.15 MTX2 Ivone Leong gene: MTX2 was added
gene: MTX2 was added to Growth failure in early childhood. Sources: Literature,Expert Review
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 Mandibuloacral dysplasia; lipodystrophy; arterial calcification; growth retardation
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 growth retardation is a phenotype. 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, Expert Review
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).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.210 NUS1 Eleanor Williams Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.209 PIGH Eleanor Williams Publications for gene: PIGH were set to 29603516; 29573052
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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 - narrow panel 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 - narrow panel 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
Genetic epilepsy syndromes 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 - narrow panel v2.27 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Ataxia and cerebellar anomalies - narrow panel 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 - narrow panel v2.26 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371; 29444210
Ataxia and cerebellar anomalies - narrow panel v2.25 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel 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 - narrow panel v2.25 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel 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 - narrow panel 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 - narrow panel v1.22 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
White matter disorders and cerebral calcification - narrow panel v1.22 TMEM106B Arina Puzriakova Publications for gene: TMEM106B were set to 29186371, 29444210
White matter disorders and cerebral calcification - narrow panel v1.21 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel 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 - narrow panel v1.21 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.20 TMEM106B Arina Puzriakova Tag for-review tag was added to gene: TMEM106B.
White matter disorders and cerebral calcification - narrow panel 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).
Genetic epilepsy syndromes v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.206 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.206 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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
Severe Paediatric Disorders v1.14 MAPRE2 Arina Puzriakova Publications for gene: MAPRE2 were set to 30847515
Severe Paediatric Disorders 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 - teen and adult 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 - teen and adult 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
Hearing loss v2.108 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
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)
Hearing loss v2.108 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.107 SPTBN4 Arina Puzriakova Tag watchlist tag was added to gene: SPTBN4.
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 NOT PMP22 copy number v1.17 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.17 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number 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).
Genetic epilepsy syndromes v2.205 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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
Hearing loss v2.106 PPIP5K2 Eleanor Williams Classified gene: PPIP5K2 as Amber List (moderate evidence)
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.
Hearing loss v2.106 PPIP5K2 Eleanor Williams Gene: ppip5k2 has been classified as Amber List (Moderate Evidence).
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
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
Hearing loss v2.104 PPIP5K2 Eleanor Williams commented on gene: PPIP5K2
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
Hearing loss v2.103 ROR1 Eleanor Williams Classified gene: ROR1 as Amber List (moderate evidence)
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.
Hearing loss v2.103 ROR1 Eleanor Williams Gene: ror1 has been classified as Amber List (Moderate Evidence).
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
Hearing loss v2.102 SNAI2 Eleanor Williams Tag for-review tag was added to gene: SNAI2.
Hearing loss v2.102 SNAI2 Eleanor Williams Classified gene: SNAI2 as Green List (high evidence)
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.
Hearing loss v2.102 SNAI2 Eleanor Williams Gene: snai2 has been classified as Green List (High Evidence).
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.
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
Hearing loss v2.101 SNAI2 Eleanor Williams commented on gene: SNAI2
Hearing loss v2.101 SLITRK6 Eleanor Williams Tag for-review tag was added to gene: SLITRK6.
Hearing loss v2.101 SLITRK6 Eleanor Williams Classified gene: SLITRK6 as Amber List (moderate evidence)
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.
Hearing loss v2.101 SLITRK6 Eleanor Williams Gene: slitrk6 has been classified as Amber List (Moderate Evidence).
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
Hearing loss v2.99 SLITRK6 Eleanor Williams Publications for gene: SLITRK6 were set to
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
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.
Hearing loss v2.98 SLITRK6 Eleanor Williams commented on gene: SLITRK6
Hearing loss v2.98 SIX5 Eleanor Williams Classified gene: SIX5 as Red List (low evidence)
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.
Hearing loss v2.98 SIX5 Eleanor Williams Gene: six5 has been classified as Red List (Low Evidence).
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
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
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
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.
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
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 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 - narrow panel 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 NOT PMP22 copy number 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 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 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 v2.369 AP3D1 Eleanor Williams Classified gene: AP3D1 as Amber List (moderate evidence)
Primary immunodeficiency v2.369 AP3D1 Eleanor Williams Added comment: Comment on list classification: Changing the rating from red to amber. Two cases now reported.
Primary immunodeficiency v2.369 AP3D1 Eleanor Williams Gene: ap3d1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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 NOT PMP22 copy number v1.15 NUDT2 Arina Puzriakova Classified gene: NUDT2 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.15 NUDT2 Arina Puzriakova Gene: nudt2 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.14 NUDT2 Arina Puzriakova Publications for gene: NUDT2 were set to 27431290; 30059600; 33058507
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.12 NEMF Arina Puzriakova Classified gene: NEMF as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number v1.12 NEMF Arina Puzriakova Gene: nemf has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number 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 NOT PMP22 copy number 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 NOT PMP22 copy number v1.10 NEMF Arina Puzriakova edited their review of gene: NEMF: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number 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
Genetic epilepsy syndromes 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 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 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 cardiomyopathy v2.12 TTN Arina Puzriakova Publications for gene: TTN were set to 30535219; 31251381
Arrhythmogenic cardiomyopathy v2.11 TTN Arina Puzriakova Tag for-review tag was added to gene: TTN.
Arrhythmogenic 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
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
Childhood onset dystonia or chorea or related movement disorder 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
Childhood onset dystonia or chorea or related movement disorder 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
Genetic epilepsy syndromes 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 - narrow panel 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
Severe Paediatric Disorders v1.12 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
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
Craniosynostosis 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
Craniosynostosis v2.11 ZIC1 Arina Puzriakova Added comment: Comment on publications: Added publications to support gene-disease association
Craniosynostosis 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
Genetic epilepsy syndromes v2.203 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.203 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.201 SLC5A6 Sarah Leigh Tag for-review tag was added to gene: SLC5A6.
Inborn errors 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
Cardiomyopathies - including childhood onset 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
Cardiomyopathies - including childhood onset 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
Genetic epilepsy syndromes v2.201 SCN8A Arina Puzriakova Tag for-review tag was added to gene: SCN8A.
Genetic epilepsy syndromes v2.201 SCN8A Arina Puzriakova commented on gene: SCN8A
Primary immunodeficiency v2.368 STAT5B Arina Puzriakova Tag for-review tag was added to gene: STAT5B.
Primary immunodeficiency v2.368 STAT5B Arina Puzriakova commented on gene: STAT5B
Primary immunodeficiency v2.368 TCF3 Arina Puzriakova Tag for-review tag was added to gene: TCF3.
Primary immunodeficiency v2.368 TCF3 Arina Puzriakova commented on gene: TCF3
Primary immunodeficiency v2.368 PIK3CD Arina Puzriakova Tag for-review tag was added to gene: PIK3CD.
Primary immunodeficiency v2.368 PIK3CD Arina Puzriakova commented on gene: PIK3CD
Primary immunodeficiency v2.368 RIPK1 Arina Puzriakova commented on gene: RIPK1
Primary immunodeficiency 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.
Genetic epilepsy syndromes v2.201 PIGP Arina Puzriakova Classified gene: PIGP as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.201 PIGP Arina Puzriakova Gene: pigp has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.200 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.200 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.199 RALGAPA1 Arina Puzriakova Classified gene: RALGAPA1 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.199 RALGAPA1 Arina Puzriakova Gene: ralgapa1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.198 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.198 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.197 RNF113A Arina Puzriakova Tag for-review tag was added to gene: RNF113A.
Genetic epilepsy syndromes v2.197 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.196 RNF13 Arina Puzriakova Classified gene: RNF13 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.196 RNF13 Arina Puzriakova Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.195 SERPINI1 Arina Puzriakova Classified gene: SERPINI1 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.195 SERPINI1 Arina Puzriakova Gene: serpini1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.194 SERPINI1 Arina Puzriakova Tag for-review tag was added to gene: SERPINI1.
Genetic epilepsy syndromes v2.194 SETD1A Arina Puzriakova Classified gene: SETD1A as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.194 SETD1A Arina Puzriakova Gene: setd1a has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.193 SETD1A Arina Puzriakova Tag for-review tag was added to gene: SETD1A.
Genetic epilepsy syndromes v2.193 SETD1B Arina Puzriakova Classified gene: SETD1B as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.193 SETD1B Arina Puzriakova Gene: setd1b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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 v2.368 SNORA31 Arina Puzriakova Classified gene: SNORA31 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.368 SNORA31 Arina Puzriakova Gene: snora31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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.
Genetic epilepsy syndromes v2.192 GAD1 Arina Puzriakova Classified gene: GAD1 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.192 GAD1 Arina Puzriakova Gene: gad1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.191 GAD1 Arina Puzriakova Tag for-review tag was added to gene: GAD1.
Primary immunodeficiency v2.367 BCL10 Arina Puzriakova Classified gene: BCL10 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.367 BCL10 Arina Puzriakova Gene: bcl10 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.366 BCL10 Arina Puzriakova Tag for-review tag was added to gene: BCL10.
Primary immunodeficiency v2.366 ZNF341 Arina Puzriakova Classified gene: ZNF341 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.366 ZNF341 Arina Puzriakova Gene: znf341 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.365 ZNF341 Arina Puzriakova Tag for-review tag was added to gene: ZNF341.
Primary immunodeficiency v2.365 WDR1 Arina Puzriakova Classified gene: WDR1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.365 WDR1 Arina Puzriakova Gene: wdr1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.364 WDR1 Arina Puzriakova Tag for-review tag was added to gene: WDR1.
Primary immunodeficiency v2.364 USP18 Arina Puzriakova Classified gene: USP18 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.364 USP18 Arina Puzriakova Gene: usp18 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.363 USP18 Arina Puzriakova Tag for-review tag was added to gene: USP18.
Primary immunodeficiency v2.363 TRIM22 Arina Puzriakova Classified gene: TRIM22 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.363 TRIM22 Arina Puzriakova Gene: trim22 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.362 TRIM22 Arina Puzriakova Tag for-review tag was added to gene: TRIM22.
Primary immunodeficiency v2.362 TOP2B Arina Puzriakova Classified gene: TOP2B as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.362 TOP2B Arina Puzriakova Gene: top2b has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.361 TOP2B Arina Puzriakova Tag for-review tag was added to gene: TOP2B.
Primary immunodeficiency v2.361 TNFRSF9 Arina Puzriakova Classified gene: TNFRSF9 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.361 TNFRSF9 Arina Puzriakova Gene: tnfrsf9 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.360 TNFRSF9 Arina Puzriakova Tag for-review tag was added to gene: TNFRSF9.
Primary immunodeficiency v2.360 NFE2L2 Arina Puzriakova Classified gene: NFE2L2 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.360 NFE2L2 Arina Puzriakova Gene: nfe2l2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.359 NFE2L2 Arina Puzriakova Tag for-review tag was added to gene: NFE2L2.
Primary immunodeficiency v2.359 SRP54 Arina Puzriakova Classified gene: SRP54 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.359 SRP54 Arina Puzriakova Gene: srp54 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.358 SRP54 Arina Puzriakova Tag for-review tag was added to gene: SRP54.
Primary immunodeficiency v2.358 SMARCD2 Arina Puzriakova Classified gene: SMARCD2 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.358 SMARCD2 Arina Puzriakova Gene: smarcd2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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 v2.357 RECQL4 Arina Puzriakova Classified gene: RECQL4 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.357 RECQL4 Arina Puzriakova Gene: recql4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.356 RECQL4 Arina Puzriakova Tag for-review tag was added to gene: RECQL4.
Primary immunodeficiency v2.356 SLC39A7 Arina Puzriakova Classified gene: SLC39A7 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.356 SLC39A7 Arina Puzriakova Gene: slc39a7 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.355 SLC39A7 Arina Puzriakova Tag for-review tag was added to gene: SLC39A7.
Primary immunodeficiency v2.355 RAC2 Arina Puzriakova Classified gene: RAC2 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.355 RAC2 Arina Puzriakova Gene: rac2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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 paediatric onset end-stage renal disease v1.11 VIPAS39 Arina Puzriakova Classified gene: VIPAS39 as Amber List (moderate evidence)
Unexplained paediatric 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 paediatric onset end-stage renal disease v1.11 VIPAS39 Arina Puzriakova Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Unexplained paediatric 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 v2.354 SLC7A7 Arina Puzriakova Classified gene: SLC7A7 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.354 SLC7A7 Arina Puzriakova Gene: slc7a7 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.353 SLC7A7 Arina Puzriakova Tag for-review tag was added to gene: SLC7A7.
Primary immunodeficiency v2.353 CIB1 Arina Puzriakova Classified gene: CIB1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.353 CIB1 Arina Puzriakova Gene: cib1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.352 CIB1 Arina Puzriakova Tag for-review tag was added to gene: CIB1.
Primary immunodeficiency v2.352 C17orf62 Arina Puzriakova Classified gene: C17orf62 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.352 C17orf62 Arina Puzriakova Gene: c17orf62 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.351 C17orf62 Arina Puzriakova Tag for-review tag was added to gene: C17orf62.
Primary immunodeficiency v2.351 ADAM17 Arina Puzriakova Classified gene: ADAM17 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.351 ADAM17 Arina Puzriakova Gene: adam17 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.350 ADAM17 Arina Puzriakova Tag for-review tag was added to gene: ADAM17.
Primary immunodeficiency v2.350 EFL1 Arina Puzriakova Classified gene: EFL1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.350 EFL1 Arina Puzriakova Gene: efl1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.349 EFL1 Arina Puzriakova Tag for-review tag was added to gene: EFL1.
Primary immunodeficiency v2.349 DBR1 Arina Puzriakova Classified gene: DBR1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.349 DBR1 Arina Puzriakova Gene: dbr1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.348 DBR1 Arina Puzriakova Tag for-review tag was added to gene: DBR1.
Primary immunodeficiency v2.348 DNASE1L3 Arina Puzriakova Classified gene: DNASE1L3 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.348 DNASE1L3 Arina Puzriakova Gene: dnase1l3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.347 DNASE1L3 Arina Puzriakova Tag for-review tag was added to gene: DNASE1L3.
Primary immunodeficiency v2.347 POLE Arina Puzriakova Classified gene: POLE as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.347 POLE Arina Puzriakova Gene: pole has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.346 POLE Arina Puzriakova Tag for-review tag was added to gene: POLE.
Primary immunodeficiency v2.346 PAX1 Arina Puzriakova Classified gene: PAX1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.346 PAX1 Arina Puzriakova Gene: pax1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.345 PAX1 Arina Puzriakova Tag for-review tag was added to gene: PAX1.
Primary immunodeficiency v2.345 LIG1 Arina Puzriakova Classified gene: LIG1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.345 LIG1 Arina Puzriakova Gene: lig1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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 v2.344 PIK3CG Arina Puzriakova Tag for-review tag was added to gene: PIK3CG.
Primary immunodeficiency v2.344 PIK3CG Arina Puzriakova Classified gene: PIK3CG as Amber List (moderate evidence)
Primary immunodeficiency 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 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 v2.343 CDC42 Arina Puzriakova Classified gene: CDC42 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.343 CDC42 Arina Puzriakova Gene: cdc42 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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.
Growth failure in early childhood v1.14 CEP57 Arina Puzriakova Classified gene: CEP57 as Amber List (moderate evidence)
Growth failure in early childhood v1.14 CEP57 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).
Growth failure in early childhood v1.14 CEP57 Arina Puzriakova Gene: cep57 has been classified as Amber List (Moderate Evidence).
Growth failure in early childhood v1.13 CEP57 Arina Puzriakova Tag for-review tag was added to gene: CEP57.
Hypogonadotropic hypogonadism idiopathic v1.10 NDNF Arina Puzriakova Classified gene: NDNF as Amber List (moderate evidence)
Hypogonadotropic hypogonadism idiopathic 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 idiopathic v1.10 NDNF Arina Puzriakova Gene: ndnf has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism idiopathic v1.9 NDNF Arina Puzriakova Tag for-review tag was added to gene: NDNF.
Primary immunodeficiency v2.342 IL6ST Arina Puzriakova Classified gene: IL6ST as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.342 IL6ST Arina Puzriakova Gene: il6st has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.341 IL6ST Arina Puzriakova Tag for-review tag was added to gene: IL6ST.
Primary immunodeficiency v2.341 FCHO1 Arina Puzriakova Classified gene: FCHO1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.341 FCHO1 Arina Puzriakova Gene: fcho1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.340 FCHO1 Arina Puzriakova Tag for-review tag was added to gene: FCHO1.
Primary immunodeficiency v2.340 IL6R Arina Puzriakova Classified gene: IL6R as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.340 IL6R Arina Puzriakova Gene: il6r has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.339 IL6R Arina Puzriakova Tag for-review tag was added to gene: IL6R.
Primary immunodeficiency v2.339 IL2RB Arina Puzriakova Classified gene: IL2RB as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.339 IL2RB Arina Puzriakova Gene: il2rb has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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 v2.338 HAVCR2 Arina Puzriakova Classified gene: HAVCR2 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.338 HAVCR2 Arina Puzriakova Gene: havcr2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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.
Genetic epilepsy syndromes v2.191 PCYT2 Arina Puzriakova Classified gene: PCYT2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.191 PCYT2 Arina Puzriakova Gene: pcyt2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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 v2.337 OAS1 Arina Puzriakova Classified gene: OAS1 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.337 OAS1 Arina Puzriakova Gene: oas1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.336 OAS1 Arina Puzriakova Tag for-review tag was added to gene: OAS1.
Craniosynostosis v2.10 SOX6 Arina Puzriakova Classified gene: SOX6 as Amber List (moderate evidence)
Craniosynostosis 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).
Craniosynostosis v2.10 SOX6 Arina Puzriakova Gene: sox6 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.9 SOX6 Arina Puzriakova Tag for-review tag was added to gene: SOX6.
Genetic epilepsy syndromes v2.190 ANKRD11 Arina Puzriakova Classified gene: ANKRD11 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.190 ANKRD11 Arina Puzriakova Gene: ankrd11 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.189 ANKRD11 Arina Puzriakova Tag for-review tag was added to gene: ANKRD11.
Genetic epilepsy syndromes v2.189 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.189 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.188 UGP2 Arina Puzriakova Tag for-review tag was added to gene: UGP2.
Genetic epilepsy syndromes v2.188 TRAPPC4 Arina Puzriakova Classified gene: TRAPPC4 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.188 TRAPPC4 Arina Puzriakova Gene: trappc4 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.187 KAT8 Arina Puzriakova Classified gene: KAT8 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.187 KAT8 Arina Puzriakova Gene: kat8 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.186 SEMA6B Arina Puzriakova Classified gene: SEMA6B as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.186 SEMA6B Arina Puzriakova Gene: sema6b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.185 SETD5 Arina Puzriakova Classified gene: SETD5 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.185 SETD5 Arina Puzriakova Gene: setd5 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.184 SETD5 Arina Puzriakova Classified gene: SETD5 as Green List (high evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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).
Inborn errors of metabolism v2.24 SLC5A6 Arina Puzriakova Classified gene: SLC5A6 as Amber List (moderate evidence)
Inborn errors 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).
Inborn errors 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).
Genetic epilepsy syndromes v2.183 SNX27 Arina Puzriakova Classified gene: SNX27 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.183 SNX27 Arina Puzriakova Gene: snx27 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.182 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes 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 v2.336 CD247 Arina Puzriakova Classified gene: CD247 as Amber List (moderate evidence)
Primary immunodeficiency 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 v2.336 CD247 Arina Puzriakova Gene: cd247 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency 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.
Genetic epilepsy syndromes v2.181 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.181 SEMA6B Arina Puzriakova Tag for-review tag was added to gene: SEMA6B.
Genetic epilepsy syndromes 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.
Inborn errors 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.
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.181 PIGK Arina Puzriakova Classified gene: PIGK as Amber List (moderate evidence)
Genetic epilepsy syndromes 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).
Genetic epilepsy syndromes v2.181 PIGK Arina Puzriakova Gene: pigk has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.180 TIMM50 Arina Puzriakova Classified gene: TIMM50 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.180 TIMM50 Arina Puzriakova Gene: timm50 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.96 SLC52A3 Arina Puzriakova Classified gene: SLC52A3 as Amber List (moderate evidence)
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.
Hearing loss v2.96 SLC52A3 Arina Puzriakova Gene: slc52a3 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.95 SLC52A2 Arina Puzriakova Classified gene: SLC52A2 as Amber List (moderate evidence)
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.
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.
Amyloidosis v1.8 NLRP3 Arina Puzriakova Classified gene: NLRP3 as Amber List (moderate evidence)
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.
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).
Genetic epilepsy syndromes 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).
Imprinted Genes v0.20 Sarah Leigh List of related panels changed from to
Panel status changed from internal to public
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
Genetic epilepsy syndromes 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
Inborn errors 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.
Cardiomyopathies - including childhood onset 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
Cardiomyopathies - including childhood onset 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
Panel version has been signed off
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 v2.14 Catherine Snow Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Panel version has been signed off
Hypogonadotropic hypogonadism idiopathic 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 v2.13 CFI Catherine Snow Tag for-review tag was added to gene: CFI.
Membranoproliferative glomerulonephritis v2.13 CFB Catherine Snow Classified gene: CFB as Green List (high evidence)
Membranoproliferative glomerulonephritis 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 v2.13 CFB Catherine Snow Gene: cfb has been classified as Green List (High Evidence).
Membranoproliferative glomerulonephritis v2.12 CFI Catherine Snow Classified gene: CFI as Green List (high evidence)
Membranoproliferative glomerulonephritis 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 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
Panel version has been signed off
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).
Confirmed Fanconi anaemia or Bloom syndrome v1.8 Catherine Snow List of related panels changed from R229 to R229; R258
Panel version has been signed off
Cytopenia - NOT Fanconi anaemia v1.30 Catherine Snow List of related panels changed from R91; R258 to R91
Panel version has been signed off
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
Panel version has been signed off
Mosaic skin disorders - deep sequencing v1.4 Catherine Snow Panel types changed to GMS Rare Disease; GMS signed-off
Panel version has been signed off
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
Panel version has been signed off
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 neoplasms 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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White matter disorders - 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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Adult onset movement disorder 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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Lipoprotein lipase deficiency 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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Aniridia v2.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
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Confirmed Fanconi anaemia or Bloom syndrome v1.7 Catherine Snow Panel version has been signed off
Confirmed Fanconi anaemia or Bloom syndrome v1.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Panel version has been signed off
Sudden cardiac death v9.84 Catherine Snow Panel version has been signed off
Arrhythmogenic cardiomyopathy v2.11 Catherine Snow Panel version has been signed off
Arrhythmogenic 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
Panel version has been signed off
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes 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 cardiomyopathy - adult and teen v1.7 Catherine Snow Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; Component Of Super Panel; GMS signed-off
Panel version has been signed off
Hypertrophic cardiomyopathy - teen and adult 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
Panel version has been signed off
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.
Genetic epilepsy syndromes v2.176 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.176 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v2.174 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393; 29156220
Genetic epilepsy syndromes v2.173 TRPM3 Arina Puzriakova Classified gene: TRPM3 as Amber List (moderate evidence)
Genetic epilepsy syndromes 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.
Genetic epilepsy syndromes v2.173 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.
Intellectual disability v3.448 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.447 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393
Intellectual disability v3.446 TRPM3 Arina Puzriakova Tag for-review tag was added to gene: TRPM3.
Intellectual disability v3.446 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
Severe microcephaly v2.27 DNMT3A Rachel Jones reviewed gene: DNMT3A: 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: PID: 30478443; Phenotypes: 618724 HEYN-SPROUL-JACKSON SYNDROME, HESJAS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 ZFYVE26 Zornitza Stark gene: ZFYVE26 was added
gene: ZFYVE26 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: ZFYVE26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE26 were set to 18394578; 14409555
Phenotypes for gene: ZFYVE26 were set to Spastic paraplegia 15, autosomal recessive MIM#270700
Review for gene: ZFYVE26 was set to GREEN
gene: ZFYVE26 was marked as current diagnostic
Added comment: Retinal degeneration can be a feature of this condition.
Sources: Expert list
Retinal disorders v2.20 WDPCP Zornitza Stark changed review comment from: Two families reported; the first one with a BBS phenotype, and in the second one affected individual had polysyndactyly and tongue hamartomas, so phenotype consistent with OFD rather than BBS. Note this gene has discordant ratings on multiple panels.; to: Four families reported, with different ciliopathy phenotypes including BBS, OFD and syndromic retinopathy.
Retinal disorders v2.20 WDPCP Zornitza Stark edited their review of gene: WDPCP: Changed rating: GREEN; Changed publications: 20671153, 25427950, 32055034, 29588463, 28289185
Retinal disorders v2.20 WDPCP Zornitza Stark reviewed gene: WDPCP: Rating: AMBER; Mode of pathogenicity: None; Publications: 20671153, 25427950; Phenotypes: Bardet-Biedl syndrome 15, MIM# 615992, OFD, Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 UNC119 Zornitza Stark reviewed gene: UNC119: Rating: GREEN; Mode of pathogenicity: None; Publications: 11006213, 23563732, 27079236; Phenotypes: Cone-rod dystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 TUBGCP6 Zornitza Stark reviewed gene: TUBGCP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 22279524, 25344692; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 1, MIM# 251270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
IUGR and IGF abnormalities v1.33 RNPC3 Ivone Leong Classified gene: RNPC3 as Amber List (moderate evidence)
IUGR and IGF abnormalities v1.33 RNPC3 Ivone Leong Added comment: Comment on list classification: This gene has been promoted from Red to Amber based on the evidence provided below.

Comments copied from Growth failure in early childhood (Version 1.13):
"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"
IUGR and IGF abnormalities v1.33 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
IUGR and IGF abnormalities v1.32 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160
IUGR and IGF abnormalities v1.31 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542
Growth failure in early childhood v1.13 RNPC3 Ivone Leong Classified gene: RNPC3 as Amber List (moderate evidence)
Growth failure in early childhood v1.13 RNPC3 Ivone Leong Added comment: 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.
Growth failure in early childhood v1.13 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.20 TUBGCP4 Zornitza Stark reviewed gene: TUBGCP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25817018, 32270730; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 3, MIM# 616335; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Retinal disorders v2.20 TUBB4B Zornitza Stark gene: TUBB4B was added
gene: TUBB4B was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TUBB4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB4B were set to 29198720
Phenotypes for gene: TUBB4B were set to Leber congenital amaurosis with early-onset deafness MIM#617879
Review for gene: TUBB4B was set to GREEN
gene: TUBB4B was marked as current diagnostic
Added comment: At least 5 affected individuals from 4 families with Leber congenital amaurosis and early-onset deafness with heterozygosity for 2 missense (R391H, R391C). Functional analysis demonstrated that the mutations have a significant dampening impact on microtubular growth.
Sources: Expert list
Retinal disorders v2.20 TRNT1 Zornitza Stark changed review comment from: The disorders associated with this gene likely represent a spectrum. RP/retinal dysfunction reported in more than 3 families, supportive functional data.; to: The disorders associated with this gene likely represent a spectrum rather than distinct conditions, therefore gene-disease association evidence assessed across publications. RP/retinal dysfunction reported in more than 3 families, supportive functional data.
Retinal disorders v2.20 TRNT1 Zornitza Stark reviewed gene: TRNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26494905, 28390992, 27389523; Phenotypes: Retinitis pigmentosa and erythrocytic microcytosis, MIM# 616959, Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, MIM# 616084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 TRIM32 Zornitza Stark reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: 16606853; Phenotypes: Bardet-Biedl syndrome 11, MIM# 615988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 TREX1 Zornitza Stark reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17660820; Phenotypes: Vasculopathy, retinal, with cerebral leukodystrophy, MIM# 192315; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 TRAF3IP1 Zornitza Stark gene: TRAF3IP1 was added
gene: TRAF3IP1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TRAF3IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAF3IP1 were set to 26487268
Phenotypes for gene: TRAF3IP1 were set to Senior-Loken syndrome 9, MIM#616629
Review for gene: TRAF3IP1 was set to GREEN
Added comment: At least 5 families reported with retinal degeneration as a feature of the condition and a zebrafish model with retinal degeneration.
Sources: Expert list
Retinal disorders v2.20 TMEM231 Zornitza Stark gene: TMEM231 was added
gene: TMEM231 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: TMEM231 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM231 were set to 23012439; 27449316
Phenotypes for gene: TMEM231 were set to Joubert syndrome 20 MIM#614970
Review for gene: TMEM231 was set to GREEN
Added comment: Three unrelated families reported with retinopathy as a feature of the condition.
Sources: Expert list
Retinal disorders v2.20 TMEM216 Zornitza Stark reviewed gene: TMEM216: Rating: GREEN; Mode of pathogenicity: None; Publications: 32687549, 20512146; Phenotypes: Joubert syndrome 2, MIM# 608091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.20 SSBP1 Zornitza Stark gene: SSBP1 was added
gene: SSBP1 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: SSBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SSBP1 were set to 31298765; 31479473; 31550237; 31550240
Phenotypes for gene: SSBP1 were set to Optic atrophy-13 with retinal and foveal abnormalities, MIM#165510
Review for gene: SSBP1 was set to GREEN
Added comment: At least 9 dominant families/cases and 1 recessive with optic atrophy with/without additional clinical features, including retinal macular dystrophy, sensorineural deafness, mitochondrial myopathy, and kidney failure. Supporting evidence in functional assays and zebrafish model.

Consider including here as well as the optic atrophy panel due to retinal features.
Sources: Expert list
Primary immunodeficiency v2.335 ISCA-37433-Loss Eleanor Williams Publications for Region: ISCA-37433-Loss were set to 15889418; 20301696; 15545748
Primary immunodeficiency v2.334 ISCA-37433-Loss Eleanor Williams edited their review of Region: ISCA-37433-Loss: Added comment: The following PubMed IDs were added to entity ISCA-37433-Loss: 12548732. These publications have been associated with OMIM phenotype MIM#188400, which is listed for this entity, by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 24198816, 20425828, 12548732
Primary immunodeficiency v2.334 ISCA-37433-Loss Eleanor Williams reviewed Region: ISCA-37433-Loss: Rating: ; Mode of pathogenicity: None; Publications: 24198816, 20425828; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v2.334 ISCA-37446-Loss Eleanor Williams Publications for Region: ISCA-37446-Loss were set to
Primary immunodeficiency v2.333 ISCA-37446-Loss Eleanor Williams reviewed Region: ISCA-37446-Loss: Rating: ; Mode of pathogenicity: None; Publications: 12548732; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v2.333 ZAP70 Eleanor Williams Classified gene: ZAP70 as Green List (high evidence)
Primary immunodeficiency v2.333 ZAP70 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.333 ZAP70 Eleanor Williams Gene: zap70 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.332 XIAP Eleanor Williams Classified gene: XIAP as Green List (high evidence)
Primary immunodeficiency v2.332 XIAP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.332 XIAP Eleanor Williams Gene: xiap has been classified as Green List (High Evidence).
Primary immunodeficiency v2.331 UNC13D Eleanor Williams Classified gene: UNC13D as Green List (high evidence)
Primary immunodeficiency v2.331 UNC13D Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.331 UNC13D Eleanor Williams Gene: unc13d has been classified as Green List (High Evidence).
Primary immunodeficiency v2.330 TTC7A Eleanor Williams Classified gene: TTC7A as Green List (high evidence)
Primary immunodeficiency v2.330 TTC7A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.330 TTC7A Eleanor Williams Gene: ttc7a has been classified as Green List (High Evidence).
Primary immunodeficiency v2.329 TREX1 Eleanor Williams Classified gene: TREX1 as Green List (high evidence)
Primary immunodeficiency v2.329 TREX1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.329 TREX1 Eleanor Williams Gene: trex1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.328 TRAC Eleanor Williams Classified gene: TRAC as Green List (high evidence)
Primary immunodeficiency v2.328 TRAC Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.328 TRAC Eleanor Williams Gene: trac has been classified as Green List (High Evidence).
Primary immunodeficiency v2.327 TPP2 Eleanor Williams Classified gene: TPP2 as Green List (high evidence)
Primary immunodeficiency v2.327 TPP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.327 TPP2 Eleanor Williams Gene: tpp2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.326 TNFRSF1A Eleanor Williams Classified gene: TNFRSF1A as Green List (high evidence)
Primary immunodeficiency v2.326 TNFRSF1A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.326 TNFRSF1A Eleanor Williams Gene: tnfrsf1a has been classified as Green List (High Evidence).
Primary immunodeficiency v2.325 TNFAIP3 Eleanor Williams Classified gene: TNFAIP3 as Green List (high evidence)
Primary immunodeficiency v2.325 TNFAIP3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.325 TNFAIP3 Eleanor Williams Gene: tnfaip3 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.324 TMEM173 Eleanor Williams Classified gene: TMEM173 as Green List (high evidence)
Primary immunodeficiency v2.324 TMEM173 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.324 TMEM173 Eleanor Williams Gene: tmem173 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.323 TCN2 Eleanor Williams Classified gene: TCN2 as Green List (high evidence)
Primary immunodeficiency v2.323 TCN2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.323 TCN2 Eleanor Williams Gene: tcn2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.322 TAP2 Eleanor Williams Classified gene: TAP2 as Green List (high evidence)
Primary immunodeficiency v2.322 TAP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.322 TAP2 Eleanor Williams Gene: tap2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.321 TAP1 Eleanor Williams Classified gene: TAP1 as Green List (high evidence)
Primary immunodeficiency v2.321 TAP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.321 TAP1 Eleanor Williams Gene: tap1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.320 STXBP2 Eleanor Williams Classified gene: STXBP2 as Green List (high evidence)
Primary immunodeficiency v2.320 STXBP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.320 STXBP2 Eleanor Williams Gene: stxbp2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.319 STXBP2 Eleanor Williams Classified gene: STXBP2 as Green List (high evidence)
Primary immunodeficiency v2.319 STXBP2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.319 STXBP2 Eleanor Williams Gene: stxbp2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.318 STX11 Eleanor Williams Classified gene: STX11 as Green List (high evidence)
Primary immunodeficiency v2.318 STX11 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.318 STX11 Eleanor Williams Gene: stx11 has been classified as Green List (High Evidence).
DDG2P v2.10 RINT1 Dmitrijs Rots Deleted their review
Primary immunodeficiency v2.317 STK4 Eleanor Williams Classified gene: STK4 as Green List (high evidence)
Primary immunodeficiency v2.317 STK4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.317 STK4 Eleanor Williams Gene: stk4 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.316 STIM1 Eleanor Williams Classified gene: STIM1 as Green List (high evidence)
Primary immunodeficiency v2.316 STIM1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.316 STIM1 Eleanor Williams Gene: stim1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.315 STAT5B Eleanor Williams Classified gene: STAT5B as Green List (high evidence)
Primary immunodeficiency v2.315 STAT5B Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.315 STAT5B Eleanor Williams Gene: stat5b has been classified as Green List (High Evidence).
Primary immunodeficiency v2.314 STAT3 Eleanor Williams Classified gene: STAT3 as Green List (high evidence)
Primary immunodeficiency v2.314 STAT3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.314 STAT3 Eleanor Williams Gene: stat3 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.313 SP110 Eleanor Williams Classified gene: SP110 as Green List (high evidence)
Primary immunodeficiency v2.313 SP110 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.313 SP110 Eleanor Williams Gene: sp110 has been classified as Green List (High Evidence).
Skeletal dysplasia v2.22 RINT1 Dmitrijs Rots gene: RINT1 was added
gene: RINT1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to PMID: 31204009
Phenotypes for gene: RINT1 were set to liver failure; short stature; skeletal abnormalities
Penetrance for gene: RINT1 were set to Complete
Review for gene: RINT1 was set to GREEN
gene: RINT1 was marked as current diagnostic
Added comment: Reported in 3 patients with similar phenotype in PMID: 31204009. Caused by one LoF allele and missense/in-frame hypomorphic allele.
Sources: Literature
Primary immunodeficiency v2.312 SMARCAL1 Eleanor Williams Classified gene: SMARCAL1 as Green List (high evidence)
Primary immunodeficiency v2.312 SMARCAL1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.312 SMARCAL1 Eleanor Williams Gene: smarcal1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.311 SLC46A1 Eleanor Williams Classified gene: SLC46A1 as Green List (high evidence)
Primary immunodeficiency v2.311 SLC46A1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.311 SLC46A1 Eleanor Williams Gene: slc46a1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.310 SLC29A3 Eleanor Williams Classified gene: SLC29A3 as Green List (high evidence)
Primary immunodeficiency v2.310 SLC29A3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.310 SLC29A3 Eleanor Williams Gene: slc29a3 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.309 SH2D1A Eleanor Williams Classified gene: SH2D1A as Green List (high evidence)
Primary immunodeficiency v2.309 SH2D1A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.309 SH2D1A Eleanor Williams Gene: sh2d1a has been classified as Green List (High Evidence).
Primary immunodeficiency v2.308 RMRP Eleanor Williams Classified gene: RMRP as Green List (high evidence)
Primary immunodeficiency v2.308 RMRP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.308 RMRP Eleanor Williams Gene: rmrp has been classified as Green List (High Evidence).
Primary immunodeficiency v2.307 RFXAP Eleanor Williams Classified gene: RFXAP as Green List (high evidence)
Primary immunodeficiency v2.307 RFXAP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.307 RFXAP Eleanor Williams Gene: rfxap has been classified as Green List (High Evidence).
Primary immunodeficiency v2.306 RFXANK Eleanor Williams Classified gene: RFXANK as Green List (high evidence)
Primary immunodeficiency v2.306 RFXANK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.306 RFXANK Eleanor Williams Gene: rfxank has been classified as Green List (High Evidence).
Primary immunodeficiency v2.305 RFX5 Eleanor Williams Classified gene: RFX5 as Green List (high evidence)
Primary immunodeficiency v2.305 RFX5 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.305 RFX5 Eleanor Williams Gene: rfx5 has been classified as Green List (High Evidence).
DDG2P v2.10 RINT1 Dmitrijs Rots reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31204009; Phenotypes: liver failure, short stature, skeletal abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency v2.304 RBCK1 Eleanor Williams Classified gene: RBCK1 as Green List (high evidence)
Primary immunodeficiency v2.304 RBCK1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.304 RBCK1 Eleanor Williams Gene: rbck1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.303 RASGRP1 Eleanor Williams Classified gene: RASGRP1 as Green List (high evidence)
Primary immunodeficiency v2.303 RASGRP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.303 RASGRP1 Eleanor Williams Gene: rasgrp1 has been classified as Green List (High Evidence).
Intellectual disability v3.446 FGF14 Arina Puzriakova Classified gene: FGF14 as Amber List (moderate evidence)
Intellectual disability v3.446 FGF14 Arina Puzriakova Added comment: Comment on list classification: Cognitive impairment has been reported in several patients, mostly mild but few cases with moderate deficits have also been described. However, the phenotype is mainly characterised by ataxia which would be the expected CI for diagnostic testing - FGF14 is already Green on Ataxia panels.

The utility of calling variants in this gene in a cohort of ID patients without the ataxic component is unlikely to be of benefit, and therefore the rating has been kept Amber on this panel.
Intellectual disability v3.446 FGF14 Arina Puzriakova Gene: fgf14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.445 FGF14 Arina Puzriakova Publications for gene: FGF14 were set to 15470364
Primary immunodeficiency v2.302 RAG2 Eleanor Williams Classified gene: RAG2 as Green List (high evidence)
Primary immunodeficiency v2.302 RAG2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.302 RAG2 Eleanor Williams Gene: rag2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.301 RAG1 Eleanor Williams Classified gene: RAG1 as Green List (high evidence)
Primary immunodeficiency v2.301 RAG1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.301 RAG1 Eleanor Williams Gene: rag1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.300 RAB27A Eleanor Williams Classified gene: RAB27A as Green List (high evidence)
Primary immunodeficiency v2.300 RAB27A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.300 RAB27A Eleanor Williams Gene: rab27a has been classified as Green List (High Evidence).
Primary immunodeficiency v2.299 PTPRC Eleanor Williams Classified gene: PTPRC as Green List (high evidence)
Primary immunodeficiency v2.299 PTPRC Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.299 PTPRC Eleanor Williams Gene: ptprc has been classified as Green List (High Evidence).
Primary immunodeficiency v2.298 PSTPIP1 Eleanor Williams Classified gene: PSTPIP1 as Green List (high evidence)
Primary immunodeficiency v2.298 PSTPIP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.298 PSTPIP1 Eleanor Williams Gene: pstpip1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.297 PSMB8 Eleanor Williams Classified gene: PSMB8 as Green List (high evidence)
Primary immunodeficiency v2.297 PSMB8 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.297 PSMB8 Eleanor Williams Gene: psmb8 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.296 PRKCD Eleanor Williams Classified gene: PRKCD as Green List (high evidence)
Primary immunodeficiency v2.296 PRKCD Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.296 PRKCD Eleanor Williams Gene: prkcd has been classified as Green List (High Evidence).
Primary immunodeficiency v2.295 PRF1 Eleanor Williams Classified gene: PRF1 as Green List (high evidence)
Primary immunodeficiency v2.295 PRF1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.295 PRF1 Eleanor Williams Gene: prf1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.294 POLA1 Eleanor Williams Classified gene: POLA1 as Green List (high evidence)
Primary immunodeficiency v2.294 POLA1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.294 POLA1 Eleanor Williams Gene: pola1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.293 PNP Eleanor Williams Classified gene: PNP as Green List (high evidence)
Primary immunodeficiency v2.293 PNP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.293 PNP Eleanor Williams Gene: pnp has been classified as Green List (High Evidence).
Primary immunodeficiency v2.292 PLCG2 Eleanor Williams Classified gene: PLCG2 as Green List (high evidence)
Primary immunodeficiency v2.292 PLCG2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.292 PLCG2 Eleanor Williams Gene: plcg2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.291 PEPD Eleanor Williams Classified gene: PEPD as Green List (high evidence)
Primary immunodeficiency v2.291 PEPD Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.291 PEPD Eleanor Williams Gene: pepd has been classified as Green List (High Evidence).
Primary immunodeficiency v2.290 OTULIN Eleanor Williams Classified gene: OTULIN as Green List (high evidence)
Primary immunodeficiency v2.290 OTULIN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.290 OTULIN Eleanor Williams Gene: otulin has been classified as Green List (High Evidence).
Primary immunodeficiency v2.289 ORAI1 Eleanor Williams Classified gene: ORAI1 as Green List (high evidence)
Primary immunodeficiency v2.289 ORAI1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.289 ORAI1 Eleanor Williams Gene: orai1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.288 NOD2 Eleanor Williams Classified gene: NOD2 as Green List (high evidence)
Primary immunodeficiency v2.288 NOD2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.288 NOD2 Eleanor Williams Gene: nod2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.287 NLRP3 Eleanor Williams Classified gene: NLRP3 as Green List (high evidence)
Primary immunodeficiency v2.287 NLRP3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.287 NLRP3 Eleanor Williams Gene: nlrp3 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.286 NLRP12 Eleanor Williams Classified gene: NLRP12 as Green List (high evidence)
Primary immunodeficiency v2.286 NLRP12 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.286 NLRP12 Eleanor Williams Gene: nlrp12 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.285 NLRC4 Eleanor Williams Classified gene: NLRC4 as Green List (high evidence)
Primary immunodeficiency v2.285 NLRC4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.285 NLRC4 Eleanor Williams Gene: nlrc4 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.284 NHEJ1 Eleanor Williams Classified gene: NHEJ1 as Green List (high evidence)
Primary immunodeficiency v2.284 NHEJ1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.284 NHEJ1 Eleanor Williams Gene: nhej1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.283 NFKBIA Eleanor Williams Classified gene: NFKBIA as Green List (high evidence)
Primary immunodeficiency v2.283 NFKBIA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.283 NFKBIA Eleanor Williams Gene: nfkbia has been classified as Green List (High Evidence).
Primary immunodeficiency v2.282 MYSM1 Eleanor Williams Classified gene: MYSM1 as Green List (high evidence)
Primary immunodeficiency v2.282 MYSM1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.282 MYSM1 Eleanor Williams Gene: mysm1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.281 MVK Eleanor Williams Classified gene: MVK as Green List (high evidence)
Primary immunodeficiency v2.281 MVK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.281 MVK Eleanor Williams Gene: mvk has been classified as Green List (High Evidence).
Primary immunodeficiency v2.280 MTHFD1 Eleanor Williams Classified gene: MTHFD1 as Green List (high evidence)
Primary immunodeficiency v2.280 MTHFD1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.280 MTHFD1 Eleanor Williams Gene: mthfd1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.279 MSN Eleanor Williams Classified gene: MSN as Green List (high evidence)
Primary immunodeficiency v2.279 MSN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.279 MSN Eleanor Williams Gene: msn has been classified as Green List (High Evidence).
Inherited ovarian cancer (without breast cancer) v2.3 PALB2 marc tischkowitz reviewed gene: PALB2: 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: PMID: 31841383: PMID: 32546565; Phenotypes: breast cancer, ovarian cancer, pancreatic cancer; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency v2.278 MEFV Eleanor Williams Classified gene: MEFV as Green List (high evidence)
Primary immunodeficiency v2.278 MEFV Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.278 MEFV Eleanor Williams Gene: mefv has been classified as Green List (High Evidence).
Primary immunodeficiency v2.277 MAP3K14 Eleanor Williams Classified gene: MAP3K14 as Green List (high evidence)
Primary immunodeficiency v2.277 MAP3K14 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.277 MAP3K14 Eleanor Williams Gene: map3k14 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.276 MALT1 Eleanor Williams Classified gene: MALT1 as Green List (high evidence)
Primary immunodeficiency v2.276 MALT1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.276 MALT1 Eleanor Williams Gene: malt1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.275 MAGT1 Eleanor Williams Classified gene: MAGT1 as Green List (high evidence)
Primary immunodeficiency v2.275 MAGT1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.275 MAGT1 Eleanor Williams Gene: magt1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.274 LYST Eleanor Williams Classified gene: LYST as Green List (high evidence)
Primary immunodeficiency v2.274 LYST Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.274 LYST Eleanor Williams Gene: lyst has been classified as Green List (High Evidence).
Primary immunodeficiency v2.273 LRBA Eleanor Williams Classified gene: LRBA as Green List (high evidence)
Primary immunodeficiency v2.273 LRBA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.273 LRBA Eleanor Williams Gene: lrba has been classified as Green List (High Evidence).
Primary immunodeficiency v2.272 LPIN2 Eleanor Williams Classified gene: LPIN2 as Green List (high evidence)
Primary immunodeficiency v2.272 LPIN2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.272 LPIN2 Eleanor Williams Gene: lpin2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.271 LIG4 Eleanor Williams Classified gene: LIG4 as Green List (high evidence)
Primary immunodeficiency v2.271 LIG4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.271 LIG4 Eleanor Williams Gene: lig4 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.270 LCK Eleanor Williams Classified gene: LCK as Green List (high evidence)
Primary immunodeficiency v2.270 LCK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.270 LCK Eleanor Williams Gene: lck has been classified as Green List (High Evidence).
Primary immunodeficiency v2.269 LAT Eleanor Williams Classified gene: LAT as Green List (high evidence)
Primary immunodeficiency v2.269 LAT Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.269 LAT Eleanor Williams Gene: lat has been classified as Green List (High Evidence).
Primary immunodeficiency v2.268 JAK3 Eleanor Williams Classified gene: JAK3 as Green List (high evidence)
Primary immunodeficiency v2.268 JAK3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.268 JAK3 Eleanor Williams Gene: jak3 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.267 ITK Eleanor Williams Classified gene: ITK as Green List (high evidence)
Primary immunodeficiency v2.267 ITK Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.267 ITK Eleanor Williams Gene: itk has been classified as Green List (High Evidence).
Primary immunodeficiency v2.266 ITCH Eleanor Williams Classified gene: ITCH as Green List (high evidence)
Primary immunodeficiency v2.266 ITCH Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.266 ITCH Eleanor Williams Gene: itch has been classified as Green List (High Evidence).
Primary immunodeficiency v2.265 IL7R Eleanor Williams Classified gene: IL7R as Green List (high evidence)
Primary immunodeficiency v2.265 IL7R Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.265 IL7R Eleanor Williams Gene: il7r has been classified as Green List (High Evidence).
Primary immunodeficiency v2.264 IL36RN Eleanor Williams Classified gene: IL36RN as Green List (high evidence)
Primary immunodeficiency v2.264 IL36RN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.264 IL36RN Eleanor Williams Gene: il36rn has been classified as Green List (High Evidence).
Primary immunodeficiency v2.263 IL2RG Eleanor Williams Classified gene: IL2RG as Green List (high evidence)
Primary immunodeficiency v2.263 IL2RG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.263 IL2RG Eleanor Williams Gene: il2rg has been classified as Green List (High Evidence).
Primary immunodeficiency v2.262 IL2RA Eleanor Williams Classified gene: IL2RA as Green List (high evidence)
Primary immunodeficiency v2.262 IL2RA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.262 IL2RA Eleanor Williams Gene: il2ra has been classified as Green List (High Evidence).
Primary immunodeficiency v2.261 IL21R Eleanor Williams Classified gene: IL21R as Green List (high evidence)
Primary immunodeficiency v2.261 IL21R Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.261 IL21R Eleanor Williams Gene: il21r has been classified as Green List (High Evidence).
Intellectual disability v3.444 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Genetic epilepsy syndromes v2.172 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Intellectual disability v3.443 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Genetic epilepsy syndromes v2.171 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Genetic epilepsy syndromes v2.171 FDFT1 Arina Puzriakova Classified gene: FDFT1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.171 FDFT1 Arina Puzriakova Added comment: Comment on list classification: Expert review on FDFT1 following a publication by Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

FDFT1 is in OMIM based on this paper. As there are only two families classifying FDFT1 as Amber until more evidence is available (added 'watchlist' tag).
Genetic epilepsy syndromes v2.171 FDFT1 Arina Puzriakova Gene: fdft1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.260 IL1RN Eleanor Williams Classified gene: IL1RN as Green List (high evidence)
Primary immunodeficiency v2.260 IL1RN Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.260 IL1RN Eleanor Williams Gene: il1rn has been classified as Green List (High Evidence).
Primary immunodeficiency v2.259 IL10RB Eleanor Williams Classified gene: IL10RB as Green List (high evidence)
Primary immunodeficiency v2.259 IL10RB Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.259 IL10RB Eleanor Williams Gene: il10rb has been classified as Green List (High Evidence).
Primary immunodeficiency v2.258 IL10RA Eleanor Williams Classified gene: IL10RA as Green List (high evidence)
Primary immunodeficiency v2.258 IL10RA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.258 IL10RA Eleanor Williams Gene: il10ra has been classified as Green List (High Evidence).
Primary immunodeficiency v2.257 IL10 Eleanor Williams Classified gene: IL10 as Green List (high evidence)
Primary immunodeficiency v2.257 IL10 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.257 IL10 Eleanor Williams Gene: il10 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.256 IKBKG Eleanor Williams Classified gene: IKBKG as Green List (high evidence)
Primary immunodeficiency v2.256 IKBKG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.256 IKBKG Eleanor Williams Gene: ikbkg has been classified as Green List (High Evidence).
Primary immunodeficiency v2.255 IKBKB Eleanor Williams Classified gene: IKBKB as Green List (high evidence)
Primary immunodeficiency v2.255 IKBKB Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.255 IKBKB Eleanor Williams Gene: ikbkb has been classified as Green List (High Evidence).
Primary immunodeficiency v2.254 ICOS Eleanor Williams Classified gene: ICOS as Green List (high evidence)
Primary immunodeficiency v2.254 ICOS Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.254 ICOS Eleanor Williams Gene: icos has been classified as Green List (High Evidence).
Primary immunodeficiency v2.253 FOXP3 Eleanor Williams Classified gene: FOXP3 as Green List (high evidence)
Primary immunodeficiency v2.253 FOXP3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.253 FOXP3 Eleanor Williams Gene: foxp3 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.252 FOXN1 Eleanor Williams Classified gene: FOXN1 as Green List (high evidence)
Primary immunodeficiency v2.252 FOXN1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.252 FOXN1 Eleanor Williams Gene: foxn1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.251 FAT4 Eleanor Williams Classified gene: FAT4 as Green List (high evidence)
Primary immunodeficiency v2.251 FAT4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.251 FAT4 Eleanor Williams Gene: fat4 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.250 FASLG Eleanor Williams Classified gene: FASLG as Green List (high evidence)
Primary immunodeficiency v2.250 FASLG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.250 FASLG Eleanor Williams Gene: faslg has been classified as Green List (High Evidence).
Primary immunodeficiency v2.249 FAS Eleanor Williams Classified gene: FAS as Green List (high evidence)
Primary immunodeficiency v2.249 FAS Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.249 FAS Eleanor Williams Gene: fas has been classified as Green List (High Evidence).
Primary immunodeficiency v2.248 FADD Eleanor Williams Classified gene: FADD as Green List (high evidence)
Primary immunodeficiency v2.248 FADD Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.248 FADD Eleanor Williams Gene: fadd has been classified as Green List (High Evidence).
Intellectual disability v3.443 DENND5A Arina Puzriakova Phenotypes for gene: DENND5A were changed from EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 49 617281
Primary immunodeficiency v2.247 EXTL3 Eleanor Williams Classified gene: EXTL3 as Green List (high evidence)
Primary immunodeficiency v2.247 EXTL3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.247 EXTL3 Eleanor Williams Gene: extl3 has been classified as Green List (High Evidence).
Intellectual disability v3.442 DENND5A Arina Puzriakova Classified gene: DENND5A as Amber List (moderate evidence)
Intellectual disability v3.442 DENND5A Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as disorder is mainly characterised by severe early-infantile encephalopathy, and cognitive arrest appears secondary to the onset of seizures.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting cases.
Intellectual disability v3.442 DENND5A Arina Puzriakova Gene: dennd5a has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.246 EPG5 Eleanor Williams Classified gene: EPG5 as Green List (high evidence)
Primary immunodeficiency v2.246 EPG5 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.246 EPG5 Eleanor Williams Gene: epg5 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.245 DOCK8 Eleanor Williams Classified gene: DOCK8 as Green List (high evidence)
Primary immunodeficiency v2.245 DOCK8 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.245 DOCK8 Eleanor Williams Gene: dock8 has been classified as Green List (High Evidence).
Growth failure in early childhood v1.12 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542
Primary immunodeficiency v2.244 DOCK2 Eleanor Williams Classified gene: DOCK2 as Green List (high evidence)
Primary immunodeficiency v2.244 DOCK2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.244 DOCK2 Eleanor Williams Gene: dock2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.243 DCLRE1C Eleanor Williams Classified gene: DCLRE1C as Green List (high evidence)
Primary immunodeficiency v2.243 DCLRE1C Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.243 DCLRE1C Eleanor Williams Gene: dclre1c has been classified as Green List (High Evidence).
Primary immunodeficiency v2.242 CTPS1 Eleanor Williams Classified gene: CTPS1 as Green List (high evidence)
Primary immunodeficiency v2.242 CTPS1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.242 CTPS1 Eleanor Williams Gene: ctps1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.241 CTLA4 Eleanor Williams Classified gene: CTLA4 as Green List (high evidence)
Primary immunodeficiency v2.241 CTLA4 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.241 CTLA4 Eleanor Williams Gene: ctla4 has been classified as Green List (High Evidence).
Growth failure in early childhood v1.11 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency to isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160
Primary immunodeficiency v2.240 CORO1A Eleanor Williams Classified gene: CORO1A as Green List (high evidence)
Primary immunodeficiency v2.240 CORO1A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.240 CORO1A Eleanor Williams Gene: coro1a has been classified as Green List (High Evidence).
Primary immunodeficiency v2.239 COPA Eleanor Williams Classified gene: COPA as Green List (high evidence)
Primary immunodeficiency v2.239 COPA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.239 COPA Eleanor Williams Gene: copa has been classified as Green List (High Evidence).
Primary immunodeficiency v2.238 CIITA Eleanor Williams Classified gene: CIITA as Green List (high evidence)
Primary immunodeficiency v2.238 CIITA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.238 CIITA Eleanor Williams Gene: ciita has been classified as Green List (High Evidence).
Primary immunodeficiency v2.237 CD70 Eleanor Williams Classified gene: CD70 as Green List (high evidence)
Primary immunodeficiency v2.237 CD70 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.237 CD70 Eleanor Williams Gene: cd70 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.236 CD40LG Eleanor Williams Classified gene: CD40LG as Green List (high evidence)
Primary immunodeficiency v2.236 CD40LG Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.236 CD40LG Eleanor Williams Gene: cd40lg has been classified as Green List (High Evidence).
Primary immunodeficiency v2.235 CD40 Eleanor Williams Classified gene: CD40 as Green List (high evidence)
Primary immunodeficiency v2.235 CD40 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.235 CD40 Eleanor Williams Gene: cd40 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.234 CD3G Eleanor Williams Classified gene: CD3G as Green List (high evidence)
Primary immunodeficiency v2.234 CD3G Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.234 CD3G Eleanor Williams Gene: cd3g has been classified as Green List (High Evidence).
Primary immunodeficiency v2.233 CD3E Eleanor Williams Classified gene: CD3E as Green List (high evidence)
Primary immunodeficiency v2.233 CD3E Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.233 CD3E Eleanor Williams Gene: cd3e has been classified as Green List (High Evidence).
Primary immunodeficiency v2.232 CD3D Eleanor Williams Classified gene: CD3D as Green List (high evidence)
Primary immunodeficiency v2.232 CD3D Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.232 CD3D Eleanor Williams Gene: cd3d has been classified as Green List (High Evidence).
Primary immunodeficiency v2.231 CD27 Eleanor Williams Classified gene: CD27 as Green List (high evidence)
Primary immunodeficiency v2.231 CD27 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.231 CD27 Eleanor Williams Gene: cd27 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.230 CCBE1 Eleanor Williams Classified gene: CCBE1 as Green List (high evidence)
Primary immunodeficiency v2.230 CCBE1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.230 CCBE1 Eleanor Williams Gene: ccbe1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.229 CASP8 Eleanor Williams Classified gene: CASP8 as Green List (high evidence)
Primary immunodeficiency v2.229 CASP8 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.229 CASP8 Eleanor Williams Gene: casp8 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.228 CASP10 Eleanor Williams Classified gene: CASP10 as Green List (high evidence)
Primary immunodeficiency v2.228 CASP10 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.228 CASP10 Eleanor Williams Gene: casp10 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.227 CARMIL2 Eleanor Williams Classified gene: CARMIL2 as Green List (high evidence)
Primary immunodeficiency v2.227 CARMIL2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.227 CARMIL2 Eleanor Williams Gene: carmil2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.226 CARD14 Eleanor Williams Classified gene: CARD14 as Green List (high evidence)
Primary immunodeficiency v2.226 CARD14 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.226 CARD14 Eleanor Williams Gene: card14 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.225 CARD11 Eleanor Williams Classified gene: CARD11 as Green List (high evidence)
Primary immunodeficiency v2.225 CARD11 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.225 CARD11 Eleanor Williams Gene: card11 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.224 BACH2 Eleanor Williams Classified gene: BACH2 as Green List (high evidence)
Primary immunodeficiency v2.224 BACH2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.224 BACH2 Eleanor Williams Gene: bach2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.223 B2M Eleanor Williams Classified gene: B2M as Green List (high evidence)
Primary immunodeficiency v2.223 B2M Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.223 B2M Eleanor Williams Gene: b2m has been classified as Green List (High Evidence).
Primary immunodeficiency v2.222 AP3B1 Eleanor Williams Classified gene: AP3B1 as Green List (high evidence)
Primary immunodeficiency v2.222 AP3B1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.222 AP3B1 Eleanor Williams Gene: ap3b1 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.221 AK2 Eleanor Williams Classified gene: AK2 as Green List (high evidence)
Primary immunodeficiency v2.221 AK2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.221 AK2 Eleanor Williams Gene: ak2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.220 AIRE Eleanor Williams Classified gene: AIRE as Green List (high evidence)
Primary immunodeficiency v2.220 AIRE Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.220 AIRE Eleanor Williams Gene: aire has been classified as Green List (High Evidence).
Primary immunodeficiency v2.219 ADA2 Eleanor Williams Classified gene: ADA2 as Green List (high evidence)
Primary immunodeficiency v2.219 ADA2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.219 ADA2 Eleanor Williams Gene: ada2 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.218 ADA Eleanor Williams Classified gene: ADA as Green List (high evidence)
Primary immunodeficiency v2.218 ADA Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.218 ADA Eleanor Williams Gene: ada has been classified as Green List (High Evidence).
Primary immunodeficiency v2.217 ACP5 Eleanor Williams Classified gene: ACP5 as Green List (high evidence)
Primary immunodeficiency v2.217 ACP5 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.217 ACP5 Eleanor Williams Gene: acp5 has been classified as Green List (High Evidence).
Primary immunodeficiency v2.216 TBX1 Eleanor Williams Classified gene: TBX1 as Amber List (moderate evidence)
Primary immunodeficiency v2.216 TBX1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.216 TBX1 Eleanor Williams Gene: tbx1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.215 TAPBP Eleanor Williams Classified gene: TAPBP as Amber List (moderate evidence)
Primary immunodeficiency v2.215 TAPBP Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.215 TAPBP Eleanor Williams Gene: tapbp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.214 RHOH Eleanor Williams Classified gene: RHOH as Amber List (moderate evidence)
Primary immunodeficiency v2.214 RHOH Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.214 RHOH Eleanor Williams Gene: rhoh has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.213 NLRP1 Eleanor Williams Classified gene: NLRP1 as Amber List (moderate evidence)
Primary immunodeficiency v2.213 NLRP1 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.213 NLRP1 Eleanor Williams Gene: nlrp1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.212 IL21 Eleanor Williams Classified gene: IL21 as Amber List (moderate evidence)
Primary immunodeficiency v2.212 IL21 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.212 IL21 Eleanor Williams Gene: il21 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.211 CD8A Eleanor Williams Classified gene: CD8A as Amber List (moderate evidence)
Primary immunodeficiency v2.211 CD8A Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.211 CD8A Eleanor Williams Gene: cd8a has been classified as Amber List (Moderate Evidence).
DDG2P v2.10 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME 614615 to Joubert syndrome 25, 616781
Fetal anomalies v1.105 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME to Joubert syndrome 25, 616781
Primary immunodeficiency v2.210 AP1S3 Eleanor Williams Classified gene: AP1S3 as Amber List (moderate evidence)
Primary immunodeficiency v2.210 AP1S3 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency v2.210 AP1S3 Eleanor Williams Gene: ap1s3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.441 CEP104 Arina Puzriakova changed review comment from: Four related cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.; to: Four unrelated cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.
Intellectual disability v3.441 CEP104 Arina Puzriakova Phenotypes for gene: CEP104 were changed from JOUBERT SYNDROME to Joubert syndrome 25, 616781
Intellectual disability v3.440 CEP104 Arina Puzriakova Publications for gene: CEP104 were set to
Intellectual disability v3.439 CEP104 Arina Puzriakova Classified gene: CEP104 as Amber List (moderate evidence)
Intellectual disability v3.439 CEP104 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support a Green rating on this panel, and so this gene will be flagged for review at the next GMS panel update (added 'for-review' tag)
Intellectual disability v3.439 CEP104 Arina Puzriakova Gene: cep104 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.438 CEP104 Arina Puzriakova Tag for-review tag was added to gene: CEP104.
Intellectual disability v3.438 CEP104 Arina Puzriakova edited their review of gene: CEP104: Added comment: Four related cases reported (PMID:26477546 and 31625690). Moderate-severe ID recorded in two patients and was formally assessed in the remaining two due to young age. However, significant DD was noted in both and in line with the diagnosis of Joubert, it can be anticipated that their presentation is within the scope of this panel.; Changed publications: 26477546, 31625690
Intellectual disability v3.438 CEP104 Arina Puzriakova reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: None; Publications: 31625690; Phenotypes: Joubert syndrome 25, 616781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.39 MPV17 Ivone Leong Phenotypes for gene: MPV17 were changed from Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), MIM# 256810 to Mitochondrial DNA depletion syndrome 6 (hepatocerebral type), 256810
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Tag for-review tag was added to gene: OCRL.
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Classified gene: OCRL as Amber List (moderate evidence)
Hypophosphataemia or rickets v2.10 OCRL 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 even evidence to support a gene-disease assocation and therefore this gene should be rated Green for this panel. It has been given an Amber rating for now until the next major review of this panel.
Hypophosphataemia or rickets v2.10 OCRL Ivone Leong Gene: ocrl has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Classified gene: CACNA2D2 as Amber List (moderate evidence)
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Added comment: Comment on list classification: Kept rating Amber as severe GDD is a neurodegenerative manifestation that is secondary to the onset of seizures, which represent the key phenotypic feature of this disorder.

This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting these cases.
Intellectual disability v3.438 CACNA2D2 Arina Puzriakova Gene: cacna2d2 has been classified as Amber List (Moderate Evidence).
Hypophosphataemia or rickets v2.9 OCRL Ivone Leong Phenotypes for gene: OCRL were changed from Lowe syndrome, MIM# 309000 to Lowe syndrome, 309000
Hypertrophic cardiomyopathy - teen and adult v2.11 JPH2 Zornitza Stark reviewed gene: JPH2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30681346, 17509612, 23973696, 26869393, 28393127, 30235249; Phenotypes: Cardiomyopathy, hypertrophic, MIM#613873; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.20 RIMS2 Zornitza Stark gene: RIMS2 was added
gene: RIMS2 was added to Retinal disorders. Sources: Expert list
Mode of inheritance for gene: RIMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIMS2 were set to 32470375
Phenotypes for gene: RIMS2 were set to Cone-rod synaptic disorder syndrome, congenital nonprogressive, MIM# 618970
Review for gene: RIMS2 was set to GREEN
gene: RIMS2 was marked as current diagnostic
Added comment: Biallelic LoF variants reported with syndromic congenital cone-rod synaptic disease in 7 individuals from 4 families.
Sources: Expert list
Retinal disorders v2.20 RDH11 Zornitza Stark reviewed gene: RDH11: Rating: RED; Mode of pathogenicity: None; Publications: 24916380, 15634683, 30731079, 18326732; Phenotypes: Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.437 CARS2 Arina Puzriakova Publications for gene: CARS2 were set to 25787132
Intellectual disability v3.436 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Intellectual disability v3.436 CARS2 Arina Puzriakova Added comment: 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.
Intellectual disability v3.436 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Classified gene: C2CD3 as Amber List (moderate evidence)
Intellectual disability v3.435 C2CD3 Arina Puzriakova Added comment: Comment on list classification: Despite phenotypic diversity among cases with C2CD3 variants, ID/DD is consistently reported in living patients.

Therefore, this gene could be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).
Intellectual disability v3.435 C2CD3 Arina Puzriakova Gene: c2cd3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.434 C2CD3 Arina Puzriakova Phenotypes for gene: C2CD3 were changed from ?Orofaciodigital syndrome XIV 615948 to Orofaciodigital syndrome XIV, 615948; Joubert-related disorder
Intellectual disability v3.433 C2CD3 Arina Puzriakova Publications for gene: C2CD3 were set to 27094867; 24997988
Intellectual disability v3.432 C2CD3 Arina Puzriakova Tag for-review tag was added to gene: C2CD3.
Intellectual disability v3.432 C2CD3 Arina Puzriakova edited their review of gene: C2CD3: Changed publications: 24997988, 26092869, 26477546, 27094867, 30097616
Intellectual disability v3.432 C2CD3 Arina Puzriakova changed review comment from: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with occipital encephalocele and a ventricular septal defect. Similar abnormalities were identified in another sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.; to: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.
Intellectual disability v3.432 C2CD3 Arina Puzriakova reviewed gene: C2CD3: Rating: ; Mode of pathogenicity: None; Publications: 24997988, 26092869, 26477546, 27094867; Phenotypes: Orofaciodigital syndrome XIV, 615948, Joubert-related disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypophosphataemia or rickets v2.8 FAH Ivone Leong Phenotypes for gene: FAH were changed from Tyrosinemia, type I, MIM# 276700 to Tyrosinemia, type I, 276700
Primary immunodeficiency v2.209 SH3BP2 Eleanor Williams Source Other was added to SH3BP2.
Publications for gene SH3BP2 were updated from 29669173; 22640988; 32048120; 28914985; 11381256; 32086639; 25705883; 25470448; 25220465 to 25220465; 11381256; 25705883; 25470448; 32048120; 32086639; 29669173; 11113824; 22640988; 28914985; 16053841
Primary immunodeficiency v2.209 TFRC Eleanor Williams Source Other was added to TFRC.
Publications for gene TFRC were updated from 32048120; 32086639; 26642240 to 32086639; 26642240; 32048120
Primary immunodeficiency v2.209 TBX1 Eleanor Williams Source Other was added to TBX1.
Publications for gene TBX1 were updated from 11242110; 14585638; 24198816; 32048120; 32086639 to 11242110; 32048120; 32086639; 14585638; 24198816; 12548732
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NLRP1 Eleanor Williams Source Other was added to NLRP1.
Publications for gene NLRP1 were updated from 29850521; 27662089; 31484767; 27965258 to 27965258; 31484767; 27662089; 29850521
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL21 Eleanor Williams Source Other was added to IL21.
Publications for gene IL21 were updated from 32048120; 24746753; 32086639 to 32086639; 24746753; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 BCL11B Eleanor Williams Publications for gene BCL11B were updated from 27959755; 32086639; 29296816; 32048120 to 27959755; 32086639; 29296816; 32048120
Primary immunodeficiency v2.209 AP1S3 Eleanor Williams Source Other was added to AP1S3.
Publications for gene AP1S3 were updated from 32048120; 32086639 to 32086639; 24791904; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 XIAP Eleanor Williams Source Other was added to XIAP.
Publications for gene XIAP were updated from 17080092; 21119115; 25943627; 21173700; 22228567 to 26581487; 21119115; 23973892; 17080092; 21173700; 22228567; 23131490; 25943627; 31754776
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 UNC13D Eleanor Williams Source Other was added to UNC13D.
Publications for gene UNC13D were updated from 14622600; 16278825; 15632205; 17993578; 15703195 to 15703195; 16278825; 17993578; 27914778; 15632205; 14622600; 29312353
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TREX1 Eleanor Williams Source Other was added to TREX1.
Publications for gene TREX1 were updated from 20799324; 16845398; 21808053; 25604658 to 16845398; 25604658; 21808053; 17846997; 20799324
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TRAC Eleanor Williams Source Other was added to TRAC.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TNFRSF1A Eleanor Williams Source Other was added to TNFRSF1A.
Publications for gene TNFRSF1A were updated from 10199409; 11175303; 10902757; 17360963 to 10199409; 12209523; 11175303; 10902757; 23965844; 17360963; 11115159
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TNFAIP3 Eleanor Williams Source Other was added to TNFAIP3.
Publications for gene TNFAIP3 were updated from 26642243; 27845235; 29572183; 28659290; 29317407 to 31164164; 29317407; 26642243; 28659290; 27845235; 29572183
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TMEM173 Eleanor Williams Source Other was added to TMEM173.
Publications for gene TMEM173 were updated from 25029335; 25401470; 30705050; 29976662; 29491158; 29425920 to 25401470; 29425920; 25029335; 29491158; 29976662; 30705050
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 STXBP2 Eleanor Williams Source Other was added to STXBP2.
Publications for gene STXBP2 were updated from 19804848; 19884660; 20798128; 20301617 to 19884660; 30557712; 29776323; 22451424; 20798128; 20301617; 19804848
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 STX11 Eleanor Williams Source Other was added to STX11.
Publications for gene STX11 were updated from 15703195; 16278825; 16582076; 24459464; 20301617 to 16278825; 18710388; 16582076; 20301617; 24459464; 15703195
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 STK4 Eleanor Williams Source Other was added to STK4.
Publications for gene STK4 were updated from 22174160; 22294732; 26801501; 26117625; 24453252 to 22294732; 26801501; 24453252; 26117625; 22174160
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 STAT3 Eleanor Williams Source Other was added to STAT3.
Publications for gene STAT3 were updated from 17676033; 17881745; 25038750; 25359994 to 28402852; 25349174; 17881745; 17676033; 25359994; 25038750
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 SLC29A3 Eleanor Williams Source Other was added to SLC29A3.
Publications for gene SLC29A3 were updated from 16650224; 18940313; 20619369; 17461801; 19336477; 16155931; 20140240; 16118898; 21178579; 19175903; 9545394; 21888995; 23530176; 18947330; 22238637; 22653152; 22875837 to 17461801; 19336477; 23530176; 18940313; 22238637; 16118898; 22875837; 19175903; 21888995; 20140240; 16155931; 21178579; 9545394; 16650224; 22653152; 18947330; 20619369
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 SH2D1A Eleanor Williams Source Other was added to SH2D1A.
Publications for gene SH2D1A were updated from 9771704; 10556288; 10598819; 10694488; 11049992; 29670631; 9774102 to 21119115; 29670631; 10556288; 9774102; 11049992; 10598819; 9771704; 10694488; 25085526; 31754776
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PSTPIP1 Eleanor Williams Source Other was added to PSTPIP1.
Publications for gene PSTPIP1 were updated from 28251506; 28628471; 28960754; 29575118; 26025129 to 21532836; 9212761; 28628471; 28251506; 28960754; 22161697; 26025129; 29575118
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PRF1 Eleanor Williams Source Other was added to PRF1.
Publications for gene PRF1 were updated from 11179007; 10583959; 12229880; 14757862; 20301617; 15365097; 15632205; 14757862; 16860143 to 28468610; 22248322; 12229880; 28806468; 15365097; 11179007; 14757862; 16860143; 10583959; 15632205; 20301617
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 POLA1 Eleanor Williams Source Other was added to POLA1.
Publications for gene POLA1 were updated from 27019227 to 27019227; 6794369; 15804299
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PLCG2 Eleanor Williams Source Other was added to PLCG2.
Publications for gene PLCG2 were updated from 22236196; 23000145; 29538758 to 23000145; 29538758; 25760457; 22236196
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 OTULIN Eleanor Williams Source Other was added to OTULIN.
Publications for gene OTULIN were updated from 27523608; 27559085 to 27559085; 27523608
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NOD2 Eleanor Williams Source Other was added to NOD2.
Publications for gene NOD2 were updated from 11528384; 18955195; 15459013; 4056967 to 11528384; 25416713; 4056967; 25136265; 15459013; 19479837; 18955195; 28887115
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NLRP3 Eleanor Williams Publications for gene NLRP3 were updated from 28847925; 12522564; 11590390; 14872505; 14476827; 29366613; 11992256; 12032915; 11687797 to 28847925; 12522564; 11590390; 14872505; 18423104; 14476827; 29366613; 11992256; 12032915; 11687797
Primary immunodeficiency v2.209 NLRP3 Eleanor Williams Publications for gene NLRP3 were updated from 28847925; 12522564; 29366613; 11992256; 12032915; 11687797 to 28847925; 12522564; 11590390; 14872505; 14476827; 29366613; 11992256; 12032915; 11687797
Primary immunodeficiency v2.209 NLRP3 Eleanor Williams Source Other was added to NLRP3.
Publications for gene NLRP3 were updated from 11687797; 11992256; 12032915; 12522564; 28847925; 29366613 to 28847925; 12522564; 29366613; 11992256; 12032915; 11687797
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NLRP12 Eleanor Williams Source Other was added to NLRP12.
Publications for gene NLRP12 were updated from 18230725; 27779193; 27633793; 29178652; 29248470 to 18230725; 27633793; 29178652; 21360512; 27779193; 29248470
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NLRC4 Eleanor Williams Publications for gene NLRC4 were updated from 27876626; 25217959; 25385754; 25217960 to 27876626; 25217959; 25385754; 25217960
Primary immunodeficiency v2.209 NLRC4 Eleanor Williams Source Other was added to NLRC4.
Publications for gene NLRC4 were updated from 25217960; 25217959; 25385754; 27876626 to 27876626; 25217959; 25385754; 25217960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MVK Eleanor Williams Source Other was added to MVK.
Publications for gene MVK were updated from 10369261; 16435210 to 19011501; 16435210; 22038276; 21708801; 10369261
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MSN Eleanor Williams Source Other was added to MSN.
Publications for gene MSN were updated from 27405666; 29556235 to 29556235; 27405666
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MEFV Eleanor Williams Publications for gene MEFV were updated from 9288094; 9668175; 14679589; 10090880; 9266193; 10787449; 11903360; 15643295; 11242116 to 9288094; 9668175; 14679589; 10090880; 9266193; 10787449; 11903360; 15643295; 11242116
Primary immunodeficiency v2.209 MEFV Eleanor Williams Source Other was added to MEFV.
Publications for gene MEFV were updated from 14679589; 10787449; 11903360; 11242116; 10090880; 9668175; 9288094 to 9288094; 9668175; 14679589; 10090880; 9266193; 10787449; 11903360; 15643295; 11242116
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MALT1 Eleanor Williams Source Other was added to MALT1.
Publications for gene MALT1 were updated from 23727036; 24332264; 25627829 to 25627829; 23727036; 24332264
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MAGT1 Eleanor Williams Source Other was added to MAGT1.
Publications for gene MAGT1 were updated from 21796205; 23846901; 27095930; 25956530; 25504528; 25205404; 24550228; 23871722; 21983175 to 25205404; 27095930; 25956530; 23846901; 21796205; 25504528; 29635109; 23871722; 21983175; 24550228
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 LYST Eleanor Williams Source Other was added to LYST.
Publications for gene LYST were updated from 8896560; 9215679; 9215680; 10482950 to 9215679; 18043242; 8717042; 9215680; 10482950; 8896560; 26944273; 29939658
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 LRBA Eleanor Williams Source Other was added to LRBA.
Publications for gene LRBA were updated from 22608502; 25468195; 22721650 to 26768763; 25468195; 25931386; 22608502; 22721650; 26707784
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 LPIN2 Eleanor Williams Source Other was added to LPIN2.
Publications for gene LPIN2 were updated from 29387759; 15994876; 17330256; 27860302 to 2809904; 27252506; 29387759; 10969284; 17330256; 15994876; 27860302
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 LCK Eleanor Williams Source Other was added to LCK.
Publications for gene LCK were updated from 22985903; 9664084; 11351273 to 22985903; 11351273; 9664084
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL36RN Eleanor Williams Source Other was added to IL36RN.
Publications for gene IL36RN were updated from 23303454; 23698098; 22903787 to 23303454; 21848462; 23698098; 22903787; 21839423
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL2RA Eleanor Williams Source Other was added to IL2RA.
Publications for gene IL2RA were updated from 9096364; 17196245; 23416241; 24116927 to 9096364; 24116927; 17196245; 23416241
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL21R Eleanor Williams Source Other was added to IL21R.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL1RN Eleanor Williams Source Other was added to IL1RN.
Publications for gene IL1RN were updated from 19494218; 19494219 to 19494219; 22127713; 19494218
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL10RB Eleanor Williams Source Other was added to IL10RB.
Publications for gene IL10RB were updated from 19890111; 21519361; 28785144; 27350736; 27302973 to 22236434; 27350736; 27302973; 19890111; 21519361; 28785144
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL10RA Eleanor Williams Source Other was added to IL10RA.
Publications for gene IL10RA were updated from 19890111; 21519361; 22476154; 29788474; 29248579; 29140941; 28864178; 29059189 to 22476154; 29248579; 19890111; 21519361; 29059189; 29140941; 28864178; 22236434; 29788474
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 FOXP3 Eleanor Williams Source Other was added to FOXP3.
Publications for gene FOXP3 were updated from 17635943; 16741580; 14671208; 11120765; 11295725 to 11295725; 29241729; 30443250; 17635943; 18951619; 11120765; 16741580; 14671208
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 FASLG Eleanor Williams Source Other was added to FASLG.
Publications for gene FASLG were updated from 17605793; 20301287; 8787672; 17605793; 27848183 to 8806292; 16537120; 16394653; 8787672; 20301287; 17605793; 26907631; 27848183; 25451160; 22857792; 7511063; 22983577
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 FAS Eleanor Williams Source Other was added to FAS.
Publications for gene FAS were updated from 7540117; 9028321; 9821419; 9927496; 10709732; 15459302; 8929361; 28668589; 26258116 to 26258116; 10709732; 15459302; 28668589; 8806292; 16537120; 16394653; 7540117; 26907631; 9927496; 9028321; 8929361; 9821419; 25451160; 22857792; 7511063; 22983577
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 DOCK8 Eleanor Williams Source Other was added to DOCK8.
Publications for gene DOCK8 were updated from 19776401; 20004785; 25627830; 25724123 to 25724123; 20004785; 25627830; 19776401
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CTLA4 Eleanor Williams Source Other was added to CTLA4.
Publications for gene CTLA4 were updated from 25213377; 25329329 to 25213377; 25329329; 29729943
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 COPA Eleanor Williams Source Other was added to COPA.
Publications for gene COPA were updated from 25894502; 28956095; 25894502; 29137621 to 28956095; 25894502; 29137621
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CARD14 Eleanor Williams Source Other was added to CARD14.
Publications for gene CARD14 were updated from 23648549; 22521418; 22703878; 23067081; 29704870; 29689250; 23711932; 30248356; 29980436 to 22521418; 30248356; 23648549; 29689250; 22703878; 29980436; 23067081; 29704870; 23711932
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CARD11 Eleanor Williams Source Other was added to CARD11.
Publications for gene CARD11 were updated from 25352053; 23374270; 29074947; 23561803; 23129749; 30170123; 28628108; 28826773 to 29074947; 30170123; 28628108; 23129749; 25352053; 23374270; 23561803; 26289640; 28826773
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 BCL10 Eleanor Williams Source Other was added to BCL10.
Publications for gene BCL10 were updated from 32048120; 25365219; 32086639 to 32086639; 25365219; 32048120
Primary immunodeficiency v2.209 AIRE Eleanor Williams Source Other was added to AIRE.
Publications for gene AIRE were updated from 28911151; 29437776; 29108822; 9398839; 9837820; 9888391; 10677297; 11836330; 19758376; 11600535; 19807739 to 19758376; 29949487; 29108822; 28257655; 19807739; 10677297; 9398839; 11600535; 29483906; 9888391; 28911151; 9735375; 11836330; 29437776; 9837820; 30565240
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ADAM17 Eleanor Williams Source Other was added to ADAM17.
Publications for gene ADAM17 were updated from 22010916; 28930861; 20603312; 32048120; 25171914; 11149563; 25058236; 32086639; 29560122; 26683521; 25804906 to 29560122; 22010916; 25058236; 32048120; 20603312; 32086639; 26683521; 11149563; 25804906; 25171914; 28930861
Primary immunodeficiency v2.209 ADA2 Eleanor Williams Source Other was added to ADA2.
Publications for gene ADA2 were updated from 24552284; 24552285; 26922074; 29564582 to 24552284; 24552285; 29564582; 27059682; 26922074; 27444081
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ACP5 Eleanor Williams Source Other was added to ACP5.
Publications for gene ACP5 were updated from 26789720; 26951490; 26346816; 18924170; 21217755; 26789720; 21217752 to 21217755; 26789720; 21217752; 18924170; 26951490; 26346816
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TNFRSF4 Eleanor Williams Source Other was added to TNFRSF4.
Publications for gene TNFRSF4 were updated from 32048120; 32086639 to 32086639; 23897980; 32048120
Primary immunodeficiency v2.209 SEMA3E Eleanor Williams Source Other was added to SEMA3E.
Publications for gene SEMA3E were updated from 12144540; 1735828; 32048120; 21055784; 32086639 to 12144540; 1735828; 11241468; 32048120; 21055784; 32086639
Primary immunodeficiency v2.209 RNU4ATAC Eleanor Williams Source Other was added to RNU4ATAC.
Publications for gene RNU4ATAC were updated from 32048120; 32086639 to 26522830; 32086639; 21474760; 32048120
Primary immunodeficiency v2.209 RELB Eleanor Williams Source Other was added to RELB.
Publications for gene RELB were updated from 32048120; 26385063; 32086639 to 26385063; 32086639; 32048120
Primary immunodeficiency v2.209 NFAT5 Eleanor Williams Source Other was added to NFAT5.
Publications for gene NFAT5 were updated from 32048120; 32086639 to 32086639; 25667416; 32048120
Primary immunodeficiency v2.209 KMT2D Eleanor Williams Source Other was added to KMT2D.
Publications for gene KMT2D were updated from 25142838; 32048120; 15887282; 15523604; 26411453; 32086639 to 25142838; 15523604; 21671394; 32048120; 15887282; 21607748; 32086639; 23913813; 26411453
Primary immunodeficiency v2.209 KDM6A Eleanor Williams Source Other was added to KDM6A.
Publications for gene KDM6A were updated from 25546742; 25142838; 32048120; 15887282; 15523604; 26411453; 32086639 to 25142838; 15523604; 32048120; 25546742; 15887282; 32086639; 26411453; 22197486; 23076834
Primary immunodeficiency v2.209 JAK1 Eleanor Williams Source Other was added to JAK1.
Publications for gene JAK1 were updated from 32048120; 28111307; 32086639 to 32086639; 28111307; 32048120
Primary immunodeficiency v2.209 FAAP24 Eleanor Williams Source Other was added to FAAP24.
Publications for gene FAAP24 were updated from 32048120; 27473539; 32086639 to 32086639; 17289582; 27473539; 32048120
Primary immunodeficiency v2.209 AP3D1 Eleanor Williams Source Other was added to AP3D1.
Publications for gene AP3D1 were updated from 32048120; 26744459; 32086639 to 32086639; 26744459; 30472485; 32048120
Primary immunodeficiency v2.209 TAPBP Eleanor Williams Source Other was added to TAPBP.
Publications for gene TAPBP were updated from 32048120; 12149238; 32086639 to 32086639; 12149238; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RNF31 Eleanor Williams Source Other was added to RNF31.
Publications for gene RNF31 were updated from 32048120; 26008899; 32086639; 30936877 to 30936877; 32086639; 26008899; 32048120
Primary immunodeficiency v2.209 RHOH Eleanor Williams Source Other was added to RHOH.
Publications for gene RHOH were updated from 32048120; 22850876; 24189071; 32086639 to 32086639; 24189071; 22850876; 32048120
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD8A Eleanor Williams Source Other was added to CD8A.
Publications for gene CD8A were updated from 32048120; 17658607; 11435463; 32086639 to 32048120; 32086639; 26563160; 17658607; 11435463
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 BCL11B Eleanor Williams Source Other was added to BCL11B.
Publications for gene BCL11B were updated from 32048120; 27959755; 29296816; 32086639 to 27959755; 32086639; 29296816; 32048120
Primary immunodeficiency v2.209 ZAP70 Eleanor Williams Publications for gene ZAP70 were updated from 8202713; 19548248; 18509675; 26783323; 25732729; 25805655 to 1333922; 8202713; 19548248; 21094993; 18509675; 26783323; 2511270; 25732729; 8124727; 25805655
Primary immunodeficiency v2.209 ZAP70 Eleanor Williams Source Other was added to ZAP70.
Publications for gene ZAP70 were updated from to 8202713; 19548248; 18509675; 26783323; 25732729; 25805655
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TTC7A Eleanor Williams Source Other was added to TTC7A.
Publications for gene TTC7A were updated from 24292712; 23423984; 23830146; 24417819; 24417819 to 23423984; 23830146; 24292712; 24417819
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TPP2 Eleanor Williams Source Other was added to TPP2.
Publications for gene TPP2 were updated from 25414442; 25525876 to 25414442; 25525876
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TCN2 Eleanor Williams Source Other was added to TCN2.
Publications for gene TCN2 were updated from 24305960; 7980584; 7849710; 20352340; 18956254 to 18956254; 20352340; 7849710; 7980584; 12107818; 19373259; 24305960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TAP2 Eleanor Williams Source Other was added to TAP2.
Publications for gene TAP2 were updated from 7517574; 10560675; 11529920; 20083708 to 11529920; 7517574; 10560675; 20083708
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 TAP1 Eleanor Williams Source Other was added to TAP1.
Publications for gene TAP1 were updated from to 11529920; 7517574; 10560675; 20083708; 10074494
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 STIM1 Eleanor Williams Source Other was added to STIM1.
Publications for gene STIM1 were updated from 19420366; 20876309; 22190180; 24621671; 26560041 to 26560041; 20876309; 22190180; 19420366; 24621671; 24570283
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 STAT5B Eleanor Williams Source Other was added to STAT5B.
Publications for gene STAT5B were updated from 13679528; 16920911; 15827093; 16787985; 17030597; 17389811; 20538865; 26703237; 29844444 to 29844444; 26703237; 17030597; 16920911; 15827093; 16787985; 17389811; 13679528; 20538865
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 SP110 Eleanor Williams Source Other was added to SP110.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 SMARCAL1 Eleanor Williams Source Other was added to SMARCAL1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 SLC46A1 Eleanor Williams Source Other was added to SLC46A1.
Publications for gene SLC46A1 were updated from 17129779; 17446347; 27664775 to 17129779; 27664775; 17446347
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RMRP Eleanor Williams Source Other was added to RMRP.
Publications for gene RMRP were updated from 25663137; 26830278; 26279652; 24217815; 3582365; 2328993 to 25663137; 3582365; 14569125; 12107819; 11207361; 26830278; 24217815; 26279652; 2328993
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RFXAP Eleanor Williams Source Other was added to RFXAP.
Publications for gene RFXAP were updated from 9118943; 9287230; 22390233; 20197681; 18336911; 12498778; 9806639 to 22390233; 9118943; 9806639; 9806639; 9287230; 18336911; 20197681; 12498778
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RFXANK Eleanor Williams Source Other was added to RFXANK.
Publications for gene RFXANK were updated from 11313409; 12618906; 22863278; 20414676; 9806546 to 20414676; 9806546; 12618906; 22863278; 11313409
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RFX5 Eleanor Williams Source Other was added to RFX5.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RBCK1 Eleanor Williams Source Other was added to RBCK1.
Publications for gene RBCK1 were updated from 23104095; 29260357 to 23798481; 610924; 29260357; 23104095
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RASGRP1 Eleanor Williams Source Other was added to RASGRP1.
Publications for gene RASGRP1 were updated from 30030704; 29282224; 29155103; 28822832; 27776107 to 29155103; 28822832; 29282224; 27776107; 30030704
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RAG2 Eleanor Williams Source Other was added to RAG2.
Publications for gene RAG2 were updated from to 16960852; 30046960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RAG1 Eleanor Williams Source Other was added to RAG1.
Publications for gene RAG1 were updated from to 16960852; 8810255; 30046960
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 RAB27A Eleanor Williams Source Other was added to RAB27A.
Publications for gene RAB27A were updated from 12058346; 12531900; 12522785; 15163896; 15163896 to 12531900; 9486701; 12058346; 10835631; 24134793; 12522785; 15163896; 16517541
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PTPRC Eleanor Williams Source Other was added to PTPRC.
Publications for gene PTPRC were updated from 10700239; 11145714; 22689986 to 11145714; 10700239; 22689986
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PSMB8 Eleanor Williams Source Other was added to PSMB8.
Publications for gene PSMB8 were updated from 21129723; 21953331; 21881205; 21852578; 21953331 to 21881205; 20159315; 21953331; 21129723; 20534754; 21852578
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PRKCD Eleanor Williams Publications for gene PRKCD were updated from 23319571; 27541826; 23666743; 23430113 to 19075392; 23430113; 25842288; 23722905; 23319571; 27541826; 23666743
Primary immunodeficiency v2.209 PRKCD Eleanor Williams Source Other was added to PRKCD.
Publications for gene PRKCD were updated from 23319571; 23666743; 23430113 to 23319571; 27541826; 23666743; 23430113
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PNP Eleanor Williams Source Other was added to PNP.
Publications for gene PNP were updated from to 1384322; 3029074
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 PEPD Eleanor Williams Source Other was added to PEPD.
Publications for gene PEPD were updated from 2365824; 1972707; 6637477; 2365824; 16470701; 8900231; 15309682; 17142620; 19308961 to 8900231; 2365824; 17142620; 26110198; 15309682; 6637477; 16470701; 19308961; 22726576; 1972707
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ORAI1 Eleanor Williams Source Other was added to ORAI1.
Publications for gene ORAI1 were updated from 16582901; 20004786 to 7798233; 16582901; 8814256; 20004786
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NHEJ1 Eleanor Williams Source Other was added to NHEJ1.
Publications for gene NHEJ1 were updated from to 16439204; 20113890
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 NFKBIA Eleanor Williams Source Other was added to NFKBIA.
Publications for gene NFKBIA were updated from 14523047; 15337789; 17931563; 18412279 to 15337789; 23708964; 18412279; 17931563; 28597146; 28417298; 14523047
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MYSM1 Eleanor Williams Source Other was added to MYSM1.
Publications for gene MYSM1 were updated from 24288411; 26220525; 28115216; 28446309; 22184403; 26474655 to 26474655; 26220525; 24288411; 28446309; 28115216; 22184403
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MTHFD1 Eleanor Williams Source Other was added to MTHFD1.
Publications for gene MTHFD1 were updated from 27707659; 25633902 to 27707659; 25633902; 21813566; 9611072; 12384833
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 MAP3K14 Eleanor Williams Source Other was added to MAP3K14.
Publications for gene MAP3K14 were updated from 29230214; 25406581; 29259025 to 29230214; 25406581; 29259025
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 LIG4 Eleanor Williams Source Other was added to LIG4.
Publications for gene LIG4 were updated from to 20113890; 16357942
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 LAT Eleanor Williams Source Other was added to LAT.
Publications for gene LAT were updated from 27522155; 27242165 to 27522155; 27242165
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 JAK3 Eleanor Williams Source Other was added to JAK3.
Publications for gene JAK3 were updated from to 7481768; 7659163
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ITK Eleanor Williams Source Other was added to ITK.
Publications for gene ITK were updated from 19425169; 22289921; 21109689 to 29867957; 22289921; 21109689; 19425169
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ITCH Eleanor Williams Source Other was added to ITCH.
Publications for gene ITCH were updated from 20170897; 26854353; 19592251; 20962770; 27322655 to 30705142; 20962770; 26854353; 20170897; 19592251; 27322655
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL7R Eleanor Williams Source Other was added to IL7R.
Publications for gene IL7R were updated from to 9843216
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL2RG Eleanor Williams Source Other was added to IL2RG.
Publications for gene IL2RG were updated from to 8712778; 9921912; 8462096; 7668284
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IL10 Eleanor Williams Source Other was added to IL10.
Publications for gene IL10 were updated from 19890111; 20951137 to 19890111; 20951137; 22236434
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IKBKG Eleanor Williams Source Other was added to IKBKG.
Publications for gene IKBKG were updated from 11047757 to 16818673; 11179023; 16950813; 15356572; 11047757
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 IKBKB Eleanor Williams Source Other was added to IKBKB.
Publications for gene IKBKB were updated from 25216719; 24369075; 30337470 to 30337470; 25216719; 24369075
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ICOS Eleanor Williams Source Other was added to ICOS.
Publications for gene ICOS were updated from 29867948; 28861081; 12577056; 15507387; 19380800; 25678089; 26399252; 10413651; 29867948; 25678089; 24795713; 29226302; 29226301 to 10413651; 26399252; 25678089; 29226301; 19380800; 28861081; 15507387; 24795713; 12577056; 29226302; 29867948
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 FOXN1 Eleanor Williams Source Other was added to FOXN1.
Publications for gene FOXN1 were updated from 28636882; 15180707; 21507891; 11159512; 31447097; 10206641; 28077132; 29593714 to 11159512; 29593714; 21507891; 10206641; 28636882; 15180707; 28077132; 31447097
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 FAT4 Eleanor Williams Source Other was added to FAT4.
Publications for gene FAT4 were updated from 24913602; 25616299; 29681106 to 29681106; 22473091; 22469822; 25616299; 24056717; 24913602
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 FADD Eleanor Williams Source Other was added to FADD.
Publications for gene FADD were updated from 21109225; 17656375; 25794656 to 18070632; 17656375; 25794656; 21109225
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 EXTL3 Eleanor Williams Source Other was added to EXTL3.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 EPG5 Eleanor Williams Source Other was added to EPG5.
Publications for gene EPG5 were updated from 23222957; 25331754; 26917586; 26395118; 23838600; 23674064; 28624465 to 23674064; 28624465; 26917586; 28168853; 26395118; 23222957; 23838600; 25331754
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 DOCK2 Eleanor Williams Source Other was added to DOCK2.
Publications for gene DOCK2 were updated from 26083206; 28694805; 29503648 to 26083206; 29503648; 29204803; 28694805
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 DCLRE1C Eleanor Williams Source Other was added to DCLRE1C.
Publications for gene DCLRE1C were updated from to 32092471; 11336668; 12569164; 10416610; 26476407; 24144642; 31393046; 12406895; 12055248; 16540517; 15731174
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CTPS1 Eleanor Williams Source Other was added to CTPS1.
Publications for gene CTPS1 were updated from 24870241; 26424649; 27638562; 17576681; 9536098 to 26424649; 17576681; 27638562; 9536098; 29884857; 24870241
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CORO1A Eleanor Williams Source Other was added to CORO1A.
Publications for gene CORO1A were updated from 23522482; 18836449; 19097825 to 23522482; 19097825; 18836449; 25073507
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CIITA Eleanor Williams Source Other was added to CIITA.
Publications for gene CIITA were updated from 8402893; 9099848; 11862382 to 8402893; 11862382; 9099848
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD70 Eleanor Williams Source Other was added to CD70.
Publications for gene CD70 were updated from 28011863; 28011864; 29434583 to 28011864; 28011863; 29434583
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD40LG Eleanor Williams Source Other was added to CD40LG.
Publications for gene CD40LG were updated from 7679801; 7678782; 7679206; 8094231; 7586644; 17146684; 7882172; 11875495; 20301576 to 11875495; 7678782; 7679801; 27189378; 8094231; 20301576; 27697500; 19931163; 17146684; 7882172; 25840720; 7586644; 7679206
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD40 Eleanor Williams Source Other was added to CD40.
Publications for gene CD40 were updated from 11675497; 12584544; 20301287; 17502893 to 11675497; 20301287; 12584544; 24122029; 17502893
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD3G Eleanor Williams Source Other was added to CD3G.
Publications for gene CD3G were updated from 1635567; 17277165 to 29653965; 17277165; 1635567; 24910257
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD3E Eleanor Williams Source Other was added to CD3E.
Publications for gene CD3E were updated from to 15546002; 8490660
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD3D Eleanor Williams Source Other was added to CD3D.
Publications for gene CD3D were updated from to 14602880; 21926461; 15546002
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD27 Eleanor Williams Source Other was added to CD27.
Publications for gene CD27 were updated from 22197273; 22801960; 25843314 to 25843314; 22801960; 22197273
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CD247 Eleanor Williams Source Other was added to CD247.
Publications for gene CD247 were updated from 16672702; 26690594; 17170122; 27555457; 25688246; https://doi.org/10.14785/lpsn-2014-0012; 26542031 to 26690594; 26542031; 17170122; 27555457; 25688246; 16672702; https://doi.org/10.14785/lpsn-2014-0012
Primary immunodeficiency v2.209 CCBE1 Eleanor Williams Source Other was added to CCBE1.
Publications for gene CCBE1 were updated from 19935664; 19911200; 24913602 to 19911200; 24913602; 19935664
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CASP8 Eleanor Williams Source Other was added to CASP8.
Publications for gene CASP8 were updated from 12353035; 16157684; 24240292; 20301287 to 12353035; 20301287; 16157684; 24240292; 15492869
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CASP10 Eleanor Williams Source Other was added to CASP10.
Publications for gene CASP10 were updated from 25663566; 21447005; 10412980; 16446975; 9028957; 16611303 to 25663566; 16446975; 16611303; 10412980; 21447005; 27378136; 9028957
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 CARMIL2 Eleanor Williams Source Other was added to CARMIL2.
Publications for gene CARMIL2 were updated from 27896283; 27647349; 28112205 to 27647349; 27896283; 28112205; 29479355
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 BACH2 Eleanor Williams Source Other was added to BACH2.
Publications for gene BACH2 were updated from 27807919; 27680876; 28530713 to 27680876; 28530713; 27807919; 30527062
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 B2M Eleanor Williams Source Other was added to B2M.
Publications for gene B2M were updated from 4186801; 25702838 to 25702838; 4186801
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 AP3B1 Eleanor Williams Source Other was added to AP3B1.
Publications for gene AP3B1 were updated from 10024875; 14566336; 8042664; 11809908; 16537806; 19679886; 23403622; 16507770; 28585318 to 19679886; 11809908; 10024875; 16551969; 16537806; 16507770; 28585318; 30974211; 23403622; 8042664; 14566336
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 AK2 Eleanor Williams Source Other was added to AK2.
Publications for gene AK2 were updated from 19043416; 19043417 to 19043416; 19043417
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.209 ADA Eleanor Williams Source Other was added to ADA.
Publications for gene ADA were updated from to 3475710; 6134754; 8227344; 2567118; 6200875; 2166947
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency v2.208 ZAP70 Eleanor Williams edited their review of gene: ZAP70: Added comment: The following PubMed IDs were added to gene ZAP70 (OMIM gene MIM#176947): 19548248;18509675;8202713;26783323;25805655;25732729. These publications have been associated with the gene by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 19548248, 18509675, 8202713, 26783323, 25805655, 25732729
Primary immunodeficiency v2.208 XIAP Eleanor Williams edited their review of gene: XIAP: Added comment: The following PubMed IDs were added to entity XIAP: 31754776;23973892;21119115;26581487;23131490.