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Intellectual disability v2.1066 TANC2 Andrea Haworth commented on gene: TANC2
Autism v0.15 TANC2 Andrea Haworth commented on gene: TANC2
Undiagnosed metabolic disorders v1.399 NNT Catherine Snow Classified gene: NNT as Green List (high evidence)
Undiagnosed metabolic disorders v1.399 NNT Catherine Snow Gene: nnt has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.398 NNT Catherine Snow gene: NNT was added
gene: NNT was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: NNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NNT were set to 27129361; 28546232
Phenotypes for gene: NNT were set to Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736
Review for gene: NNT was set to GREEN
Added comment: Relevant phenotype in OMIM but not in Gene2Phenotype. Sufficient cases in OMIM to classify NNT as Green
Sources: Expert Review
Inborn errors of metabolism v1.377 NNT Catherine Snow Publications for gene: NNT were set to
Unexplained paediatric onset end-stage renal disease v0.48 MUC1 Eleanor Williams Mode of pathogenicity for gene: MUC1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Unexplained paediatric onset end-stage renal disease v0.47 MUC1 Eleanor Williams Publications for gene: MUC1 were set to 25738250; 24670410; 23396133; 27157321
Unexplained paediatric onset end-stage renal disease v0.46 MUC1 Eleanor Williams commented on gene: MUC1: Numerous reports of variants within VNTR associated with mutant protein and single report of 2bp deletion outside VNTR with equivalent effect on protein (PMID: 29156055). Note: variants within VNTR are unlikely to be detected by NGS.
Unexplained paediatric onset end-stage renal disease v0.46 COL4A4 Eleanor Williams Added comment: Comment on mode of inheritance: Changing to BOTH monoallelic and biallelic, autosomal or pseudoautosomal because it is associated with two relevant disorders one which shows biallelic and one which shows monoallelic inheritance ( Alport syndrome 2, autosomal recessive is AR and Hematuria, familial benign is AD).
Unexplained paediatric onset end-stage renal disease v0.46 COL4A4 Eleanor Williams Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained paediatric onset end-stage renal disease v0.45 CLCN5 Eleanor Williams changed review comment from: Comment on mode of inheritance: PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate; to: Comment on mode of inheritance: PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate. However, this gene is associated with 4 renal diseases in OMIM (Dent disease, Hypophosphatemic rickets, Nephrolithiasis, type I, Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis) which are all reported as XLR so keeping as Xlinked (biallelic in females) just now.
Inborn errors of metabolism v1.376 NNT Catherine Snow reviewed gene: NNT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27129361; Phenotypes: Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.376 NNT Catherine Snow Phenotypes for gene: NNT were changed from to Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736
Inborn errors of metabolism v1.375 NNT Catherine Snow Classified gene: NNT as Green List (high evidence)
Inborn errors of metabolism v1.375 NNT Catherine Snow Gene: nnt has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.375 NNT Catherine Snow Mode of inheritance for gene: NNT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained paediatric onset end-stage renal disease v0.45 ANOS1 Eleanor Williams Added comment: Comment on mode of inheritance: Changing mode of inheritance to X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not present with a disease phenotype.
Unexplained paediatric onset end-stage renal disease v0.45 ANOS1 Eleanor Williams Mode of inheritance for gene: ANOS1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Unexplained paediatric onset end-stage renal disease v0.44 ANOS1 Eleanor Williams commented on gene: ANOS1: Note on MOI - PMID: 11297579 - Oliveira et al 2001 - report that "Genetically proven female carriers of KAL mutations in 3 families all had normal pubertal development, with regular menstrual cycles and normal olfaction". They also evaluated three families in which anosmic women gave birth to sons with KS, and none had any mutation in the coding sequence of the KAL gene.

ANOS1 was previously known as KAL1.

Therefore I think the MOI should be X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not appear to present with the relevant phenotype.
Primary immunodeficiency v1.132 TNFRSF11A Sophie Hambleton commented on gene: TNFRSF11A
Primary immunodeficiency v1.132 SAMD9L Sophie Hambleton commented on gene: SAMD9L
Primary immunodeficiency v1.132 PTEN Sophie Hambleton reviewed gene: PTEN: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 MBL2 Sophie Hambleton reviewed gene: MBL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 LYZ Sophie Hambleton reviewed gene: LYZ: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 SPPL2A Sophie Hambleton reviewed gene: SPPL2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 RIPK1 Sophie Hambleton reviewed gene: RIPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30026316; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency v1.132 POMP Sophie Hambleton reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29805043; Phenotypes: combined immunodeficiency with autoinflammation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency v1.132 RASGRP1 Sophie Hambleton reviewed gene: RASGRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 WDR1 Sophie Hambleton reviewed gene: WDR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 USP18 Sophie Hambleton reviewed gene: USP18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 ORAI1 Sophie Hambleton edited their review of gene: ORAI1: Added comment: As stated below, there is good evidence that AR mutations in this gene cause immunodeficiency; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency v1.132 ISCA-37433-Loss Sophie Hambleton reviewed Region: ISCA-37433-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 ISCA-37446-Loss Sophie Hambleton reviewed Region: ISCA-37446-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 CSF3R Sophie Hambleton commented on gene: CSF3R: Agree there is good evidence that biallelic variation in this gene causes SCN
Unexplained kidney failure in young people v1.73 FAN1 John Sayer gene: FAN1 was added
gene: FAN1 was added to Unexplained kidney failure in young people. Sources: Expert list
Mode of inheritance for gene: FAN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAN1 were set to 22772369
Phenotypes for gene: FAN1 were set to interstitial nephritis; chronic kidney disease
Penetrance for gene: FAN1 were set to Complete
Review for gene: FAN1 was set to GREEN
Added comment: Important recessive cause of karyomegalic interstitial NEPHRITIS. May mimic nephronophthisis
Sources: Expert list
Inborn errors of metabolism v1.374 UQCC3 Catherine Snow commented on gene: UQCC3
Inborn errors of metabolism v1.374 UQCC2 Catherine Snow commented on gene: UQCC2
Inborn errors of metabolism v1.374 TXN2 Catherine Snow commented on gene: TXN2
Genetic epilepsy syndromes v1.377 CLN6 Rebecca Foulger Classified gene: CLN6 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.377 CLN6 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on Amber review by Tracy Lester and PMID:21549341 (Arsov et al., 2011) where seizures are a consistent feature across families.
Genetic epilepsy syndromes v1.377 CLN6 Rebecca Foulger Gene: cln6 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.397 TRAP1 Catherine Snow Classified gene: TRAP1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.397 TRAP1 Catherine Snow Gene: trap1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.374 TRAP1 Catherine Snow Mode of inheritance for gene: TRAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.396 TRAP1 Catherine Snow gene: TRAP1 was added
gene: TRAP1 was added to Undiagnosed metabolic disorders. Sources: Expert list
Mode of inheritance for gene: TRAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAP1 were set to 24152966
Phenotypes for gene: TRAP1 were set to VACTERL; CAKUT
Review for gene: TRAP1 was set to GREEN
Added comment: Not in OMIM or Gene2Phenotype. Recessive mutations reported in 2 families with CAKUT, and 3 families with VACTERL. Metabolism phenotype as the encoded protein has ATPase activity and interacts with tumor necrosis factor type I.
Sources: Expert list
Inborn errors of metabolism v1.376 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Inborn errors of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Inborn errors of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Inborn errors of metabolism v1.375 TRAP1 Catherine Snow Mode of inheritance for gene: TRAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Inborn errors of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from to VACTERL; CAKUT
Inborn errors of metabolism v1.374 TRAP1 Catherine Snow Classified gene: TRAP1 as Green List (high evidence)
Inborn errors of metabolism v1.374 TRAP1 Catherine Snow Gene: trap1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.374 TRAP1 Catherine Snow Mode of inheritance for gene: TRAP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.374 TRAP1 Catherine Snow Classified gene: TRAP1 as Green List (high evidence)
Inborn errors of metabolism v1.374 TRAP1 Catherine Snow Gene: trap1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.373 TRAP1 Catherine Snow reviewed gene: TRAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24152966; Phenotypes: VACTERL, CAKUT; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.373 OGDH Catherine Snow reviewed gene: OGDH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alpha-ketoglutarate dehydrogenase deficiency, 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.376 NDUFS7 Rebecca Foulger Phenotypes for gene: NDUFS7 were changed from to Mitochondrial complex I deficiency, nuclear type 3, 618224
Genetic epilepsy syndromes v1.375 CLN6 Rebecca Foulger Mode of inheritance for gene: CLN6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.374 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to
Limb girdle muscular dystrophy v1.99 DOK7 Louise Daugherty Added comment: Comment on phenotypes: removed Fetal akinesia deformation sequence 1, 208150- the phenotype is related to variants in the gene MUSK not the gene DOK7
Limb girdle muscular dystrophy v1.99 DOK7 Louise Daugherty Phenotypes for gene: DOK7 were changed from Fetal akinesia deformation sequence 1, 208150; Congenital myasthenic syndrome; Limb-girdle muscular dystrophy to Congenital myasthenic syndrome; Limb-girdle muscular dystrophy
Genetic epilepsy syndromes v1.373 ALG2 Rebecca Foulger Phenotypes for gene: ALG2 were changed from to ?Congenital disorder of glycosylation type Ii, 607906; Myasthenic syndrome congenital 14 with tubular aggregates, 616228
Genetic epilepsy syndromes v1.372 ALG2 Rebecca Foulger Mode of inheritance for gene: ALG2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophy v1.98 POGLUT1 Louise Daugherty Phenotypes for gene: POGLUT1 were changed from Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 21, 617232
Inborn errors of metabolism v1.373 NFS1 Catherine Snow edited their review of gene: NFS1: Changed rating: RED
Inborn errors of metabolism v1.373 NFS1 Catherine Snow commented on gene: NFS1
Inborn errors of metabolism v1.373 NDUFA13 Catherine Snow reviewed gene: NDUFA13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inborn errors of metabolism v1.373 NDUFA13 Catherine Snow Publications for gene: NDUFA13 were set to
Inborn errors of metabolism v1.372 MRPS7 Catherine Snow reviewed gene: MRPS7: Rating: RED; Mode of pathogenicity: None; Publications: 25556185; Phenotypes: ; Mode of inheritance: None
Inborn errors of metabolism v1.372 MRPS23 Catherine Snow reviewed gene: MRPS23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Genetic epilepsy syndromes v1.371 TXN2 Rebecca Foulger commented on gene: TXN2
Genetic epilepsy syndromes v1.371 MT-CO3 Rebecca Foulger commented on gene: MT-CO3
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger Added comment: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.370 CLPB Rebecca Foulger commented on gene: CLPB
Genetic epilepsy syndromes v1.370 TXN2 Rebecca Foulger gene: TXN2 was added
gene: TXN2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene: TXN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXN2 were set to 26626369
Phenotypes for gene: TXN2 were set to ?Combined oxidative phosphorylation deficiency 29, 616811; infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy
Genetic epilepsy syndromes v1.370 MT-CO3 Rebecca Foulger gene: MT-CO3 was added
gene: MT-CO3 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene gene: MT-CO3 was set to MITOCHONDRIAL
Publications for gene: MT-CO3 were set to 8739943; 12915481
Phenotypes for gene: MT-CO3 were set to seizures
Genetic epilepsy syndromes v1.370 EXT2 Rebecca Foulger gene: EXT2 was added
gene: EXT2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: EXT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXT2 were set to 26246518; 30997052; 30288735; 30075207
Phenotypes for gene: EXT2 were set to Seizures, scoliosis, and macrocephaly syndrome, 616682
Genetic epilepsy syndromes v1.370 CLPB Rebecca Foulger gene: CLPB was added
gene: CLPB was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Phenotypes for gene: CLPB were set to Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271
Undiagnosed metabolic disorders v1.395 MRPL12 Catherine Snow gene: MRPL12 was added
gene: MRPL12 was added to Undiagnosed metabolic disorders. Sources: Expert list
Mode of inheritance for gene: MRPL12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL12 were set to 23603806
Phenotypes for gene: MRPL12 were set to Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Review for gene: MRPL12 was set to RED
Added comment: A single reported family in the literature therefore classified as Red.
Sources: Expert list
Genetic epilepsy syndromes v1.369 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070
Genetic epilepsy syndromes v1.368 GPHN Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from BIALLELIC to BOTH monoallelic and biallelic. Although OMIM records AR inheritance, a review by Tracy Lester notes PMIDs:24561070, 23393157 who report the association of hemizygous GPHN microdeletions with an epilepsy phenotype. The biallelic and monoallelic MOI matches the MOI of GPHN on the metabolism panels.
Genetic epilepsy syndromes v1.368 GPHN Rebecca Foulger Mode of inheritance for gene: GPHN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.394 LYRM4 Catherine Snow gene: LYRM4 was added
gene: LYRM4 was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: LYRM4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LYRM4 were set to 23814038
Phenotypes for gene: LYRM4 were set to ?Combined oxidative phosphorylation deficiency 19, 615595
Review for gene: LYRM4 was set to AMBER
Added comment: LYRM4 is in OMIM but not in Gene2Phenotype. Two related patients in PMID 23814038 and some functional work. As <3 unrelated patients, classifying LYRM4 as Amber.
Sources: Expert Review
Genetic epilepsy syndromes v1.367 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995
Inborn errors of metabolism v1.372 LYRM4 Catherine Snow commented on gene: LYRM4
Limb girdle muscular dystrophy v1.97 SMN1 Chiara Marini Bettolo reviewed gene: SMN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 CASQ1 Chiara Marini Bettolo reviewed gene: CASQ1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 ORAI1 Chiara Marini Bettolo reviewed gene: ORAI1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 STIM1 Chiara Marini Bettolo reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 TNPO3 Chiara Marini Bettolo reviewed gene: TNPO3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 POGLUT1 Chiara Marini Bettolo commented on gene: POGLUT1: new gene added after analysis. Currently provided by HSS for LGMDin Ncl via LGMD panel. Known form of LGMD2Z or LGMDR21
Limb girdle muscular dystrophy v1.97 VMA21 Chiara Marini Bettolo edited their review of gene: VMA21: Added comment: XMEA. Differential diagnosis with LGMD (proximal weakness and raised CK) particularly in milder adult onset forms; Changed rating: GREEN
Limb girdle muscular dystrophy v1.97 TTN Chiara Marini Bettolo commented on gene: TTN: Disese spectrum can be very variable from congenital myopathy, cardiomyopathy, distal weakness, HMERF to LGMD. Known form of LGMD2J or LGMDR10
Limb girdle muscular dystrophy v1.97 TPM3 Chiara Marini Bettolo edited their review of gene: TPM3: Added comment: CAP myopathy, nemaline myopathy, congenital myopathy with fibre type disproportion; Changed rating: RED
Limb girdle muscular dystrophy v1.97 TPM2 Chiara Marini Bettolo reviewed gene: TPM2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 TNNT3 Chiara Marini Bettolo edited their review of gene: TNNT3: Added comment: Arthrogryposis (distal); Changed rating: RED
Limb girdle muscular dystrophy v1.97 SYNE2 Chiara Marini Bettolo commented on gene: SYNE2: Form of EDMD. Differential diagnosis with AD LGMD. (proximal weakness and raised CK)
Limb girdle muscular dystrophy v1.97 SMCHD1 Chiara Marini Bettolo commented on gene: SMCHD1: FSHD2, differential diagnosis with LGMD.
Limb girdle muscular dystrophy v1.97 SELENON Chiara Marini Bettolo commented on gene: SELENON: Rigid spine syndrome, but not all patients present with rigid spine. Muscle biopsy can range from myoathic to dystrophic. Differential diagnosis with LGMD.
Limb girdle muscular dystrophy v1.97 SCN4A Chiara Marini Bettolo edited their review of gene: SCN4A: Added comment: muscle channelopathy. ; Changed rating: RED
Limb girdle muscular dystrophy v1.97 RYR1 Chiara Marini Bettolo commented on gene: RYR1: Variable disease spectrum from congenital myopathy, metabolic myopathy, MH. Differential diagnosis with LGMD
Limb girdle muscular dystrophy v1.97 RAPSN Chiara Marini Bettolo edited their review of gene: RAPSN: Added comment: CMS gene.; Changed rating: RED
Limb girdle muscular dystrophy v1.97 PYGM Chiara Marini Bettolo commented on gene: PYGM: McArdle's disease. Differential diagnosis with LGMD
Limb girdle muscular dystrophy v1.97 POMK Chiara Marini Bettolo edited their review of gene: POMK: Added comment: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), autosomal recessive disorder with congenital muscular dystrophy; Changed rating: RED
Limb girdle muscular dystrophy v1.97 POMGNT2 Chiara Marini Bettolo commented on gene: POMGNT2: Known form to muscular dystrophy.according to new classification is LGMDR24
Limb girdle muscular dystrophy v1.97 POLG Chiara Marini Bettolo reviewed gene: POLG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 PHKA1 Chiara Marini Bettolo reviewed gene: PHKA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 PGK1 Chiara Marini Bettolo reviewed gene: PGK1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 PFKM Chiara Marini Bettolo reviewed gene: PFKM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 NEB Chiara Marini Bettolo edited their review of gene: NEB: Added comment: Nemaline myopathy. Variable disease spectrum from severe early onset to milder late onset. Usually CK normal or mildly raised ; Changed rating: RED
Limb girdle muscular dystrophy v1.97 MYH7 Chiara Marini Bettolo commented on gene: MYH7: Scapuloperoneal syndrome. Variable phenotype fromsevere cardiomyopathy, distal myopathy, proximal and distal myopathy and asymptomatic hyperCKemia.
Limb girdle muscular dystrophy v1.97 MYH14 Chiara Marini Bettolo reviewed gene: MYH14: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 MATR3 Chiara Marini Bettolo edited their review of gene: MATR3: Added comment: Predominantly distal myopathy with vocal cord parlysis and dysphagia. Raised CK; Changed rating: RED
Limb girdle muscular dystrophy v1.97 LPIN1 Chiara Marini Bettolo commented on gene: LPIN1: Recurrent episodes of myoglobinuria and high CK. Differential diagnosis with LGMD.
Limb girdle muscular dystrophy v1.97 LIMS2 Chiara Marini Bettolo edited their review of gene: LIMS2: Added comment: Rare form of muscular dystrophy; Changed rating: RED
Limb girdle muscular dystrophy v1.97 LAMP2 Chiara Marini Bettolo commented on gene: LAMP2: Danon disease. Differential diagnosis with LGMD.
Limb girdle muscular dystrophy v1.97 LAMA2 Chiara Marini Bettolo commented on gene: LAMA2: Form of congenital muscular dystrophy, now listed on new LGMD classification as LGMDR23
Limb girdle muscular dystrophy v1.97 ISPD Chiara Marini Bettolo edited their review of gene: ISPD: Added comment: Known as LGMD 2U or LGMDR20 on new nomenclature; Changed rating: GREEN
Limb girdle muscular dystrophy v1.97 HNRNPDL Chiara Marini Bettolo commented on gene: HNRNPDL: Listed as LGMD D3 on new nomenclature/classification.
Limb girdle muscular dystrophy v1.97 GYG1 Chiara Marini Bettolo reviewed gene: GYG1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 GNE Chiara Marini Bettolo commented on gene: GNE: currently provided through LGMD panel at HSS LGMD in Ncl. Proximal and distal weakness, differential diagnosis with LGMD.
Limb girdle muscular dystrophy v1.97 GFPT1 Chiara Marini Bettolo edited their review of gene: GFPT1: Added comment: CMS gene.; Changed rating: RED
Limb girdle muscular dystrophy v1.97 GBE1 Chiara Marini Bettolo reviewed gene: GBE1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 ETFDH Chiara Marini Bettolo reviewed gene: ETFDH: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophy v1.97 DPM3 Chiara Marini Bettolo edited their review of gene: DPM3: Added comment: MDDGC15. Rare form of muscular dystrophy with high CK; Changed rating: AMBER
Limb girdle muscular dystrophy v1.97 DOK7 Chiara Marini Bettolo commented on gene: DOK7: CMS gene, but clinically can present as LGMD
Limb girdle muscular dystrophy v1.97 DNM2 Chiara Marini Bettolo edited their review of gene: DNM2: Added comment: congenital myopathy; Changed rating: RED
Limb girdle muscular dystrophy v1.97 DES Chiara Marini Bettolo commented on gene: DES: currently provided through LGMD panel at HSS LGMD in Ncl. Form of myofibrillar myopathy that can present with variable phenotypes from distal weakness, scapuloperoneal weakness and cardiomyopathy and arrythmia
Limb girdle muscular dystrophy v1.97 DAG1 Chiara Marini Bettolo commented on gene: DAG1: Known form of LGMD2P or LGMDR16
Limb girdle muscular dystrophy v1.97 CRYAB Chiara Marini Bettolo commented on gene: CRYAB: currently provided through LGMD panel at HSS LGMD in Ncl. Rare form of myofibrillar myopathy
Limb girdle muscular dystrophy v1.97 CPT2 Chiara Marini Bettolo commented on gene: CPT2: metabolic myoapthy, can present with high CK - differential diagnosis with LGMD
Limb girdle muscular dystrophy v1.97 COLQ Chiara Marini Bettolo edited their review of gene: COLQ: Added comment: CMS; Changed rating: RED
Limb girdle muscular dystrophy v1.97 COL12A1 Chiara Marini Bettolo edited their review of gene: COL12A1: Added comment: congenital myopathy; Changed rating: RED
Limb girdle muscular dystrophy v1.97 CLCN1 Chiara Marini Bettolo edited their review of gene: CLCN1: Added comment: muscle channelopathy. Myotonia congenita; Changed rating: RED
Limb girdle muscular dystrophy v1.97 CHRND Chiara Marini Bettolo edited their review of gene: CHRND: Added comment: form of CMS; Changed rating: RED
Limb girdle muscular dystrophy v1.97 BVES Chiara Marini Bettolo edited their review of gene: BVES: Added comment: only reported in one family; Changed rating: RED
Limb girdle muscular dystrophy v1.97 BAG3 Chiara Marini Bettolo commented on gene: BAG3: currently provided through LGMD panel at HSS LGMD in Ncl. Rare and severe form of myopathy with proximal and distal weakness.
Limb girdle muscular dystrophy v1.97 ATP2A1 Chiara Marini Bettolo edited their review of gene: ATP2A1: Added comment: Brody myopathy; Changed rating: RED
Limb girdle muscular dystrophy v1.97 AGL Chiara Marini Bettolo edited their review of gene: AGL: Added comment: metabolic myopathy. Glycongen storage disease IIIa/b; Changed rating: RED
Limb girdle muscular dystrophy v1.97 ACTA1 Chiara Marini Bettolo edited their review of gene: ACTA1: Added comment: congenital myopathy; Changed rating: RED
Limb girdle muscular dystrophy v1.97 ACADVL Chiara Marini Bettolo commented on gene: ACADVL: metabolic myopathy but differential diagnosis with LGMD
Inborn errors of metabolism v1.372 LYRM4 Catherine Snow Classified gene: LYRM4 as Amber List (moderate evidence)
Inborn errors of metabolism v1.372 LYRM4 Catherine Snow Gene: lyrm4 has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.372 LYRM4 Catherine Snow Classified gene: LYRM4 as Amber List (moderate evidence)
Inborn errors of metabolism v1.372 LYRM4 Catherine Snow Gene: lyrm4 has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.371 LYRM4 Catherine Snow Mode of inheritance for gene: LYRM4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.370 LYRM4 Catherine Snow Publications for gene: LYRM4 were set to
Inborn errors of metabolism v1.370 LYRM4 Catherine Snow Mode of inheritance for gene: LYRM4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.393 LARS Catherine Snow Classified gene: LARS as Green List (high evidence)
Undiagnosed metabolic disorders v1.393 LARS Catherine Snow Gene: lars has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow Tag new-gene-name tag was added to gene: LARS.
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow changed review comment from: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to upgrade LARS1 from Red to Green.
Sources: Expert Review; to: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to classify LARS1 as Green.
Sources: Expert Review
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow gene: LARS was added
gene: LARS was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 28774368; 30349989; 22607940
Phenotypes for gene: LARS were set to ?Infantile liver failure syndrome 1, 615438
Review for gene: LARS was set to GREEN
Added comment: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to upgrade LARS1 from Red to Green.
Sources: Expert Review
Inborn errors of metabolism v1.369 LARS Catherine Snow Phenotypes for gene: LARS were changed from ?Infantile liver failure syndrome 1, 615438 to ?Infantile liver failure syndrome 1, 615438
Inborn errors of metabolism v1.368 LARS Catherine Snow Publications for gene: LARS were set to 28774368; 30349989; 22607940
Inborn errors of metabolism v1.368 LARS Catherine Snow Phenotypes for gene: LARS were changed from to ?Infantile liver failure syndrome 1, 615438
Inborn errors of metabolism v1.367 LARS Catherine Snow Publications for gene: LARS were set to
Inborn errors of metabolism v1.367 LARS Catherine Snow Mode of inheritance for gene: LARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.367 LARS Catherine Snow Classified gene: LARS as Green List (high evidence)
Inborn errors of metabolism v1.367 LARS Catherine Snow Gene: lars has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.366 LARS Catherine Snow reviewed gene: LARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28774368, 30349989, 22607940; Phenotypes: ?Infantile liver failure syndrome 1, 615438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophy v1.96 SMN1 Louise Daugherty Source NHS GMS was added to SMN1.
Source Yorkshire and North East GLH was added to SMN1.
Limb girdle muscular dystrophy v1.96 CASQ1 Louise Daugherty Source NHS GMS was added to CASQ1.
Source Yorkshire and North East GLH was added to CASQ1.
Limb girdle muscular dystrophy v1.96 ORAI1 Louise Daugherty Source NHS GMS was added to ORAI1.
Source Yorkshire and North East GLH was added to ORAI1.
Limb girdle muscular dystrophy v1.96 STIM1 Louise Daugherty Source NHS GMS was added to STIM1.
Source Yorkshire and North East GLH was added to STIM1.
Limb girdle muscular dystrophy v1.96 TNPO3 Louise Daugherty Source NHS GMS was added to TNPO3.
Source Yorkshire and North East GLH was added to TNPO3.
Limb girdle muscular dystrophy v1.95 SMN1 Louise Daugherty gene: SMN1 was added
gene: SMN1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: SMN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SMN1 were set to Spinal muscular atrophy-4, 271150
Review for gene: SMN1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
Limb girdle muscular dystrophy v1.94 CASQ1 Louise Daugherty gene: CASQ1 was added
gene: CASQ1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: CASQ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CASQ1 were set to Myopathy, vacuolar, with CASQ1 aggregates, 616231
Review for gene: CASQ1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
Limb girdle muscular dystrophy v1.93 ORAI1 Louise Daugherty gene: ORAI1 was added
gene: ORAI1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: ORAI1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ORAI1 were set to Myopathy, tubular aggregate, 2, 615883
Review for gene: ORAI1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
Limb girdle muscular dystrophy v1.92 STIM1 Louise Daugherty gene: STIM1 was added
gene: STIM1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: STIM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: STIM1 were set to Myopathy, tubular aggregate, 1, 160565
Review for gene: STIM1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
DDG2P v1.141 DCX Rebecca Foulger Mode of inheritance for gene: DCX was changed from X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v1.140 CASK Rebecca Foulger Mode of inheritance for gene: CASK was changed from X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Limb girdle muscular dystrophy v1.91 TNPO3 Louise Daugherty gene: TNPO3 was added
gene: TNPO3 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: TNPO3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TNPO3 were set to Muscular dystrophy, limb-girdle, autosomal dominant 2, 608423
Review for gene: TNPO3 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
DDG2P v1.139 STAG2 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from XLD to XLR to match 'hemizygous' allelic requirement in Gene2Phenotype.
DDG2P v1.139 STAG2 Rebecca Foulger Mode of inheritance for gene: STAG2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
DDG2P v1.138 SLC35A2 Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating: confirmed for Epileptic Encephalopathy due to congenital disorder of glycosylation. DDG2P Allelic requirement: x-linked dominant. DDG2P mutation consequence: loss of function.
DDG2P v1.138 SLC35A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed mode of inheritance to XLD to match Gene2Phenotype.
DDG2P v1.138 SLC35A2 Rebecca Foulger Mode of inheritance for gene: SLC35A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Paediatric disorders v4.258 Rebecca Foulger List of related panels changed from Acutely unwell children with a likely monogenic disorder; Congenital malformation and dysmorphism syndromes - microarray and sequencing to Acutely unwell children with a likely monogenic disorder; Congenital malformation and dysmorphism syndromes - microarray and sequencing; R14; R27
Paroxysmal central nervous system disorders v0.172 GLRA1 Rebecca Foulger Phenotypes for gene: GLRA1 were changed from Hyperekplexia, hereditary 1, 149400 to Hyperekplexia 1, 149400
Paroxysmal central nervous system disorders v0.171 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2, 602481; Migraine, familial basilar, 602481alternating hemiplegia of childhood 104290 to Migraine, familial hemiplegic, 2, 602481; Migraine, familial basilar, 602481; alternating hemiplegia of childhood 104290
Paroxysmal central nervous system disorders v0.170 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from familial basilar migraine 602481; alternating hemiplegia of childhood 104290; familial hemiplegic migraine type 2, 602481 to Migraine, familial hemiplegic, 2, 602481; Migraine, familial basilar, 602481alternating hemiplegia of childhood 104290
Paroxysmal central nervous system disorders v0.169 ATAD1 Rebecca Foulger changed review comment from: Comment on list classification: Upgraded ATAD1 from Amber to Green to match Green rating of other Hyperkeplexia genes (GLRA1, GLRB, SLC6A5). A comment from Robyn Labrum (University College London Hospitals) on behalf of London North GLH for the GMS Neurology specialist test group (received via email, September 30th 2019) notes that Hyperkeplexia genes should be included on the panel if the clinicians agree.; to: Comment on list classification: Upgraded ATAD1 from Amber to Green to match Green rating of other Hyperkeplexia genes (GLRA1, GLRB, SLC6A5). A comment from Robyn Labrum (University College London Hospitals) on behalf of London North GLH for the GMS Neurology specialist test group (received via email, September 30th 2019) notes that Hyperekplexia genes should be included on the panel if the clinicians agree.
Genetic epilepsy syndromes v1.366 ABAT Rebecca Foulger Publications for gene: ABAT were set to 20052547; 27376954
Paroxysmal central nervous system disorders v0.169 Rebecca Foulger List of related panels changed from Paroxysmal neurological disorders; pain disorders and sleep disorders to Paroxysmal neurological disorders; pain disorders and sleep disorders; R66
Unexplained paediatric onset end-stage renal disease v0.44 CLCN5 Eleanor Williams Added comment: Comment on mode of inheritance: PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate
Unexplained paediatric onset end-stage renal disease v0.44 CLCN5 Eleanor Williams Mode of inheritance for gene: CLCN5 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams changed review comment from: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms of Dents disease so Xlinked (monoalllelic in females) may be more appropriate.; to: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate.
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams changed review comment from: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms so Xlinked (monoalllelic in females) may be more appropriate.; to: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms of Dents disease so Xlinked (monoalllelic in females) may be more appropriate.
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams changed review comment from: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females; to: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms so Xlinked (monoalllelic in females) may be more appropriate.
Nephrocalcinosis or nephrolithiasis v1.22 PHEX Eleanor Williams changed review comment from: Associated with Hypophosphatemic rickets, X-linked dominant (#307800)(XLD) in OMIM.

PMID: 31514490 - Şıklar et al 2019 - From 24 centers in Turkey, 166 patients with Hypophosphatemic rickets were included in the study data. Genetic analysis (n:75) showed PHEX mutation in 80% patients (60 patients). 27 patients developed nephrocalcinosis. However, higher treatment dose of phosphate and calcitriol has been detected in nephrocalcinosis group.

PMID: 29460029 - Chesher et al 2018 - clinical records of 59 adult patients from 35 kindreds with X-linked hypophosphatemia attending a single inherited metabolic disease service from 1998 were retrospectively reviewed. All had PHEX mutations (either directly obtained or inferred from the result of a first degree relative). 37 distinct variants were identified (14 not previously reported). Nephrocalcinosis was reported in 16/38 patients (42%) with at least one renal ultrasound performed. Treatment with vitamin D was associated with a small increase in urine calcium but there was no association between the presence or absence of nephrocalcinosis and whether or not the patient was currently being treated with vitamin D.

Will consult with Genomics England Clinical team with regards to nephrocalcinosis being associated with PHEX variants or a result of treatment for Hypophosphatemic rickets.; to: Associated with Hypophosphatemic rickets, X-linked dominant (#307800)(XLD) in OMIM.

PMID: 31514490 - Şıklar et al 2019 - Study of 166 patients with Hypophosphatemic rickets from 24 centers in Turkey. Genetic analysis (n:75) showed PHEX mutation in 80% patients (60 patients). 27 patients developed nephrocalcinosis. However, higher treatment dose of phosphate and calcitriol has been detected in nephrocalcinosis group.

PMID: 29460029 - Chesher et al 2018 - clinical records of 59 adult patients from 35 kindreds with X-linked hypophosphatemia attending a single inherited metabolic disease service from 1998 were retrospectively reviewed. All had PHEX mutations (either directly obtained or inferred from the result of a first degree relative). 37 distinct variants were identified (14 not previously reported). Nephrocalcinosis was reported in 16/38 patients (42%) with at least one renal ultrasound performed. Treatment with vitamin D was associated with a small increase in urine calcium but there was no association between the presence or absence of nephrocalcinosis and whether or not the patient was currently being treated with vitamin D.

Will consult with Genomics England Clinical team with regards to nephrocalcinosis being associated with PHEX variants or a result of treatment for Hypophosphatemic rickets.
Nephrocalcinosis or nephrolithiasis v1.22 HNF4A Eleanor Williams commented on gene: HNF4A
Nephrocalcinosis or nephrolithiasis v1.22 FGF23 Eleanor Williams commented on gene: FGF23
Nephrocalcinosis or nephrolithiasis v1.22 FGF23 Eleanor Williams gene: FGF23 was added
gene: FGF23 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list
Mode of inheritance for gene: FGF23 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nephrocalcinosis or nephrolithiasis v1.21 PHEX Eleanor Williams reviewed gene: PHEX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Nephrocalcinosis or nephrolithiasis v1.21 PHEX Eleanor Williams gene: PHEX was added
gene: PHEX was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list,Literature
Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Nephrocalcinosis or nephrolithiasis v1.20 ZNF365 Eleanor Williams changed review comment from: Provisional association with {Nephrolithiasis, uric acid, susceptibility to} #605990 in OMIM.
PubMed search did not find any further papers beyond the association study of 2003 (PMID: 12740763)
Keep red rating.; to: Provisional association with {Nephrolithiasis, uric acid, susceptibility to} #605990 in OMIM.
PubMed search did not find any further papers beyond the study of 2003 (PMID: 12740763)
Keep red rating.
Nephrocalcinosis or nephrolithiasis v1.20 ZNF365 Eleanor Williams commented on gene: ZNF365
Nephrocalcinosis or nephrolithiasis v1.20 TRPM6 Eleanor Williams commented on gene: TRPM6
Nephrocalcinosis or nephrolithiasis v1.20 STRADA Eleanor Williams commented on gene: STRADA
Nephrocalcinosis or nephrolithiasis v1.20 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9) in renal hypouricemic patients who have no URAT1 mutations (R380W and R198C) but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case renal hypouricemia and with variant in SLC2A9 - no nephrolithiasis reported; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.20 SLC2A9 Eleanor Williams commented on gene: SLC2A9
Nephrocalcinosis or nephrolithiasis v1.20 SLC22A12 Eleanor Williams edited their review of gene: SLC22A12: Changed publications: 29486147, 29958533, 18492088, 15912381; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.20 SLC22A12 Eleanor Williams commented on gene: SLC22A12
Nephrocalcinosis or nephrolithiasis v1.20 HPRT1 Eleanor Williams changed review comment from: Associated with HPRT-related gout #300323 (XLR) and Lesch-Nyhan syndrome #300322 (XLR) in OMIM, both of which have Nephrolithiasis listed as a clinical feature.

HPRT encodes the Hypoxanthine-guanine phosphoribosyltransferase enzyme. Partial deficiency can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome.

PMID: 31129767 - Cho et al 2019 - studied 26 Korean LNS patients from 23 unrelated families. Twenty one of the 23 LNS patients with available data (91.3%) showed renal manifestations such as hyperuricemia, nephrocalcinosis, or urinary stones. 16 patients from 13 families had nephrocalcinosis. Twenty different mutations in HPRT1 were identified from the 23 independent pedigrees.

PMID: 27079129 - Vargiami E et al 2016 - report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.; to: Associated with HPRT-related gout #300323 (XLR) and Lesch-Nyhan syndrome #300322 (XLR) in OMIM, both of which have Nephrolithiasis listed as a clinical feature.

HPRT encodes the Hypoxanthine-guanine phosphoribosyltransferase enzyme. Partial deficiency can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes Lesch-Nyhan syndrome.

PMID: 31129767 - Cho et al 2019 - studied 26 Korean LNS patients from 23 unrelated families. Twenty one of the 23 LNS patients with available data (91.3%) showed renal manifestations such as hyperuricemia, nephrocalcinosis, or urinary stones. 16 patients from 13 families had nephrocalcinosis. Twenty different mutations in HPRT1 were identified from the 23 independent pedigrees.

PMID: 27079129 - Vargiami E et al 2016 - report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.
Nephrocalcinosis or nephrolithiasis v1.20 HPRT1 Eleanor Williams commented on gene: HPRT1
Cerebral vascular malformations v1.48 Louise Daugherty List of related panels changed from Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease to Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease; R336
Hydrocephalus v2.0 Louise Daugherty promoted panel to version 2.0
Hydrocephalus v1.39 Louise Daugherty List of related panels changed from Hydrocephalus;R86 to Hydrocephalus; R86
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Holoprosencephaly v2.0 Louise Daugherty promoted panel to version 2.0
Holoprosencephaly v1.24 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Hereditary spastic paraplegia - childhood onset v2.0 Louise Daugherty promoted panel to version 2.0
Hereditary spastic paraplegia - childhood onset v1.180 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia;R61 to Childhood onset hereditary spastic paraplegia; R61
Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Dilated cardiomyopathy - adult and teen v0.50 FKTN James Eden reviewed gene: FKTN: Rating: AMBER; Mode of pathogenicity: None; Publications: 19015585, 17036286, 27521547; Phenotypes: Cardiomyopathy, dilated, 1X 611615, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 253800, Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 613152, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 611588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - adult onset v1.0 Louise Daugherty promoted panel to version 1.0
Hereditary spastic paraplegia - adult onset v0.158 CCT5 Louise Daugherty Mode of inheritance for gene: CCT5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - adult onset v0.157 Louise Daugherty Panel types changed to GMS Rare Disease; GMS signed-off
Congenital myopathy v1.191 VPS33B Louise Daugherty changed review comment from: Comment on list classification: Changed from Amber to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Amber to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 ECEL1 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 MYBPC1 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 PIEZO2 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 TNNT3 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 TNNT3 Louise Daugherty Classified gene: TNNT3 as Green List (high evidence)
Congenital myopathy v1.191 TNNT3 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 TNNT3 Louise Daugherty Gene: tnnt3 has been classified as Green List (High Evidence).
Congenital myopathy v1.190 VPS33B Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Amber to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.190 VPS33B Louise Daugherty Classified gene: VPS33B as Green List (high evidence)
Congenital myopathy v1.190 VPS33B Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.190 VPS33B Louise Daugherty Gene: vps33b has been classified as Green List (High Evidence).
Congenital myopathy v1.189 VPS33B Louise Daugherty Publications for gene: VPS33B were set to
Congenital myopathy v1.188 VPS33B Louise Daugherty Mode of inheritance for gene: VPS33B was changed from to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.187 TNNI2 Louise Daugherty Classified gene: TNNI2 as Green List (high evidence)
Congenital myopathy v1.187 TNNI2 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.187 TNNI2 Louise Daugherty Gene: tnni2 has been classified as Green List (High Evidence).
Congenital myopathy v1.186 PIEZO2 Louise Daugherty Classified gene: PIEZO2 as Green List (high evidence)
Congenital myopathy v1.186 PIEZO2 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.186 PIEZO2 Louise Daugherty Gene: piezo2 has been classified as Green List (High Evidence).
Congenital myopathy v1.185 MYBPC1 Louise Daugherty Classified gene: MYBPC1 as Green List (high evidence)
Congenital myopathy v1.185 MYBPC1 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.185 MYBPC1 Louise Daugherty Gene: mybpc1 has been classified as Green List (High Evidence).
Congenital myopathy v1.184 ECEL1 Louise Daugherty Classified gene: ECEL1 as Green List (high evidence)
Congenital myopathy v1.184 ECEL1 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.184 ECEL1 Louise Daugherty Gene: ecel1 has been classified as Green List (High Evidence).
Neuromuscular arthrogryposis v0.20 ZC4H2 Louise Daugherty Added comment: Comment on mode of inheritance: MOI changed to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as some female carriers also show signs of disease.
Neuromuscular arthrogryposis v0.20 ZC4H2 Louise Daugherty Mode of inheritance for gene: ZC4H2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Arthrogryposis v2.46 ZC4H2 Louise Daugherty Added comment: Comment on mode of inheritance: MOI changed to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as some female carriers also show signs of disease.
Arthrogryposis v2.46 ZC4H2 Louise Daugherty Mode of inheritance for gene: ZC4H2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital myopathy v1.183 ZC4H2 Louise Daugherty Added comment: Comment on mode of inheritance: MOI changed to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as some female carriers also show signs of disease.
Congenital myopathy v1.183 ZC4H2 Louise Daugherty Mode of inheritance for gene: ZC4H2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital myopathy v1.182 ZC4H2 Louise Daugherty edited their review of gene: ZC4H2: Added comment: After review with Genomics England clinical team this gene was deemed valid to include on the congenital myopathy panel, as affected individuals clearly have muscle weakness. The majority of boys with it have a level of severity that it is onset in utero, leading to contractures. Arthrogryposis and congenital myopathy are a clinical continuum and as long as the neuromuscular group do not disagree, so should on both panels.; Changed rating: GREEN
Limb girdle muscular dystrophy v1.90 Louise Daugherty List of related panels changed from to R82
Nephrocalcinosis or nephrolithiasis v1.20 FAM20A Eleanor Williams Publications for gene: FAM20A were set to
Nephrocalcinosis or nephrolithiasis v1.19 FAM20A Eleanor Williams Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690
Nephrocalcinosis or nephrolithiasis v1.18 FAM20A Eleanor Williams changed review comment from: Associated with Amelogenesis imperfecta, type IG (enamel-renal syndrome) (#204690)(AR) in OMIM and AMELOGENESIS IMPERFECTA AND GINGIVAL FIBROMATOSIS SYNDROME (confirmed, biallelic) in Gene2Phenotype.

PMID: 23468644 - Wang et al 2013 - Characterized three families (from the Carribean, Jordan and Iran) with amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS) and identified, in each case, recessive FAM20A mutations with different variants in each family. Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to Enamel-renal syndrome. Ultrasounds were not possible to obtain from families 1 and 3.

PMID: 30394349 - Dourado et al 2018 - investigated ERS characteristics in 11 patients from 5 Brazilian families.
All showed hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis. A biallelic loss of function variant in FAM20A [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect.

PMID: 28298625 - Kantaputra et al 2017 (Abstract only accessed) - report three patients and their families with findings suggestive of Enamel-renal-gingival syndrome. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications.

PMID: 22732358 - Vogel et al 2012 - two-thirds of Fam20a–/– mice had small kidneys with pitted surfaces, which showed widespread calcification (as well as a dental phenotype)

3 independent cases with nephrocalcinosis plus mouse knockout data. Not full penetrance for the renal phenotype.; to: Associated with Amelogenesis imperfecta, type IG (enamel-renal syndrome) (#204690)(AR) in OMIM and AMELOGENESIS IMPERFECTA AND GINGIVAL FIBROMATOSIS SYNDROME (confirmed, biallelic) in Gene2Phenotype.

PMID: 23468644 - Wang et al 2013 - Characterized three families (from the Caribbean, Jordan and Iran) with amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS) and identified, in each case, recessive FAM20A mutations with different variants in each family. Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to Enamel-renal syndrome. Ultrasounds were not possible to obtain from families 1 and 3.

PMID: 30394349 - Dourado et al 2018 - investigated ERS characteristics in 11 patients from 5 Brazilian families.
All showed hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis. A biallelic loss of function variant in FAM20A [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect.

PMID: 28298625 - Kantaputra et al 2017 (Abstract only accessed) - report three patients and their families with findings suggestive of Enamel-renal-gingival syndrome. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications.

PMID: 22732358 - Vogel et al 2012 - two-thirds of Fam20a–/– mice had small kidneys with pitted surfaces, which showed widespread calcification (as well as a dental phenotype)

3 independent cases with nephrocalcinosis plus mouse knockout data. Not full penetrance for the renal phenotype.
Nephrocalcinosis or nephrolithiasis v1.18 FAM20A Eleanor Williams commented on gene: FAM20A
Congenital myopathy v1.182 TNNC2 Louise Daugherty changed review comment from: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26924529 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene TRIP4, but for TNNC2 the publication field was blank (no data was supplied as evidence). The Green review rating for TNNC2 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.; to: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26924529 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene TRIP4, but for TNNC2 the publication field was blank (no data was supplied as evidence). The Green review rating for TNNC2 is the rating given by London South GLH. There is currently not enough evidence to support a Amber rating.
Congenital myopathy v1.182 TNNC2 Louise Daugherty commented on gene: TNNC2: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26924529 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene TRIP4, but for TNNC2 the publication field was blank (no data was supplied as evidence). The Green review rating for TNNC2 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Congenital myopathy v1.182 MYL1 Louise Daugherty edited their review of gene: MYL1: Changed rating: GREEN
Congenital myopathy v1.182 MYPN Louise Daugherty edited their review of gene: MYPN: Changed rating: GREEN
Undiagnosed metabolic disorders v1.391 TTC37 Catherine Snow Publications for gene: TTC37 were set to 27604308
Undiagnosed metabolic disorders v1.390 TTC37 Catherine Snow Classified gene: TTC37 as Green List (high evidence)
Undiagnosed metabolic disorders v1.390 TTC37 Catherine Snow Gene: ttc37 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.389 TTC37 Catherine Snow reviewed gene: TTC37: Rating: GREEN; Mode of pathogenicity: None; Publications: 25976726, 28292286, 31132033; Phenotypes: Trichohepatoenteric syndrome 1, 222470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.366 TTC37 Catherine Snow Classified gene: TTC37 as Green List (high evidence)
Inborn errors of metabolism v1.366 TTC37 Catherine Snow Gene: ttc37 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.365 TTC37 Catherine Snow Publications for gene: TTC37 were set to 27604308
Inborn errors of metabolism v1.364 TTC37 Catherine Snow reviewed gene: TTC37: Rating: GREEN; Mode of pathogenicity: None; Publications: 25976726, 28292286, 31132033; Phenotypes: Trichohepatoenteric syndrome 1, 222470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.182 MYH8 Louise Daugherty Phenotypes for gene: MYH8 were changed from Trismus-pseudocamptodactyly syndrome 158300 to Trismus-pseudocamptodactyly syndrome, 158300
Congenital myopathy v1.181 ACTN2 Louise Daugherty Deleted their comment
Congenital myopathy v1.181 ACTN2 Louise Daugherty Classified gene: ACTN2 as Green List (high evidence)
Congenital myopathy v1.181 ACTN2 Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (with functional work), and external review comment all support gene-disease association.
Congenital myopathy v1.181 ACTN2 Louise Daugherty Gene: actn2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.364 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Inborn errors of metabolism v1.364 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Inborn errors of metabolism v1.363 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308
Inborn errors of metabolism v1.363 ST3GAL3 Catherine Snow Classified gene: ST3GAL3 as Green List (high evidence)
Inborn errors of metabolism v1.363 ST3GAL3 Catherine Snow Gene: st3gal3 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.389 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308
Undiagnosed metabolic disorders v1.388 ST3GAL3 Catherine Snow Classified gene: ST3GAL3 as Green List (high evidence)
Undiagnosed metabolic disorders v1.388 ST3GAL3 Catherine Snow Gene: st3gal3 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.387 ST3GAL3 Catherine Snow reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907012, 23252400, 31584066; Phenotypes: Epileptic encephalopathy, early infantile, 15, 615006: Mental retardation, autosomal recessive 12, 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.362 ST3GAL3 Catherine Snow reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907012, 23252400, 31584066; Phenotypes: Epileptic encephalopathy, early infantile, 15, 615006: Mental retardation, autosomal recessive 12, 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.180 LAMP2 Louise Daugherty Phenotypes for gene: LAMP2 were changed from vacuolar myopathy? to vacuolar myopathy?; Danon disease, 300257
Congenital myopathy v1.179 MTMR14 Louise Daugherty Phenotypes for gene: MTMR14 were changed from centronuclear myopathy to centronuclear myopathy; Centronuclear myopathy, autosomal, modifier of, 160150
Congenital myopathy v1.178 MYBPC3 Louise Daugherty Phenotypes for gene: MYBPC3 were changed from myopathy and cardiomyopathy to myopathy and cardiomyopathy; Cardiomyopathy, hypertrophic, 4, 115197
Congenital myopathy v1.177 MYL1 Louise Daugherty Classified gene: MYL1 as Green List (high evidence)
Congenital myopathy v1.177 MYL1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. New evidence PMID: 30215711 (2018) In 2 unrelated patients, each born of consanguineous Turkish parents, with congenital myopathy with fast-twitch (type II) fiber atrophy. Also a Zebrafish model indicated that myl1 is required for the normal formation and maintenance of myofibers.
Congenital myopathy v1.177 MYL1 Louise Daugherty Gene: myl1 has been classified as Green List (High Evidence).
Congenital myopathy v1.176 MYL1 Louise Daugherty Publications for gene: MYL1 were set to 21063730
Congenital myopathy v1.175 MYL1 Louise Daugherty Phenotypes for gene: MYL1 were changed from congenital myopathy to congenital myopathy; Myopathy, congenital, with fast-twitch (type II) fiber atrophy, 618414
Congenital myopathy v1.174 MYPN Louise Daugherty Classified gene: MYPN as Green List (high evidence)
Congenital myopathy v1.174 MYPN Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.174 MYPN Louise Daugherty Gene: mypn has been classified as Green List (High Evidence).
Congenital myopathy v1.173 ZC4H2 Louise Daugherty Classified gene: ZC4H2 as Green List (high evidence)
Congenital myopathy v1.173 ZC4H2 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Green based on recommendation from Guy's Hospital. Sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.173 ZC4H2 Louise Daugherty Gene: zc4h2 has been classified as Green List (High Evidence).
Congenital myopathy v1.172 ZC4H2 Louise Daugherty Publications for gene: ZC4H2 were set to 23623388, 26056227
Congenital myopathy v1.171 ECEL1 Louise Daugherty Publications for gene: ECEL1 were set to 23261301
Undiagnosed metabolic disorders v1.387 TH Catherine Snow reviewed gene: TH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753243; Phenotypes: Segawa syndrome, recessive, 605407; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.170 DOK7 Louise Daugherty Publications for gene: DOK7 were set to 15689448
Congenital myopathy v1.169 DMPK Louise Daugherty reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inborn errors of metabolism v1.362 TH Catherine Snow Tag treatable tag was added to gene: TH.
Inborn errors of metabolism v1.362 TREX1 Catherine Snow edited their review of gene: TREX1: Changed phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, 225750
Congenital myopathy v1.169 ACTN2 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red toProvisional Amber rating, this gene could be Green but given the discrepant ratings, this gene needs to be discussed by the Neurology Test Group to confirm; to: Comment on list classification: Changed rating from Red to provisional Amber rating. This gene could be Green based on cases and functional evidence but given the discrepant ratings this gene needs to be discussed by the Neurology Test Group to confirm.
Inborn errors of metabolism v1.362 WFS1 Catherine Snow edited their review of gene: WFS1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v1.169 ACTN2 Louise Daugherty Classified gene: ACTN2 as Amber List (moderate evidence)
Congenital myopathy v1.169 ACTN2 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red toProvisional Amber rating, this gene could be Green but given the discrepant ratings, this gene needs to be discussed by the Neurology Test Group to confirm
Congenital myopathy v1.169 ACTN2 Louise Daugherty Gene: actn2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v1.168 ACTN2 Louise Daugherty Phenotypes for gene: ACTN2 were changed from Multiple structured Core Disease to Multiple structured Core Disease; progressive early-onset muscle weakness
Congenital myopathy v1.167 ACTN2 Louise Daugherty Publications for gene: ACTN2 were set to 24692096
Hereditary neuropathy v1.334 Antonio Rueda removed STR:NOP56_GGCCTGTT from the panel
Congenital myopathy v1.166 SRPK3 Louise Daugherty changed review comment from: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446
is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.; to: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446 is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Congenital myopathy v1.166 SRPK3 Louise Daugherty commented on gene: SRPK3: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446
is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Congenital myopathy v1.166 KLHL9 Louise Daugherty commented on gene: KLHL9: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 23746549 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene KLHL40, but for KLHL9 the publication field was blank (no data was supplied as evidence). The Green review rating for KLHL9 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Undiagnosed metabolic disorders v1.387 WFS1 Catherine Snow Publications for gene: WFS1 were set to 27604308
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Classified gene: WFS1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Added comment: Comment on list classification: Promoted from Amber to Green. WFS1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Gene: wfs1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.362 WFS1 Catherine Snow Publications for gene: WFS1 were set to 27604308
Inborn errors of metabolism v1.361 WFS1 Catherine Snow Classified gene: WFS1 as Green List (high evidence)
Inborn errors of metabolism v1.361 WFS1 Catherine Snow Gene: wfs1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.360 WFS1 Catherine Snow reviewed gene: WFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30171196; Phenotypes: Wolfram syndrome 1, 222300, Wolfram-like syndrome, autosomal dominant, 614296, Diabetes mellitus, noninsulin-dependent, association with, 125853; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.70 UNC13A Louise Daugherty edited their review of gene: UNC13A: Changed rating: RED
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow changed review comment from: Comment on list classification: Promoted from Amber to Green. PTS is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: Comment on list classification: Promoted from Amber to Green. VKORC1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow Classified gene: VKORC1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow Gene: vkorc1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.384 VKORC1 Catherine Snow reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, 607473, Warfarin resistance, 122700; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.70 SYT15 Louise Daugherty changed review comment from: New gene added by reviewer. Rated as Red awaiting more information on this gene and potential disease association. gene-phenotype not listed in OMIM not publications to date supporting gene-disease association.; to: New gene added by reviewer. Rated as Red awaiting more information on this gene and potential disease association. gene-phenotype not listed in OMIM not publications to date supporting gene-disease association. To be highlighted to Test Group for further review due to potential research results
Inborn errors of metabolism v1.360 VKORC1 Catherine Snow Classified gene: VKORC1 as Green List (high evidence)
Inborn errors of metabolism v1.360 VKORC1 Catherine Snow Gene: vkorc1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.359 VKORC1 Catherine Snow reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, 607473, Warfarin resistance, 122700; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.70 SNAP25 Louise Daugherty edited their review of gene: SNAP25: Added comment: Leave as Red, awaiting more information on this gene and potential disease association.; Changed rating: RED
Congenital myaesthenic syndrome v1.70 LAMA5 Louise Daugherty commented on gene: LAMA5: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.70 CACNA1A Louise Daugherty commented on gene: CACNA1A: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.70 LAMA5 Louise Daugherty edited their review of gene: LAMA5: Changed rating: RED
Congenital myaesthenic syndrome v1.70 CACNA1A Louise Daugherty edited their review of gene: CACNA1A: Changed rating: RED
Congenital myaesthenic syndrome v1.70 RYR1 Louise Daugherty Phenotypes for gene: RYR1 were changed from RYR1-related congenital myopathy with fatigable weakness to RYR1-related congenital myopathy
Congenital myaesthenic syndrome v1.69 RYR1 Louise Daugherty Publications for gene: RYR1 were set to 24951453; 30808424; 30406384
Congenital myaesthenic syndrome v1.68 RYR1 Louise Daugherty Publications for gene: RYR1 were set to 24951453; 30808424
Congenital myaesthenic syndrome v1.67 RYR1 Louise Daugherty Phenotypes for gene: RYR1 were changed from to RYR1-related congenital myopathy with fatigable weakness
Congenital myaesthenic syndrome v1.66 LAMA5 Louise Daugherty Phenotypes for gene: LAMA5 were changed from to myopia, facial tics, and failure of neuromuscular transmission
Congenital myaesthenic syndrome v1.65 CACNA1A Louise Daugherty Publications for gene: CACNA1A were set to
Congenital myaesthenic syndrome v1.64 CACNA1A Louise Daugherty Phenotypes for gene: CACNA1A were changed from episodic ataxia plus myasthenic syndrome to episodic ataxia plus myasthenic syndrome; hemiplegic migraine plus disturbed NMJ function
Congenital myaesthenic syndrome v1.63 CACNA1A Louise Daugherty Phenotypes for gene: CACNA1A were changed from to episodic ataxia plus myasthenic syndrome
Congenital myaesthenic syndrome v1.62 CACNA1A Louise Daugherty Mode of inheritance for gene: CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myaesthenic syndrome v1.61 MYO9A Louise Daugherty edited their review of gene: MYO9A: Changed rating: GREEN
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty edited their review of gene: VAMP1: Changed rating: GREEN
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty Classified gene: VAMP1 as Green List (high evidence)
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (new publication PMID: 28168212) plus animal model and external review comment all support gene-disease association.
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty Gene: vamp1 has been classified as Green List (High Evidence).
Congenital myaesthenic syndrome v1.60 TOR1AIP1 Louise Daugherty edited their review of gene: TOR1AIP1: Added comment: Applicable to panel, but currently not enough evidence to support Amber/Green rating; Changed rating: RED
Congenital myaesthenic syndrome v1.60 TOR1AIP1 Louise Daugherty Publications for gene: TOR1AIP1 were set to
Congenital myaesthenic syndrome v1.59 TOR1AIP1 Louise Daugherty Phenotypes for gene: TOR1AIP1 were changed from to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, 617072
Congenital myaesthenic syndrome v1.58 RYR1 Louise Daugherty Publications for gene: RYR1 were set to 24951453
Congenital myaesthenic syndrome v1.57 RYR1 Louise Daugherty changed review comment from: Leave as Red, awaiting more information on this gene and potential disease association.; to: Leave as Red, awaiting more information on this gene and potential disease association. From Orphanet review: GeneReview PMID: 30808424 : Primary myopathies may go along with secondary transmission disease, which does not represent congential CMS, such as in patients with congenital myopathy due to TPM2 mutations, or patients carrying mutations in KLHL40, BIN1, DNM2, MTM1, TPM3, or RYR1. Importantly, secondary transmission disease frequently responds beneficially to AchEI.
Congenital myaesthenic syndrome v1.57 RYR1 Louise Daugherty edited their review of gene: RYR1: Changed rating: RED
Congenital myaesthenic syndrome v1.57 SYT15 Louise Daugherty edited their review of gene: SYT15: Changed rating: RED
Congenital myaesthenic syndrome v1.57 SYT15 Louise Daugherty commented on gene: SYT15: New gene added by reviewer. Rated as Red awaiting more information on this gene and potential disease association. gene-phenotype not listed in OMIM not publications to date supporting gene-disease association.
Congenital myaesthenic syndrome v1.57 SLC25A1 Louise Daugherty Classified gene: SLC25A1 as Amber List (moderate evidence)
Congenital myaesthenic syndrome v1.57 SLC25A1 Louise Daugherty Added comment: Comment on list classification: New gene added by reviewer. Rated as Amber, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.57 SLC25A1 Louise Daugherty Gene: slc25a1 has been classified as Amber List (Moderate Evidence).
Congenital myaesthenic syndrome v1.56 RYR1 Louise Daugherty commented on gene: RYR1: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.56 PREPL Louise Daugherty edited their review of gene: PREPL: Changed rating: RED
Congenital myaesthenic syndrome v1.56 PREPL Louise Daugherty commented on gene: PREPL: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.56 MYO9A Louise Daugherty Publications for gene: MYO9A were set to 29462312; 27259756
Congenital myaesthenic syndrome v1.55 MYO9A Louise Daugherty Classified gene: MYO9A as Green List (high evidence)
Congenital myaesthenic syndrome v1.55 MYO9A Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (with functional work), and external review comment all support gene-disease association.
Congenital myaesthenic syndrome v1.55 MYO9A Louise Daugherty Gene: myo9a has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.384 VIPAS39 Catherine Snow Classified gene: VIPAS39 as Green List (high evidence)
Undiagnosed metabolic disorders v1.384 VIPAS39 Catherine Snow Gene: vipas39 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.383 VIPAS39 Catherine Snow reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 22753090, 26808426; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.54 LAMB2 Louise Daugherty edited their review of gene: LAMB2: Changed rating: RED
Inborn errors of metabolism v1.359 VIPAS39 Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. VIPAS39 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. VIPAS39 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >23 cases in literature. Therefore, enough evidence for this gene to be promoted to Green status.
Inborn errors of metabolism v1.359 VIPAS39 Catherine Snow Publications for gene: VIPAS39 were set to 27604308
Congenital myaesthenic syndrome v1.54 LAMB2 Louise Daugherty commented on gene: LAMB2: Leave as Red, awaiting more information on this gene and potential disease association.
Inborn errors of metabolism v1.358 VIPAS39 Catherine Snow Classified gene: VIPAS39 as Green List (high evidence)
Inborn errors of metabolism v1.358 VIPAS39 Catherine Snow Gene: vipas39 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.357 VIPAS39 Catherine Snow reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 22753090, 26808426; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2, 613404; Mode of inheritance: None
Congenital myaesthenic syndrome v1.54 ALG2 Louise Daugherty Classified gene: ALG2 as Green List (high evidence)
Congenital myaesthenic syndrome v1.54 ALG2 Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (with functional work), and external review comment all support gene-disease association.
Congenital myaesthenic syndrome v1.54 ALG2 Louise Daugherty Gene: alg2 has been classified as Green List (High Evidence).
Inherited polyposis v1.0 Rebecca Foulger promoted panel to version 1.0
Inherited polyposis v0.56 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Inherited pancreatic cancer v1.0 Rebecca Foulger promoted panel to version 1.0
Inherited pancreatic cancer v0.42 STK11 Rebecca Foulger Publications for gene: STK11 were set to
Inherited pancreatic cancer v0.41 PRSS1 Rebecca Foulger Publications for gene: PRSS1 were set to
Inherited pancreatic cancer v0.40 PMS2 Rebecca Foulger Publications for gene: PMS2 were set to
Inherited pancreatic cancer v0.39 MSH6 Rebecca Foulger Publications for gene: MSH6 were set to
Inherited pancreatic cancer v0.38 MSH2 Rebecca Foulger Publications for gene: MSH2 were set to
Inherited pancreatic cancer v0.37 MLH1 Rebecca Foulger Publications for gene: MLH1 were set to
Inherited pancreatic cancer v0.36 CDK4 Rebecca Foulger Publications for gene: CDK4 were set to
Inherited pancreatic cancer v0.35 BRCA1 Rebecca Foulger Publications for gene: BRCA1 were set to
Inherited pancreatic cancer v0.34 PALB2 Rebecca Foulger Publications for gene: PALB2 were set to
Undiagnosed metabolic disorders v1.383 VPS33B Catherine Snow Publications for gene: VPS33B were set to 27604308
Undiagnosed metabolic disorders v1.382 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Undiagnosed metabolic disorders v1.382 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Inherited pancreatic cancer v0.33 CDKN2A Rebecca Foulger Publications for gene: CDKN2A were set to
Inherited pancreatic cancer v0.32 BRCA2 Rebecca Foulger Publications for gene: BRCA2 were set to
Undiagnosed metabolic disorders v1.381 VPS33B Catherine Snow reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18853461; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1, 208085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited pancreatic cancer v0.31 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Inborn errors of metabolism v1.357 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Inborn errors of metabolism v1.357 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.356 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Inborn errors of metabolism v1.356 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.356 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Inborn errors of metabolism v1.356 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.356 VPS33B Catherine Snow Publications for gene: VPS33B were set to 27604308
Inborn errors of metabolism v1.355 VPS33B Catherine Snow reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18853461; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1, 208085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited renal cancer v1.0 Rebecca Foulger promoted panel to version 1.0
Inherited renal cancer v0.50 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Inherited renal cancer v0.49 TMEM127 Rebecca Foulger Publications for gene: TMEM127 were set to PMID: 24334765
Inherited renal cancer v0.48 SDHD Rebecca Foulger Publications for gene: SDHD were set to PMID: 27899189
Inherited renal cancer v0.47 SDHC Rebecca Foulger Publications for gene: SDHC were set to PMID: 27899189
Inherited renal cancer v0.46 MITF Rebecca Foulger Publications for gene: MITF were set to PMID: 27899189
Inherited renal cancer v0.45 VHL Rebecca Foulger Publications for gene: VHL were set to PMID: 27899189
Inherited renal cancer v0.44 SDHB Rebecca Foulger Publications for gene: SDHB were set to PMID: 27899189
Inherited renal cancer v0.43 MET Rebecca Foulger Publications for gene: MET were set to PMID: 27899189
Inherited renal cancer v0.42 FLCN Rebecca Foulger Publications for gene: FLCN were set to PMID: 27899189
Kabuki syndrome v1.2 PQBP1 Cristina Dias gene: PQBP1 was added
gene: PQBP1 was added to Kabuki syndrome. Sources: Literature
Mode of inheritance for gene: PQBP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PQBP1 were set to 30244542
Phenotypes for gene: PQBP1 were set to intellectual disability; long triangular face; bulbous nose; hypoplastic malar region; micrognathia; partial agenesis of corpus callosum; spasticity; contractures
Penetrance for gene: PQBP1 were set to unknown
Review for gene: PQBP1 was set to RED
Added comment: Kabuki-like features reported in Abdel-Salam et al, 2018 (PMID 30244542)
Sources: Literature
Additional findings health related v0.76 CFTR Ellen McDonagh Classified gene: CFTR as No list
Additional findings health related v0.76 CFTR Ellen McDonagh Added comment: Comment on list classification: A seperate panel will be used for analysis of this gene.
Additional findings health related v0.76 CFTR Ellen McDonagh Gene: cftr has been removed from the panel.
Additional findings reproductive carrier status v0.2 CFTR Ellen McDonagh Classified gene: CFTR as Green List (high evidence)
Additional findings reproductive carrier status v0.2 CFTR Ellen McDonagh Gene: cftr has been classified as Green List (High Evidence).
Additional findings reproductive carrier status v0.1 CFTR Ellen McDonagh gene: CFTR was added
gene: CFTR was added to Additional findings reproductive carrier status. Sources: Expert list
Mode of inheritance for gene: CFTR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CFTR were set to ENST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only
Additional findings reproductive carrier status v0.0 Ellen McDonagh Added Panel Additional findings reproductive carrier status
Additional findings health related v0.75 Ellen McDonagh Panel name changed from Genomics England Additional Findings to Additional findings health related
Inborn errors of metabolism v1.355 UROC1 Catherine Snow Publications for gene: UROC1 were set to 27604308
Inborn errors of metabolism v1.354 UROC1 Catherine Snow reviewed gene: UROC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19304569, 30619714; Phenotypes: ?Urocanase deficiency, 276880; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.53 Louise Daugherty List of related panels changed from Congenital myaesthenia; Congenital myasthenia to Congenital myaesthenia; Congenital myasthenia; R80
Genetic epilepsy syndromes v1.365 ADAR Rebecca Foulger Publications for gene: ADAR were set to
Genetic epilepsy syndromes v1.364 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plu review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plus review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.
Undiagnosed metabolic disorders v1.381 UQCRB Catherine Snow Classified gene: UQCRB as Green List (high evidence)
Undiagnosed metabolic disorders v1.381 UQCRB Catherine Snow Gene: uqcrb has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.380 UQCRB Catherine Snow reviewed gene: UQCRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25446085 28604960 12709789 23454382; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3, 615158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.354 UQCRB Catherine Snow commented on gene: UQCRB
Congenital muscular dystrophy v1.68 PLEC Louise Daugherty Classified gene: PLEC as Green List (high evidence)
Congenital muscular dystrophy v1.68 PLEC Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Congenital muscular dystrophy v1.68 PLEC Louise Daugherty Gene: plec has been classified as Green List (High Evidence).
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty changed review comment from: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.; to: Added publications to support green rating. PMID: 28447722 second report on plectin associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel. From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.
Undiagnosed metabolic disorders v1.380 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow edited their review of gene: UMOD: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow changed review comment from: Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow Classified gene: UMOD as Green List (high evidence)
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow Gene: umod has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.354 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308; 31422399; 29180396
Inborn errors of metabolism v1.354 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308
Inborn errors of metabolism v1.354 UMOD Catherine Snow Classified gene: UMOD as Green List (high evidence)
Inborn errors of metabolism v1.354 UMOD Catherine Snow Gene: umod has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.378 UMOD Catherine Snow reviewed gene: UMOD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422399, 29180396; Phenotypes: Hyperuricemic nephropathy, familial juvenile 1, 162000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inborn errors of metabolism v1.353 UMOD Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty Deleted their comment
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty changed review comment from: From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.; to: From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty commented on gene: PLEC: From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.
Inborn errors of metabolism v1.353 UMOD Catherine Snow reviewed gene: UMOD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422399, 29180396; Phenotypes: Hyperuricemic nephropathy, familial juvenile 1, 162000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty changed review comment from: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.; to: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty Classified gene: PLEC as Amber List (moderate evidence)
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty Gene: plec has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty commented on gene: PLEC: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty Deleted their comment
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty Added comment: Comment on publications: added further publications to support the Green rating
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty Publications for gene: PLEC were set to 21109228
Undiagnosed metabolic disorders v1.378 TUFM Catherine Snow Classified gene: TUFM as Green List (high evidence)
Undiagnosed metabolic disorders v1.378 TUFM Catherine Snow Gene: tufm has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow edited their review of gene: TUFM: Changed phenotypes: Combined oxidative phosphorylation deficiency 4, 610678
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow edited their review of gene: TUFM: Changed publications: 28132884, 25735936, 17160893, 26741492
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 28132884, 25735936, 17160893, 26741492; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v1.65 PLEC Louise Daugherty Deleted their comment
Congenital muscular dystrophy v1.65 PLEC Louise Daugherty commented on gene: PLEC: Only one case reported with variants in this gene and CMD, provisionally rated Red pending further cases or expert opinion.
Congenital muscular dystrophy v1.65 DPM1 Louise Daugherty commented on gene: DPM1: Only one case reported with variants in this gene and CMD, not sure it fulfils the criteria to be a green gene. Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.65 DPM3 Louise Daugherty commented on gene: DPM3: Only one case reported with variants in this gene and CMD, not sure it fulfils the criteria to be a green gene. Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.65 DPM3 Louise Daugherty Phenotypes for gene: DPM3 were changed from congenital muscular dystrophies; Congenital disorder of glycosylation, type Io 612937 to congenital muscular dystrophies; Congenital disorder of glycosylation, type Io, 612937'Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937
Inborn errors of metabolism v1.353 TUFM Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Inborn errors of metabolism v1.353 TUFM Catherine Snow reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.377 TTPA Catherine Snow Publications for gene: TTPA were set to 27604308
Undiagnosed metabolic disorders v1.376 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Undiagnosed metabolic disorders v1.376 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.375 TTPA Catherine Snow reviewed gene: TTPA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia with isolated vitamin E deficiency, 277460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.353 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Inborn errors of metabolism v1.353 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.353 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Inborn errors of metabolism v1.353 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.353 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Inborn errors of metabolism v1.353 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.352 TTPA Catherine Snow Publications for gene: TTPA were set to 27604308
Inborn errors of metabolism v1.352 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Inborn errors of metabolism v1.352 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.351 TTPA Catherine Snow reviewed gene: TTPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 26981194; Phenotypes: Ataxia with isolated vitamin E deficiency, 277460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v1.64 COL4A1 Louise Daugherty Phenotypes for gene: COL4A1 were changed from walker warburg syndrome, muscle eye brain disease to walker warburg syndrome, muscle eye brain disease; Brain small vessel disease with or without ocular anomalies, 175780
Additional findings health related v0.74 CFTR Ellen McDonagh Phenotypes for gene: CFTR were changed from NST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only to ENST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only
Additional findings health related v0.73 CFTR Ellen McDonagh Phenotypes for gene: CFTR were changed from NM_000492.3; Carrier status; Cystic Fibrosis; Adult-only to NST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only
Additional findings health related v0.72 CFTR Ellen McDonagh Deleted their review
Additional findings health related v0.72 CFTR Ellen McDonagh Deleted their comment
Additional findings health related v0.72 CFTR Ellen McDonagh Classified gene: CFTR as Green List (high evidence)
Additional findings health related v0.72 CFTR Ellen McDonagh Gene: cftr has been classified as Green List (High Evidence).
Inherited renal cancer v0.41 PTEN Rebecca Foulger Classified gene: PTEN as Amber List (moderate evidence)
Inherited renal cancer v0.41 PTEN Rebecca Foulger Added comment: Comment on list classification: PTEN has been changed from red to amber based on a comment by Shazia Mahamdallie (email communication, October 11th 2019) who notes that "amber status might be more appropriate, i.e. evidence of association but not significant".
Inherited renal cancer v0.41 PTEN Rebecca Foulger Gene: pten has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v1.63 GOLGA2 Louise Daugherty commented on gene: GOLGA2: After review with Genomics England clinical team this gene was provisionally rated Amber on the basis of one family, as it is difficult to be confident about the extent of the phenotype so amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.63 Louise Daugherty List of related panels changed from to R79
Inborn errors of metabolism v1.351 TREX1 Catherine Snow Deleted their comment
Inborn errors of metabolism v1.351 TREX1 Catherine Snow Added comment: Comment on phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive TREX1 deficiency leads to the intracellular accumulation of DNA, and activation of the immune system by these accumulated NA.
Inborn errors of metabolism v1.351 TREX1 Catherine Snow Phenotypes for gene: TREX1 were changed from Intellectual disability; Familial cerebral small vessel disease; Intracerebral calcification disorders; (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS1; Inherited white matter disorders to Intellectual disability; Familial cerebral small vessel disease; Intracerebral calcification disorders; (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS1; Inherited white matter disorders
Inborn errors of metabolism v1.350 TREX1 Catherine Snow Classified gene: TREX1 as Green List (high evidence)
Inborn errors of metabolism v1.350 TREX1 Catherine Snow Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype
Inborn errors of metabolism v1.350 TREX1 Catherine Snow Gene: trex1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.375 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308
Undiagnosed metabolic disorders v1.374 TREX1 Catherine Snow Classified gene: TREX1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.374 TREX1 Catherine Snow Gene: trex1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.373 TREX1 Catherine Snow reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 12624136, 25604658; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inborn errors of metabolism v1.349 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308; 12624136; 25604658
Inborn errors of metabolism v1.349 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308; 12624136; 25604658
Inborn errors of metabolism v1.349 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308
Inborn errors of metabolism v1.348 TREX1 Catherine Snow reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12624136, 25604658; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger reviewed Region: ISCA-37433-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger reviewed Region: ISCA-37446-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger Region: ISCA-37433-Loss was added
Region: ISCA-37433-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Loss were set to 15545748; 15889418; 20301696
Phenotypes for Region: ISCA-37433-Loss were set to Learning difficulties; immune deficiency; renal anomalies; cleft palate, polydactyly; 22q11.2 deletion syndrome; diaphragmatic hernia; 192430; polyhydramnios; DiGeorge syndrome; Velocardiofacial syndrome; 188400; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; congenital heart disease
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37446-Loss were set to micrognathia; neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; clefting; DiGeorge syndrome; Velocardiofacial syndrome; 188400; cardiac malformations; Hearing deficits
Primary immunodeficiency v1.132 PIK3CD Ilenia Simeoni reviewed gene: PIK3CD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29226301; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Additional findings health related v0.71 VHL Ellen McDonagh Phenotypes for gene: VHL were changed from NM_000551.3; Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child to ENST00000256474.2; Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child
Additional findings health related v0.70 RET Ellen McDonagh Phenotypes for gene: RET were changed from NM_020975.4; Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child to ENST00000355710.7; Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child
Additional findings health related v0.69 PCSK9 Ellen McDonagh Phenotypes for gene: PCSK9 were changed from NM_174936.3; Familial hypercholesterolaemia; Adult and child to ENST00000302118.5; Familial hypercholesterolaemia; Adult and child
Additional findings health related v0.68 MUTYH Ellen McDonagh Phenotypes for gene: MUTYH were changed from NM_001128425.1; Bowel cancer predisposition; MYH-associated polyposis; Adult only to ENST00000450313.5; Bowel cancer predisposition; MYH-associated polyposis; Adult only
Additional findings health related v0.67 MSH6 Ellen McDonagh Phenotypes for gene: MSH6 were changed from NM_000179.2; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to ENST00000234420.9; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related v0.66 MSH2 Ellen McDonagh Phenotypes for gene: MSH2 were changed from NM_000251.2; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to ENST00000233146.6; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related v0.65 MLH1 Ellen McDonagh Phenotypes for gene: MLH1 were changed from NM_000249.3; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to ENST00000231790.6; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related v0.64 MEN1 Ellen McDonagh Phenotypes for gene: MEN1 were changed from NM_000244.3; Other cancer predisposition; Myltiple endocrine Neoplasia Type 1; Adult and child to ENST00000394374.6; Other cancer predisposition; Myltiple endocrine Neoplasia Type 1; Adult and child
Additional findings health related v0.63 LDLR Ellen McDonagh Phenotypes for gene: LDLR were changed from NM_000527.4; Familial hypercholesterolaemia; Adult and child to ENST00000558518.5; Familial hypercholesterolaemia; Adult and child
Additional findings health related v0.62 CFTR Ellen McDonagh Classified gene: CFTR as No list
Additional findings health related v0.62 CFTR Ellen McDonagh Gene: cftr has been removed from the panel.
Additional findings health related v0.61 BRCA2 Ellen McDonagh Phenotypes for gene: BRCA2 were changed from NM_000059.3; Breast and ovarian cancer predisposition; Adult only to ENST00000544455.5; Breast and ovarian cancer predisposition; Adult only
Additional findings health related v0.60 BRCA1 Ellen McDonagh Phenotypes for gene: BRCA1 were changed from NM_007294.3; Breast and ovarian cancer predisposition; Adult only to ENST00000357654.8; Breast and ovarian cancer predisposition; Adult only
Additional findings health related v0.59 APC Ellen McDonagh Phenotypes for gene: APC were changed from ENST00000257430; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Additional findings health related v0.58 APOB Ellen McDonagh Phenotypes for gene: APOB were changed from NM_000384.2; Familial hypercholesterolaemia; Adult and child to ENST00000233242.5; Familial hypercholesterolaemia; Adult and child
Additional findings health related v0.57 APC Ellen McDonagh Phenotypes for gene: APC were changed from NM_000038.5; ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to ENST00000257430; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Additional findings health related v0.56 APC Ellen McDonagh Phenotypes for gene: APC were changed from NM_000038.5; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to NM_000038.5; ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Nephrocalcinosis or nephrolithiasis v1.18 CLCNKA Eleanor Williams commented on gene: CLCNKA
Nephrocalcinosis or nephrolithiasis v1.18 ADCY10 Eleanor Williams commented on gene: ADCY10
Cerebral malformations v2.74 Louise Daugherty List of related panels changed from Cerebral malformation to Cerebral malformation; R87
Pain syndromes v1.9 NMNAT2 Rebecca Foulger Classified gene: NMNAT2 as Red List (low evidence)
Pain syndromes v1.9 NMNAT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Red. Gene was added to the panel and rated Green by external expert Michael Coleman (11 Sept 2019). Currently insufficient evidence for a Green rating: one case (2 siblings) with pain disorder in PMID:31132363, and a mouse model. Not currently associated with a phenotype in OMIM or Gene2Phenotype. Therefore rated Red awaiting further evidence.
Pain syndromes v1.9 NMNAT2 Rebecca Foulger Gene: nmnat2 has been classified as Red List (Low Evidence).
Pain syndromes v1.8 NMNAT2 Rebecca Foulger commented on gene: NMNAT2
Intellectual disability v2.1066 MED25 Rebecca Foulger Classified gene: MED25 as Green List (high evidence)
Intellectual disability v2.1066 MED25 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on the recent Lebanese cases reported by Nair et al (DOI:10.1159/000501114 and PMID:30800049). Advice and a Green review by Helen Brittain supports the upgrade to Green.
Intellectual disability v2.1066 MED25 Rebecca Foulger Gene: med25 has been classified as Green List (High Evidence).
DDG2P v1.137 SOX11 Rebecca Foulger commented on gene: SOX11: The rating of genes on the DDG2P panel directly reflects the Gene2Phenotype Disease confidence. Therefore I have added SOX11 to the panel 'Paediatric disorders - additional genes' as a Green gene based on the review by Alisdair McNeil, so that SOX11 will feature as a Green gene on the 'Paediatric disorders' Super panel.
Paediatric disorders - additional genes v0.33 SOX11 Rebecca Foulger commented on gene: SOX11: Alisdair McNeill (Sheffield Childrens Hospital) review, copied from DDG2P Panel Version: 1.128, Created: 7 Oct 2019, 2:38 p.m.: I have identified a series (unpublished) of around 20 children with de novo variants in SOX11 and overlapping clinical features. I think this is a real, though rare, cause of neurodevelopmental disorders.
Paediatric disorders - additional genes v0.33 SOX11 Rebecca Foulger Mode of inheritance for gene: SOX11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v0.32 SOX11 Rebecca Foulger Classified gene: SOX11 as Green List (high evidence)
Paediatric disorders - additional genes v0.32 SOX11 Rebecca Foulger Gene: sox11 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v0.31 SOX11 Rebecca Foulger gene: SOX11 was added
gene: SOX11 was added to Paediatric disorders - additional genes. Sources: Expert list
Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SOX11 were set to MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27; Coffin-Siris syndrome 9, 615866
Added comment: Added SOX11 to the panel based on a Green review left by Alisdair McNeill (Sheffield Childrens Hospital) for SOX11 on the PanelApp DDG2P panel. SOX11 currently has a probable Disease confidence in Gene2Phenotype for MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27, but Alisdair McNeil's review provides sufficient cases for a Green rating on the Paediatric disorders Super panel.
Sources: Expert list
Severe microcephaly v1.74 UFC1 Helen Brittain reviewed gene: UFC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29868776; Phenotypes: Neurodevelopmental disorder with spasticity and poor growth, 618076; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 ZNHIT3 Helen Brittain reviewed gene: ZNHIT3: Rating: RED; Mode of pathogenicity: ; Publications: 28335020; Phenotypes: PEHO syndrome, 260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 PCLO Helen Brittain reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: ; Publications: 25832664; Phenotypes: ?Pontocerebellar hypoplasia, type 3, 608027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 UFM1 Helen Brittain reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28931644, 29868776, 27545674; Phenotypes: Leukodystrophy, hypomyelinating, 14, 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 UBA5 Helen Brittain reviewed gene: UBA5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 44, 617132; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 CCDC88A Helen Brittain reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: ; Publications: 26917597, 30392057; Phenotypes: ?PEHO syndrome-like, 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.73 Louise Daugherty List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88
Congenital myopathy v1.166 TRIP4 Louise Daugherty changed review comment from: Reviewed by Ivone Leong (Genomics England Curator)
PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this.
There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case?

Genomics England clinical team who noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene

The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; to: Reviewed by Ivone Leong (Genomics England Curator)
PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this.
There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case?

Genomics England clinical team noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene

The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.
Proteinuric renal disease v1.225 OCRL Eleanor Williams changed review comment from: Associated with Dent disease 2 (300555) and Lowe syndrome (309000) in OMIM.

PMID: 21249396 - Tasic et al 2011 - 5 unrelated Macedonian patients with 4 different variants in OCRL. 2 diagnosed with Lowe Syndrome (both with LMWP and hypercalciuria) and 3 with Dent disease 2 (all with asymptomatic proteinuria). All five patients had LMWP and hypercalciuria/


PMID: 17384968 - Sekine et al 2007 - 3 distinct OCRL1 mutations in 3 patients with the Dent disease phenotype are described. All the patients manifested an extremely high degree of low-molecular-weight proteinuria and showed no ocular abnormalities or apparent mental retardation. Urinalysis and blood chemistry showed no findings suggestive of Fanconi syndrome with renal tubular acidosis. Mutations in CLCN5 were ruled out. The mutations identified in OCRL1 are one frame-shift mutation (I127stop) and two missense mutations (R301C and R476W).

PMID: 27625797 - Böckenhauer et al 2012 - 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease were assessed for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. All showed low molecular weight proteinuria.; to: Associated with Dent disease 2 (300555) and Lowe syndrome (309000) in OMIM.

PMID: 21249396 - Tasic et al 2011 - 5 unrelated Macedonian patients with 4 different variants in OCRL. 2 diagnosed with Lowe Syndrome (both with LMWP and hypercalciuria) and 3 with Dent disease 2 (all with asymptomatic proteinuria). All five patients had LMWP and hypercalciuria. Sex of patients not stated.


PMID: 17384968 - Sekine et al 2007 - 3 distinct OCRL1 mutations in 3 male patients with the Dent disease phenotype are described. All the patients manifested an extremely high degree of low-molecular-weight proteinuria and showed no ocular abnormalities or apparent mental retardation. Urinalysis and blood chemistry showed no findings suggestive of Fanconi syndrome with renal tubular acidosis. Mutations in CLCN5 were ruled out. The mutations identified in OCRL1 are one frame-shift mutation (I127stop) and two missense mutations (R301C and R476W).

PMID: 27625797 - Böckenhauer et al 2012 - 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease were assessed for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. All showed low molecular weight proteinuria. Sex of patients not explicitly stated but each had mothers who were 'carriers'.
Structural eye disease v0.93 CRYAA Catherine Snow Added comment: Comment on mode of inheritance: OMIM with publication support has this both AD and AR therefore changing MOI to both monoallelic and biallelic.
Structural eye disease v0.93 CRYAA Catherine Snow Mode of inheritance for gene: CRYAA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neuromuscular disorders v1.11 Louise Daugherty List of related panels changed from Other rare neuromuscular disorders;R381 to Other rare neuromuscular disorders; R381
Neuromuscular disorders v1.10 Louise Daugherty List of related panels changed from Other rare neuromuscular disorders to Other rare neuromuscular disorders;R381
Congenital myopathy v1.166 Louise Daugherty List of related panels changed from to R81
Congenital myopathy v1.165 TRIP4 Louise Daugherty Classified gene: TRIP4 as Green List (high evidence)
Congenital myopathy v1.165 TRIP4 Louise Daugherty Added comment: Comment on list classification: After review, it was agreed that it was an appropriate phenotype, sufficient cases to support gene-disease association. The gene is also Green on Neuromuscular disorders
Congenital myopathy v1.165 TRIP4 Louise Daugherty Gene: trip4 has been classified as Green List (High Evidence).
Congenital myopathy v1.164 TRIP4 Louise Daugherty Publications for gene: TRIP4 were set to 26924529
Congenital myopathy v1.163 TRIP4 Louise Daugherty edited their review of gene: TRIP4: Added comment: Reviewed by Ivone Leong (Genomics England Curator)
PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this.
There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case?

Genomics England clinical team who noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene

The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN
Congenital muscular dystrophy v1.62 TRAPPC11 Louise Daugherty Classified gene: TRAPPC11 as Green List (high evidence)
Congenital muscular dystrophy v1.62 TRAPPC11 Louise Daugherty Added comment: Comment on list classification: After review, it was agreed that it was an appropriate phenotype, sufficient cases to support gene-disease association.
Congenital muscular dystrophy v1.62 TRAPPC11 Louise Daugherty Gene: trappc11 has been classified as Green List (High Evidence).
Congenital muscular dystrophy v1.61 TRAPPC11 Louise Daugherty edited their review of gene: TRAPPC11: Added comment: Reviewed by Genomics England clinical team who noted the phenotype described in the OMIM cases have significant overlap with those described as 'Congenital muscular dystrophy'. There is a relevant muscular phenotype with onset in infancy / early childhood, a raised CK and dystrophic changes on muscle biopsy. The GLH representative has rated it green so would support green rating based on the evidence. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN
Retinal disorders v1.199 KIZ Mohammed Abdallah changed review comment from: Although this gene is reported under the specified human phenotype ontology, and Retnet genes, it had the misfortune of being classified historically as non-coding gene in the Ensembl grch37 release, which has been archived since then, but by consulting the new hg38 Ensembl release and both Refseq grch37 and grch38 we could see that this gene is actually an important protein-coding gene that has been identified as a causal gene for Retinitis pigmentosa. Moreover it has three pathogenic mutations reported in Clinvar and from more than three unrelated families reported by three different and independent studies.; to: Although this gene is reported under the specified human phenotype ontology, and Retnet genes, it had the misfortune of being classified historically as non-coding gene in the Ensembl grch37 release, which has been archived since then, However, when consulting the new hg38 Ensembl release and both Refseq grch37 and grch38 we can clearly see that this gene is actually an important protein-coding gene that has been identified as a causal gene for Retinitis pigmentosa. Moreover it has three pathogenic mutations reported in Clinvar and from more than three unrelated families reported by three different and independent studies.
Retinal disorders v1.199 KIZ Mohammed Abdallah reviewed gene: KIZ: 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 ( 31556760, 29057815, 28837078, 24680887); Phenotypes: Phenotypes (HP:0000556, HP:0000510); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v1.61 SIL1 Louise Daugherty Classified gene: SIL1 as Green List (high evidence)
Congenital muscular dystrophy v1.61 SIL1 Louise Daugherty Added comment: Comment on list classification: After review, it was agreed that it was an appropriate phenotype, sufficient cases to support gene-disease association.
Congenital muscular dystrophy v1.61 SIL1 Louise Daugherty Gene: sil1 has been classified as Green List (High Evidence).
Congenital muscular dystrophy v1.60 SIL1 Louise Daugherty edited their review of gene: SIL1: Added comment: Reviewed by Genomics England clinical team who noted it is associated with a raised CK, muscle weakness and abnormalities on biopsy so a relevant phenotype. The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN
Congenital myopathy v1.163 PAX7 Louise Daugherty Classified gene: PAX7 as Green List (high evidence)
Congenital myopathy v1.163 PAX7 Louise Daugherty Added comment: Comment on list classification: New gene added from recommendation by Genomics Clinical team. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Congenital myopathy v1.163 PAX7 Louise Daugherty Gene: pax7 has been classified as Green List (High Evidence).
Congenital myopathy v1.162 PAX7 Louise Daugherty gene: PAX7 was added
gene: PAX7 was added to Congenital myopathy. Sources: Expert Review
Mode of inheritance for gene: PAX7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX7 were set to 31092906
Phenotypes for gene: PAX7 were set to Hypotonia; Axial hypotonia; Ptosis; Scoliosis; Delayed motor milestones; Myopathy, congenital, progressive, with scoliosis, 618578
Review for gene: PAX7 was set to GREEN
Added comment: As a result of adding PAX7 to Neuromuscular Disorders panel as recommended by external reviewer, Genomics England clinical team recommended this gene was added to Congenital Myopathy panel.

Original review:
Feichtinger et. al. report four independent consanguineous families with four different (homozygous) mutations in PAX7. Sources: Literature
Cristina Dias (The Francis Crick Institute), 17 Sep 2019
Sources: Expert Review
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams edited their review of gene: CLCN5: Added comment: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females; Changed publications: PMID27757584, PMID: 25907713; Changed phenotypes: Dent disease #300009, Proteinuria low molecular weight #308990
Proteinuric renal disease v1.225 LAMA5 Eleanor Williams Phenotypes for gene: LAMA5 were changed from to Nephrotic syndrome
Proteinuric renal disease v1.224 LAMA5 Eleanor Williams Mode of inheritance for gene: LAMA5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v1.223 LAMA5 Eleanor Williams Classified gene: LAMA5 as Amber List (moderate evidence)
Proteinuric renal disease v1.223 LAMA5 Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene to Amber. 3 cases with homozygous missense variants reported but authors classify as VUS as there is no experimental evidence to link the impact of these genetic variants on protein function to disease pathogenesis.
Proteinuric renal disease v1.223 LAMA5 Eleanor Williams Gene: lama5 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v1.193 GATM Eleanor Williams Mode of pathogenicity for gene: GATM 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
Genodermatoses with malignancies v1.6 ACTRT1 Catherine Snow Phenotypes for gene: ACTRT1 were changed from Basal cell carcinoma to Basal cell carcinoma; Bazex–Dupré–Christol syndrome
Inborn errors of metabolism v1.348 TH Catherine Snow Publications for gene: TH were set to 27604308
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow changed review comment from: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.; to: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.
Membranoproliferative glomerulonephritis v2.1 Ellen McDonagh List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; R197 to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; R197
Ehlers Danlos syndromes v2.1 Ellen McDonagh List of related panels changed from Classical Ehlers Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; R101 to Classical Ehlers Danlos Syndrome; Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; R101
Familial hypercholesterolaemia - targeted panel v0.5 LDLRAP1 Rebecca Foulger Phenotypes for gene: LDLRAP1 were changed from Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia; Hypercholesterolemia, familial, 4, 603813 to Hypercholesterolemia, familial, autosomal recessive; Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia; Hypercholesterolemia, familial, 4, 603813
Familial hypercholesterolaemia - targeted panel v0.4 LDLR Rebecca Foulger Phenotypes for gene: LDLR were changed from LDL cholesterol level QTL2, 143890; Familial Hypercholesterolaemia; Hypercholesterolemia; Familial Hypercholesterolemia; Hypercholesterolemia, familial, 1, 143890 to LDL cholesterol level QTL2, 143890; Familial Hypercholesterolaemia; Hypercholesterolemia; Familial Hypercholesterolemia; Hypercholesterolemia, familial, 1, 143890; C3 Hypercholesterolemia, familial
Familial hypercholesterolaemia - targeted panel v0.3 PCSK9 Rebecca Foulger commented on gene: PCSK9
Familial hypercholesterolaemia - targeted panel v0.3 LDLR Rebecca Foulger commented on gene: LDLR
Familial hypercholesterolaemia - targeted panel v0.3 APOB Rebecca Foulger commented on gene: APOB
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow changed review comment from: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located
in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1
expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.; to: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow edited their review of gene: ACTRT1: Added comment: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located
in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1
expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.; Changed rating: RED; Changed phenotypes: Basal cell carcinoma, Bazex–Dupré–Christol syndrome
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow gene: ACTRT1 was added
gene: ACTRT1 was added to Genodermatoses with malignancies. Sources: Literature,Expert list
Mode of inheritance for gene: ACTRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACTRT1 were set to 28869610; 30653245
Phenotypes for gene: ACTRT1 were set to Basal cell carcinoma
Review for gene: ACTRT1 was set to AMBER
Added comment: Sources: Literature, Expert list
DDG2P v1.137 AIFM1 Rebecca Foulger Phenotypes for gene: AIFM1 were changed from COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6 319521; COWCHOCK SYNDROME to COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6 300816; COWCHOCK SYNDROME 310490
DDG2P v1.136 SMAD4 Rebecca Foulger Phenotypes for gene: SMAD4 were changed from JUVENILE POLYPOSIS SYNDROME 174900; MYHRE SYNDROME; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME 175050 to JUVENILE POLYPOSIS SYNDROME 174900; MYHRE SYNDROME 139210; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME 175050
DDG2P v1.135 ALX4 Rebecca Foulger Phenotypes for gene: ALX4 were changed from PARIETAL FORAMINA 2 221704; FRONTONASAL DYSPLASIA 2 605420 to PARIETAL FORAMINA 2 609597; FRONTONASAL DYSPLASIA 2 613451
DDG2P v1.134 SALL4 Rebecca Foulger Phenotypes for gene: SALL4 were changed from ACRO-RENAL-OCULAR SYNDROME 217001; DUANE-RADIAL RAY SYNDROME 173212 to ACRO-RENAL-OCULAR SYNDROME 607323; DUANE-RADIAL RAY SYNDROME 607323
Inborn errors of metabolism v1.347 TH Catherine Snow Classified gene: TH as Green List (high evidence)
Inborn errors of metabolism v1.347 TH Catherine Snow Gene: th has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.346 TH Catherine Snow reviewed gene: TH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753243; Phenotypes: Segawa syndrome, recessive, 605407; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v1.133 COG4 Rebecca Foulger Phenotypes for gene: COG4 were changed from COG4-CDG 319493; Saul-Wilson syndrome to COG4-CDG 319493; Saul-Wilson syndrome 618150
DDG2P v1.132 ARID1B Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed (for all listed disorders). ; to: Original DDG2P rating: confirmed (for both disorders: MENTAL RETARDATION, AUTOSOMAL DOMINANT 12 135900; COFFIN SIRIS SYNDROME 135900).
DDG2P v1.132 ARID1B Rebecca Foulger Phenotypes for gene: ARID1B were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 12 614562; COFFIN SIRIS SYNDROME to MENTAL RETARDATION, AUTOSOMAL DOMINANT 12 135900; COFFIN SIRIS SYNDROME 135900
DDG2P v1.131 MUT Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for METHYLMALONIC ACIDURIA TYPE MUT: confirmed. DDG2P allelic requirement: biallelic. DDG2P mutation consequence: loss of function.
DDG2P v1.131 KARS Rebecca Foulger commented on gene: KARS: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B; DEAFNESS, AUTOSOMAL RECESSIVE 89.
DDG2P v1.131 SMCHD1 Rebecca Foulger commented on gene: SMCHD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Isolated Arhinia/Bosma Arhinia syndrome.
DDG2P v1.131 FAM161A Rebecca Foulger commented on gene: FAM161A: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RETINITIS PIGMENTOSA 28.
DDG2P v1.131 ALDOB Rebecca Foulger commented on gene: ALDOB: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for HEREDITARY FRUCTOSE INTOLERANCE.
DDG2P v1.131 CISD2 Rebecca Foulger commented on gene: CISD2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for WOLFRAM SYNDROME TYPE 2.
DDG2P v1.131 DARS2 Rebecca Foulger commented on gene: DARS2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION.
DDG2P v1.131 ATP13A2 Rebecca Foulger commented on gene: ATP13A2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for PARKINSON DISEASE 9.
DDG2P v1.131 SLC4A11 Rebecca Foulger commented on gene: SLC4A11: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 4.
DDG2P v1.131 THAP1 Rebecca Foulger commented on gene: THAP1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for DYSTONIA 6, TORSION.
DDG2P v1.131 PDCD10 Rebecca Foulger commented on gene: PDCD10: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CEREBRAL CAVERNOUS MALFORMATIONS TYPE 3.
DDG2P v1.131 ANO5 Rebecca Foulger commented on gene: ANO5: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for MIYOSHI MUSCULAR DYSTROPHY TYPE 3; GNATHODIAPHYSEAL DYSPLASIA.
DDG2P v1.131 SYNE1 Rebecca Foulger commented on gene: SYNE1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8; EMERY-DREIFUSS MUSCULAR DYSTROPHY 4, AUTOSOMAL RECESSIVE.
DDG2P v1.131 AIRE Rebecca Foulger commented on gene: AIRE: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE 1.
DDG2P v1.131 ACADS Rebecca Foulger commented on gene: ACADS: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for SHORT CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY.
DDG2P v1.131 CLN6 Rebecca Foulger commented on gene: CLN6: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CEROID LIPOFUSCINOSIS, NEURONAL, 6; CEROID LIPOFUSCINOSIS, NEURONAL, KUFS TYPE, ADULT ONSET.
DDG2P v1.131 GBA Rebecca Foulger commented on gene: GBA: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for GAUCHER DISEASE PERINATAL LETHAL; GAUCHER DISEASE TYPE 3C; GAUCHER DISEASE TYPE 1; GAUCHER DISEASE; GAUCHER DISEASE TYPE 2; GAUCHER DISEASE TYPE 3.
DDG2P v1.131 LDB3 Rebecca Foulger commented on gene: LDB3: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CARDIOMYOPATHY DILATED TYPE 1C; LEFT VENTRICULAR NON-COMPACTION TYPE 3; MYOPATHY MYOFIBRILLAR TYPE 4.
DDG2P v1.131 SPTLC2 Rebecca Foulger commented on gene: SPTLC2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IC.
DDG2P v1.131 RRM2B Rebecca Foulger commented on gene: RRM2B: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Mitochondrial depletion syndrome.
DDG2P v1.131 AGXT Rebecca Foulger commented on gene: AGXT: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for HYPEROXALURIA, PRIMARY, TYPE 1.
DDG2P v1.131 KRIT1 Rebecca Foulger commented on gene: KRIT1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CEREBRAL CAVERNOUS MALFORMATIONS TYPE 1.
DDG2P v1.131 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for INFANTILE NEUROAXONAL DYSTROPHY 1; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2B.
DDG2P v1.131 GJB3 Rebecca Foulger commented on gene: GJB3: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA; DEAFNESS AUTOSOMAL DOMINANT TYPE 2B; DEAFNESS, AUTOSOMAL RECESSIVE.
DDG2P v1.131 SMAD4 Rebecca Foulger commented on gene: SMAD4: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for JUVENILE POLYPOSIS SYNDROME; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME.
DDG2P v1.131 BRCA2 Rebecca Foulger commented on gene: BRCA2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for FANCONI ANEMIA COMPLEMENTATION GROUP D TYPE 1.
DDG2P v1.131 AR Rebecca Foulger commented on gene: AR: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ANDROGEN INSENSITIVITY SYNDROME; SPINAL AND BULBAR MUSCULAR ATROPHY.
DDG2P v1.131 FMR1 Rebecca Foulger commented on gene: FMR1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for FRAGILE X TREMOR/ATAXIA SYNDROME; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1.
DDG2P v1.131 BGN Rebecca Foulger commented on gene: BGN: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Severe syndromic form of thoracic aortic aneurysm & dissection.
DDG2P v1.131 AMER1 Rebecca Foulger commented on gene: AMER1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS.
DDG2P v1.131 ABCD1 Rebecca Foulger commented on gene: ABCD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ADRENOLEUKODYSTROPHY, X-LINKED.
DDG2P v1.131 TIMM8A Rebecca Foulger commented on gene: TIMM8A: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for JENSEN SYNDROME; MOHR-TRANEBJAERG SYNDROME.
DDG2P v1.131 MYO7A Rebecca Foulger commented on gene: MYO7A: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for DEAFNESS AUTOSOMAL RECESSIVE TYPE 2; USHER SYNDROME TYPE 1B.
DDG2P v1.131 CDH1 Rebecca Foulger commented on gene: CDH1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Blepharo-cheiro-dontic syndrome.
DDG2P v1.131 TGFB2 Rebecca Foulger commented on gene: TGFB2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LOEYS-DIETZ SYNDROME, TYPE 4.
DDG2P v1.131 NR5A1 Rebecca Foulger commented on gene: NR5A1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for 46XY SEX REVERSAL 3; SPERMATOGENIC FAILURE 8.
DDG2P v1.131 ATP1A3 Rebecca Foulger commented on gene: ATP1A3: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RAPID-ONSET DYSTONIA-PARKINSONISM; ALTERNATING HEMIPLEGIA OF CHILDHOOD.
DDG2P v1.131 KCNE1 Rebecca Foulger commented on gene: KCNE1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for JERVELL AND LANGE-NIELSEN SYNDROME TYPE 2.
DDG2P v1.131 POLD1 Rebecca Foulger commented on gene: POLD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for SUBCUTANEOUS LIPODYSTROPHY, DEAFNESS, MANDIBULAR HYPOPLASIA AND MALE HYPOGONADISM .
DDG2P v1.131 KIT Rebecca Foulger commented on gene: KIT: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for HUMAN PIEBALDISM.
DDG2P v1.131 RET Rebecca Foulger commented on gene: RET: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RENAL AGENESIS; MULTIPLE ENDOCRINE NEOPLASIA IIB.
DDG2P v1.131 MYH8 Rebecca Foulger commented on gene: MYH8: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for DISTAL ARTHROGRYPOSIS TYPE; CARNEY COMPLEX VARIANT.
DDG2P v1.131 LMNA Rebecca Foulger commented on gene: LMNA: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LETHAL TIGHT SKIN CONTRACTURE SYNDROME; FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2; EMERY-DREIFUSS MUSCULAR DYSTROPHY TYPE 2; MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY; HEART-HAND SYNDROME SLOVENIAN TYPE;HUTCHINSON-GILFORD PROGERIA SYNDROME; CHARCOT-MARIE-TOOTH DISEASE TYPE 2B1; MUSCULAR DYSTROPHY CONGENITAL LMNA-RELATED;CARDIOMYOPATHY DILATED TYPE 1A; CARDIOMYOPATHY DILATED WITH HYPERGONADOTROPIC HYPOGONADISM; LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 1B.
DDG2P v1.131 ALAD Rebecca Foulger commented on gene: ALAD: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ACUTE HEPATIC PORPHYRIA.
DDG2P v1.131 COL4A1 Rebecca Foulger commented on gene: COL4A1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for PORENCEPHALY 1.
DDG2P v1.131 COL4A2 Rebecca Foulger commented on gene: COL4A2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for PORENCEPHALY 2.
DDG2P v1.131 HSPD1 Rebecca Foulger commented on gene: HSPD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LEUKODYSTROPHY HYPOMYELINATING TYPE 4.
DDG2P v1.131 SLC4A1 Rebecca Foulger commented on gene: SLC4A1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RENAL TUBULAR ACIDOSIS, DISTAL, AR; RENAL TUBULAR ACIDOSIS, DISTAL, AD.
DDG2P v1.131 ACTA2 Rebecca Foulger commented on gene: ACTA2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for AORTIC ANEURYSM, FAMILIAL THORACIC 6; MOYAMOYA DISEASE 5.
DDG2P v1.130 TARS Rebecca Foulger reviewed gene: TARS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 FAM149B1 Rebecca Foulger reviewed gene: FAM149B1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 LEMD2 Rebecca Foulger reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DHX37 Rebecca Foulger reviewed gene: DHX37: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DHX34 Rebecca Foulger reviewed gene: DHX34: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DDX54 Rebecca Foulger reviewed gene: DDX54: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 TAOK1 Rebecca Foulger reviewed gene: TAOK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 RINT1 Rebecca Foulger reviewed gene: RINT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 BRSK2 Rebecca Foulger reviewed gene: BRSK2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 BNC2 Rebecca Foulger reviewed gene: BNC2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 PIGU Rebecca Foulger reviewed gene: PIGU: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 ROBO4 Rebecca Foulger reviewed gene: ROBO4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 HNRNPR Rebecca Foulger reviewed gene: HNRNPR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DLL1 Rebecca Foulger reviewed gene: DLL1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 B3GAT3 Rebecca Foulger reviewed gene: B3GAT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 MYOCD Rebecca Foulger reviewed gene: MYOCD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 FBXW11 Rebecca Foulger reviewed gene: FBXW11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 PIGB Rebecca Foulger reviewed gene: PIGB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DHX16 Rebecca Foulger reviewed gene: DHX16: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DYNC1I2 Rebecca Foulger reviewed gene: DYNC1I2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 CDK8 Rebecca Foulger reviewed gene: CDK8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 KCNN3 Rebecca Foulger reviewed gene: KCNN3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 POU3F3 Rebecca Foulger reviewed gene: POU3F3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 SMARCD1 Rebecca Foulger reviewed gene: SMARCD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 AP2M1 Rebecca Foulger reviewed gene: AP2M1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 CACNA1B Rebecca Foulger reviewed gene: CACNA1B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 RRAS2 Rebecca Foulger reviewed gene: RRAS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 WDR37 Rebecca Foulger reviewed gene: WDR37: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 POLA1 Rebecca Foulger reviewed gene: POLA1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 GPC4 Rebecca Foulger reviewed gene: GPC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 VAMP2 Rebecca Foulger reviewed gene: VAMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 POLR2A Rebecca Foulger reviewed gene: POLR2A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 CSF1R Rebecca Foulger reviewed gene: CSF1R: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 GOT2 Rebecca Foulger reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 NUP214 Rebecca Foulger reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.129 TARS Rebecca Foulger gene: TARS was added
gene: TARS was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: TARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS were set to 31374204
Phenotypes for gene: TARS were set to Non-photosensitive trichothiodystrophy
DDG2P v1.129 FAM149B1 Rebecca Foulger gene: FAM149B1 was added
gene: FAM149B1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Ciliopathy-related syndromic intellectual disability
DDG2P v1.129 LEMD2 Rebecca Foulger gene: LEMD2 was added
gene: LEMD2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: LEMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LEMD2 were set to 30905398
Phenotypes for gene: LEMD2 were set to Nuclear Envelopathy with Early Progeroid Appearance
Mode of pathogenicity for gene: LEMD2 was set to Other - please provide details in the comments
DDG2P v1.129 DHX37 Rebecca Foulger gene: DHX37 was added
gene: DHX37 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DHX37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to 31256877
Phenotypes for gene: DHX37 were set to Intellectual Disability and Central Nervous System anomalies
Mode of pathogenicity for gene: DHX37 was set to Other - please provide details in the comments
DDG2P v1.129 DHX34 Rebecca Foulger gene: DHX34 was added
gene: DHX34 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DHX34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHX34 were set to 31256877
Phenotypes for gene: DHX34 were set to INTELLECTUAL DISABILITY 616579
Mode of pathogenicity for gene: DHX34 was set to Other - please provide details in the comments
DDG2P v1.129 DDX54 Rebecca Foulger gene: DDX54 was added
gene: DDX54 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DDX54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX54 were set to 31256877
Phenotypes for gene: DDX54 were set to Intellectual Disability and Central Nervous System anomalies
Mode of pathogenicity for gene: DDX54 was set to Other - please provide details in the comments
DDG2P v1.129 TAOK1 Rebecca Foulger gene: TAOK1 was added
gene: TAOK1 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: TAOK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TAOK1 were set to 31230721
Phenotypes for gene: TAOK1 were set to INTELLECTUAL DISABILITY 616579
DDG2P v1.129 RINT1 Rebecca Foulger gene: RINT1 was added
gene: RINT1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to 31204009
Phenotypes for gene: RINT1 were set to Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities
DDG2P v1.129 BRSK2 Rebecca Foulger gene: BRSK2 was added
gene: BRSK2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK2 were set to 30879638
Phenotypes for gene: BRSK2 were set to Neurodevelopmental Disorder
DDG2P v1.129 BNC2 Rebecca Foulger gene: BNC2 was added
gene: BNC2 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: BNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BNC2 were set to 31051115
Phenotypes for gene: BNC2 were set to Congenital Lower Urinary Tract Obstruction
DDG2P v1.129 PIGU Rebecca Foulger gene: PIGU was added
gene: PIGU was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: PIGU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PIGU were set to 31353022
Phenotypes for gene: PIGU were set to Intellectual Disability, Central Nervous System anomalies and Scoliosis
Mode of pathogenicity for gene: PIGU was set to Other - please provide details in the comments
DDG2P v1.129 ROBO4 Rebecca Foulger gene: ROBO4 was added
gene: ROBO4 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: ROBO4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ROBO4 were set to 30455415
Phenotypes for gene: ROBO4 were set to Bicuspid Aortic Valve and Aortic Aneurysm 618496
DDG2P v1.129 HNRNPR Rebecca Foulger gene: HNRNPR was added
gene: HNRNPR was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPR were set to 31079900
Phenotypes for gene: HNRNPR were set to INTELLECTUAL DISABILITY 616579
DDG2P v1.129 DLL1 Rebecca Foulger gene: DLL1 was added
gene: DLL1 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to INTELLECTUAL DISABILITY 616579
DDG2P v1.129 B3GAT3 Rebecca Foulger gene: B3GAT3 was added
gene: B3GAT3 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: B3GAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GAT3 were set to 31438591
Phenotypes for gene: B3GAT3 were set to MULTIPLE JOINT DISLOCATIONS, SHORT STATURE, AND CRANIOFACIAL DYSMORPHISM WITH OR WITHOUT CONGENITAL HEART DEFECTS 245600
Mode of pathogenicity for gene: B3GAT3 was set to Other - please provide details in the comments
DDG2P v1.129 MYOCD Rebecca Foulger gene: MYOCD was added
gene: MYOCD was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: MYOCD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYOCD were set to 31513549
Phenotypes for gene: MYOCD were set to Congenital megabladder
DDG2P v1.129 FBXW11 Rebecca Foulger gene: FBXW11 was added
gene: FBXW11 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: FBXW11 was set to Other - please provide details in the comments
DDG2P v1.129 PIGB Rebecca Foulger gene: PIGB was added
gene: PIGB was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality
DDG2P v1.129 DHX16 Rebecca Foulger gene: DHX16 was added
gene: DHX16 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Intellectual Disability, Central Nervous System anomalies and Seizures
Mode of pathogenicity for gene: DHX16 was set to Other - please provide details in the comments
DDG2P v1.129 DYNC1I2 Rebecca Foulger gene: DYNC1I2 was added
gene: DYNC1I2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY AND STRUCTURAL BRAIN ANOMALIES 618492
DDG2P v1.129 CDK8 Rebecca Foulger gene: CDK8 was added
gene: CDK8 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDK8 were set to 30905399
Phenotypes for gene: CDK8 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: CDK8 was set to Other - please provide details in the comments
DDG2P v1.129 KCNN3 Rebecca Foulger gene: KCNN3 was added
gene: KCNN3 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN3 were set to 31155282
Phenotypes for gene: KCNN3 were set to ZIMMERMANN-LABAND SYNDROME
Mode of pathogenicity for gene: KCNN3 was set to Other - please provide details in the comments
DDG2P v1.129 POU3F3 Rebecca Foulger gene: POU3F3 was added
gene: POU3F3 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POU3F3 were set to 31303265
Phenotypes for gene: POU3F3 were set to INTELLECTUAL DISABILITY 616579
Mode of pathogenicity for gene: POU3F3 was set to Other - please provide details in the comments
DDG2P v1.129 SMARCD1 Rebecca Foulger gene: SMARCD1 was added
gene: SMARCD1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: SMARCD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCD1 were set to 30879640
Phenotypes for gene: SMARCD1 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: SMARCD1 was set to Other - please provide details in the comments
DDG2P v1.129 AP2M1 Rebecca Foulger gene: AP2M1 was added
gene: AP2M1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP2M1 were set to 31104773
Phenotypes for gene: AP2M1 were set to Developmental and Epileptic Encephalopathy
Mode of pathogenicity for gene: AP2M1 was set to Other - please provide details in the comments
DDG2P v1.129 CACNA1B Rebecca Foulger gene: CACNA1B was added
gene: CACNA1B was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1B were set to 30982612
Phenotypes for gene: CACNA1B were set to NEURODEVELOPMENTAL DISORDER WITH SEIZURES AND NONEPILEPTIC HYPERKINETIC MOVEMENTS 618497
DDG2P v1.129 RRAS2 Rebecca Foulger gene: RRAS2 was added
gene: RRAS2 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: RRAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RRAS2 were set to 31130282; 31130285; 24705357
Phenotypes for gene: RRAS2 were set to Noonan syndrome
Mode of pathogenicity for gene: RRAS2 was set to Other - please provide details in the comments
DDG2P v1.129 WDR37 Rebecca Foulger gene: WDR37 was added
gene: WDR37 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WDR37 were set to 31327508; 31327510
Phenotypes for gene: WDR37 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: WDR37 was set to Other - please provide details in the comments
DDG2P v1.129 POLA1 Rebecca Foulger gene: POLA1 was added
gene: POLA1 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: POLA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: POLA1 were set to 31006512
Phenotypes for gene: POLA1 were set to VAN ESCH-O'DRISCOLL SYNDROME 301030
DDG2P v1.129 GPC4 Rebecca Foulger gene: GPC4 was added
gene: GPC4 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: GPC4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPC4 were set to 30982611
Phenotypes for gene: GPC4 were set to KEIPERT SYNDROME 301026
DDG2P v1.129 VAMP2 Rebecca Foulger gene: VAMP2 was added
gene: VAMP2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: VAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VAMP2 were set to 30929742
Phenotypes for gene: VAMP2 were set to INTELLECTUAL DISABILITY 616579
Mode of pathogenicity for gene: VAMP2 was set to Other - please provide details in the comments
DDG2P v1.129 POLR2A Rebecca Foulger gene: POLR2A was added
gene: POLR2A was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR2A were set to 31353023
Phenotypes for gene: POLR2A were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: POLR2A was set to Other - please provide details in the comments
DDG2P v1.129 CSF1R Rebecca Foulger gene: CSF1R was added
gene: CSF1R was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSF1R were set to 30982608; 30982609
Phenotypes for gene: CSF1R were set to BRAIN ABNORMALITIES, NEURODEGENERATION, AND DYSOSTEOSCLEROSIS 618476
DDG2P v1.129 GOT2 Rebecca Foulger gene: GOT2 was added
gene: GOT2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOT2 were set to 31422819
Phenotypes for gene: GOT2 were set to Malate-Aspartate Shuttle-Related Encephalopathy
Mode of pathogenicity for gene: GOT2 was set to Other - please provide details in the comments
DDG2P v1.129 NUP214 Rebecca Foulger gene: NUP214 was added
gene: NUP214 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128
Phenotypes for gene: NUP214 were set to Acute Febrile Encephalopathy 618426
Renal tubulopathies v1.192 AVPR2 Eleanor Williams Added comment: Comment on mode of pathogenicity: From Emma Ashton - NSIAD caused by gain of function mutations (mainly codon 137)
Renal tubulopathies v1.192 AVPR2 Eleanor Williams Mode of pathogenicity for gene: AVPR2 was changed from None to Other
Renal tubulopathies v1.191 AVPR2 Eleanor Williams commented on gene: AVPR2: Note: left mode of inheritance as X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males as there are reports of heterozygous females with NDI due to X-inactivation.
Undiagnosed metabolic disorders v1.373 TCN2 Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases reported in the literature.
Undiagnosed metabolic disorders v1.373 TCN2 Catherine Snow Publications for gene: TCN2 were set to 27604308
Undiagnosed metabolic disorders v1.372 TCN2 Catherine Snow Classified gene: TCN2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.372 TCN2 Catherine Snow Gene: tcn2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.371 TCN2 Catherine Snow reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 19373259; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.346 TCN2 Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases reported in the literature.
Inborn errors of metabolism v1.346 TCN2 Catherine Snow Publications for gene: TCN2 were set to 27604308
Inborn errors of metabolism v1.346 TCN2 Catherine Snow Classified gene: TCN2 as Green List (high evidence)
Inborn errors of metabolism v1.346 TCN2 Catherine Snow Gene: tcn2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.345 TCN2 Catherine Snow reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19373259; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.371 TAT Catherine Snow Publications for gene: TAT were set to 27604308
Undiagnosed metabolic disorders v1.370 TAT Catherine Snow Classified gene: TAT as Green List (high evidence)
Undiagnosed metabolic disorders v1.370 TAT Catherine Snow Gene: tat has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.369 TAT Catherine Snow reviewed gene: TAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 28255985; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.345 TAT Catherine Snow Added comment: Comment on publications: PMID: 28255985 Reports on 106 families, represented by 143 individuals, carrying a total of 36 genetic variants. Variants include large deletions, non‐synonymous and nonsense amino‐acid changes, frameshifts and
splice variants.
Inborn errors of metabolism v1.345 TAT Catherine Snow Publications for gene: TAT were set to 27604308; 28255985
Inborn errors of metabolism v1.344 TAT Catherine Snow Publications for gene: TAT were set to 27604308; 28255985
Inborn errors of metabolism v1.344 TAT Catherine Snow Publications for gene: TAT were set to 27604308
Inborn errors of metabolism v1.343 TAT Catherine Snow Classified gene: TAT as Green List (high evidence)
Inborn errors of metabolism v1.343 TAT Catherine Snow Gene: tat has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.342 TAT Catherine Snow reviewed gene: TAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 28255985; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amyloidosis v1.0 Eleanor Williams promoted panel to version 1.0
Amyloidosis v0.19 Eleanor Williams Panel types changed to GMS Rare Disease; GMS signed-off
Amyloidosis v0.18 CST3 Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic case from a non-Icelandic individual.; to: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic case from a non-Icelandic individual. Agreement for the amber rating was confirmed with members of the GMS renal specialist test group.
Amyloidosis v0.18 B2M Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber as only 1 family has been reported.; to: Comment on list classification: Demoting from green to amber as only 1 family has been reported. Agreement for the amber rating was confirmed with members of the GMS renal specialist test group.
Amyloidosis v0.18 APOC3 Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber as only 1 family reported.; to: Comment on list classification: Demoting from green to amber as only 1 family reported. Agreement for the amber rating was confirmed with members of the GMS renal specialist test group.
Amyloidosis v0.18 CST3 Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic cases from a non-Icelandic individual.; to: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic case from a non-Icelandic individual.
Amyloidosis v0.18 TTR Eleanor Williams changed review comment from: Associated with Amyloidosis, hereditary, transthyretin-related (#105210) in OMIM. Lots of cases reported in OMIM.; to: Associated with Amyloidosis, hereditary, transthyretin-related (#105210) (AD) in OMIM. Lots of cases reported in OMIM.
Amyloidosis v0.18 GSN Eleanor Williams commented on gene: GSN: OMIM reports that Maury, 1993 (PMID: 8395367, abstract only accessed) reports that 2 2 sibs, the offspring of 2 affected parents, who were by DNA test homozygous for the mutation and showed unusually early onset and severity of the disease , thus the BIALLELIC mutations cause a more SEVERE disease form mode of inheritiance seems appropriate.
Amyloidosis v0.18 APOC2 Eleanor Williams commented on gene: APOC2: Checked that the variants are heterozygous in the two reported cases with amyloidosis (PMID: 30197986 and 27297947). Hyperlipoproteinemia, type Ib (#207750) is reported at autosomal recessive inheritance in OMIM.
Dilated Cardiomyopathy and conduction defects v1.63 PRDM16 Matthew Edwards reviewed gene: PRDM16: Rating: AMBER; Mode of pathogenicity: None; Publications: 24387996, 24387995; Phenotypes: Cardiomyopathy, LVNC; Mode of inheritance: None
Inborn errors of metabolism v1.342 STS Catherine Snow Publications for gene: STS were set to 27604308; 1539590; 29672931
Inborn errors of metabolism v1.341 STS Catherine Snow Publications for gene: STS were set to 27604308; 1539590; 29672931
Pain syndromes v1.8 PRDM12 Rebecca Foulger commented on gene: PRDM12
Inborn errors of metabolism v1.341 STS Catherine Snow Publications for gene: STS were set to 27604308
Pain syndromes v1.8 PRDM12 Rebecca Foulger Phenotypes for gene: PRDM12 were changed from Hereditary sensory and autonomic neuropathy type VIII; HSAN 8; Neuropathy, hereditary sensory and autonomic, type VIII, 616488 to HSAN VIII; insensitivity to pain; Hereditary sensory and autonomic neuropathy type VIII; HSAN 8; Neuropathy, hereditary sensory and autonomic, type VIII, 616488
Inborn errors of metabolism v1.340 STS Catherine Snow Classified gene: STS as Green List (high evidence)
Inborn errors of metabolism v1.340 STS Catherine Snow Gene: sts has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.339 STS Catherine Snow edited their review of gene: STS: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pain syndromes v1.7 PRDM12 Rebecca Foulger Publications for gene: PRDM12 were set to 26005867; 26975306
Inborn errors of metabolism v1.339 STS Catherine Snow reviewed gene: STS: Rating: GREEN; Mode of pathogenicity: None; Publications: 1539590, 29672931; Phenotypes: Ichthyosis, X-linked, 308100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.369 STS Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases.
Undiagnosed metabolic disorders v1.369 STS Catherine Snow Publications for gene: STS were set to 27604308; 1539590; 29672931
Undiagnosed metabolic disorders v1.368 STS Catherine Snow changed review comment from: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.
Undiagnosed metabolic disorders v1.368 STS Catherine Snow Publications for gene: STS were set to 27604308
Undiagnosed metabolic disorders v1.367 STS Catherine Snow Classified gene: STS as Green List (high evidence)
Undiagnosed metabolic disorders v1.367 STS Catherine Snow Gene: sts has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.366 STS Catherine Snow reviewed gene: STS: Rating: GREEN; Mode of pathogenicity: None; Publications: 1539590, 29672931; Phenotypes: Ichthyosis, X-linked, 308100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.363 NDUFAF4 Rebecca Foulger commented on gene: NDUFAF4: Amber ratings from Tracy Lester and Zornitza Stark support the current Amber rating of NDUFAF4.
Genetic epilepsy syndromes v1.363 NDUFAF4 Rebecca Foulger Publications for gene: NDUFAF4 were set to
Genetic epilepsy syndromes v1.362 NDUFAF4 Rebecca Foulger Phenotypes for gene: NDUFAF4 were changed from to Mitochondrial complex I deficiency, nuclear type 15, 618237
Genetic epilepsy syndromes v1.361 NDUFAF4 Rebecca Foulger Mode of inheritance for gene: NDUFAF4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Marked gene: CCND2 as ready
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Classified gene: CCND2 as Red List (low evidence)
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Added comment: Comment on list classification: Demoted CCND2 from Amber to Red following Red reviews by Zornitza Stark and Tracy Lester- as noted previously by Sarah Leigh: epilepsy is not a reported feature of the disorder.
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.359 CCND2 Rebecca Foulger Mode of inheritance for gene: CCND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.358 CCND2 Rebecca Foulger Publications for gene: CCND2 were set to
Genetic epilepsy syndromes v1.357 CCND2 Rebecca Foulger Phenotypes for gene: CCND2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, 615938
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger Marked gene: ARID1B as ready
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger Gene: arid1b has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger commented on gene: ARID1B: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ARID1B.
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger Publications for gene: ARID1B were set to
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger Marked gene: ASAH1 as ready
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger Gene: asah1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger commented on gene: ASAH1: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ASAH1.
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger Phenotypes for gene: ASAH1 were changed from Spinal muscular atrophy with progressive myoclonic epilepsy, 159950 to Spinal muscular atrophy with progressive myoclonic epilepsy, 159950; SMA with myoclonic epilepsy
Genetic epilepsy syndromes v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 8955159; 22703880; 29169047; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Genetic epilepsy syndromes v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 29169047; 22703880; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Genetic epilepsy syndromes v1.353 ISCA-37429-Loss Rebecca Foulger changed review comment from: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.; to: The Green rating by Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Genetic epilepsy syndromes v1.353 CREBBP Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'imprinted status unknown' to 'NOT imprinted' to match reviews from GLH experts Tracy Lester and Alisdair McNeill.
Genetic epilepsy syndromes v1.353 CREBBP Rebecca Foulger Mode of inheritance for gene: CREBBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 CREBBP Rebecca Foulger commented on gene: CREBBP: The Green rating by Dr Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of CREBBP.
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss Rebecca Foulger Marked Region: ISCA-37429-Loss as ready
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss Rebecca Foulger Region: isca-37429-loss has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss Rebecca Foulger commented on Region: ISCA-37429-Loss: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Retinal disorders v1.199 IKBKG Catherine Snow Added comment: Comment on mode of inheritance: IKBKG is associated with IP as commented by Robert Henderson GOSH. IP is XLD in OMIM
Retinal disorders v1.199 IKBKG Catherine Snow Mode of inheritance for gene: IKBKG was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.198 IKBKG Catherine Snow Added comment: Comment on phenotypes: IKBKG is associated with IP as commented by Robert Henderson GOSH
Retinal disorders v1.198 IKBKG Catherine Snow Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, 308300
Retinal disorders v1.197 IKBKG Catherine Snow Phenotypes for gene: IKBKG were changed from to Incontinentia pigmenti, 308300
Retinal disorders v1.196 IKBKG Catherine Snow Mode of inheritance for gene: IKBKG was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.195 IKBKG Catherine Snow Classified gene: IKBKG as Green List (high evidence)
Retinal disorders v1.195 IKBKG Catherine Snow Gene: ikbkg has been classified as Green List (High Evidence).
Retinal disorders v1.194 IKBKG Catherine Snow reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Incontinentia pigmenti, 308300; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.194 AIRE Catherine Snow Phenotypes for gene: AIRE were changed from to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300
Retinal disorders v1.193 AIRE Catherine Snow Mode of inheritance for gene: AIRE was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v1.192 AIRE Catherine Snow Classified gene: AIRE as Green List (high evidence)
Retinal disorders v1.192 AIRE Catherine Snow Gene: aire has been classified as Green List (High Evidence).
Retinal disorders v1.191 AIRE Catherine Snow reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v1.191 TPP1 Catherine Snow Mode of inheritance for gene: TPP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.190 TPP1 Catherine Snow Phenotypes for gene: TPP1 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 2, 204500
Retinal disorders v1.189 TPP1 Catherine Snow Mode of inheritance for gene: TPP1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.188 TPP1 Catherine Snow Classified gene: TPP1 as Green List (high evidence)
Retinal disorders v1.188 TPP1 Catherine Snow Gene: tpp1 has been classified as Green List (High Evidence).
Retinal disorders v1.187 TPP1 Catherine Snow reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, 204500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.187 TIMM8A Catherine Snow Phenotypes for gene: TIMM8A were changed from Eye Disorders to Eye Disorders; Mohr-Tranebjaerg syndrome, 304700
Retinal disorders v1.186 TIMM8A Catherine Snow Mode of inheritance for gene: TIMM8A was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Retinal disorders v1.185 TIMM8A Catherine Snow Classified gene: TIMM8A as Green List (high evidence)
Retinal disorders v1.185 TIMM8A Catherine Snow Gene: timm8a has been classified as Green List (High Evidence).
Retinal disorders v1.184 TIMM8A Catherine Snow reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mohr-Tranebjaerg syndrome, 304700; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Retinal disorders v1.184 PPT1 Catherine Snow Phenotypes for gene: PPT1 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 1, 256730
Retinal disorders v1.183 PPT1 Catherine Snow Mode of inheritance for gene: PPT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.182 PPT1 Catherine Snow Classified gene: PPT1 as Green List (high evidence)
Retinal disorders v1.182 PPT1 Catherine Snow Gene: ppt1 has been classified as Green List (High Evidence).
Retinal disorders v1.181 PPT1 Catherine Snow reviewed gene: PPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 1, 256730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v1.32 Louise Daugherty Panel types changed to Rare Disease 100K; Component Of Super Panel
Retinal disorders v1.181 HCCS Catherine Snow Phenotypes for gene: HCCS were changed from Eye Disorders to Eye Disorders; Linear skin defects with multiple congenital anomalies 1, 309801
Retinal disorders v1.180 HCCS Catherine Snow Mode of inheritance for gene: HCCS was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.179 HCCS Catherine Snow Classified gene: HCCS as Green List (high evidence)
Retinal disorders v1.179 HCCS Catherine Snow Gene: hccs has been classified as Green List (High Evidence).
Retinal disorders v1.178 HCCS Catherine Snow reviewed gene: HCCS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Linear skin defects with multiple congenital anomalies 1, 309801; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.178 CTSD Catherine Snow Phenotypes for gene: CTSD were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 10, 610127
Retinal disorders v1.177 CTSD Catherine Snow Mode of inheritance for gene: CTSD was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.176 CTSD Catherine Snow Classified gene: CTSD as Green List (high evidence)
Retinal disorders v1.176 CTSD Catherine Snow Gene: ctsd has been classified as Green List (High Evidence).
Retinal disorders v1.175 COL18A1 Catherine Snow changed review comment from: COL18A1 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: COL18A1 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CLN5 Catherine Snow changed review comment from: CLN5 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CLN5 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CLN6 Catherine Snow changed review comment from: CLN6 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CLN6 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CLN8 Catherine Snow changed review comment from: CLN8 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CLN8 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CTSD Catherine Snow changed review comment from: CTSD rated as Green and with a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CTSD rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CTSD Catherine Snow reviewed gene: CTSD: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 10, 610127; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.175 COL18A1 Catherine Snow Classified gene: COL18A1 as Green List (high evidence)
Retinal disorders v1.175 COL18A1 Catherine Snow Gene: col18a1 has been classified as Green List (High Evidence).
Retinal disorders v1.174 COL18A1 Catherine Snow reviewed gene: COL18A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Knobloch syndrome, type 1, 267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.174 CLN8 Catherine Snow Phenotypes for gene: CLN8 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 8, 600143
Retinal disorders v1.173 CLN8 Catherine Snow Mode of inheritance for gene: CLN8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.172 CLN8 Catherine Snow Classified gene: CLN8 as Green List (high evidence)
Retinal disorders v1.172 CLN8 Catherine Snow Gene: cln8 has been classified as Green List (High Evidence).
Retinal disorders v1.171 CLN8 Catherine Snow reviewed gene: CLN8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 8, 600143; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.171 CLN6 Catherine Snow Phenotypes for gene: CLN6 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 6 601780
Retinal disorders v1.170 CLN6 Catherine Snow Mode of inheritance for gene: CLN6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.169 CLN6 Catherine Snow Classified gene: CLN6 as Green List (high evidence)
Retinal disorders v1.169 CLN6 Catherine Snow Gene: cln6 has been classified as Green List (High Evidence).
Retinal disorders v1.168 CLN6 Catherine Snow reviewed gene: CLN6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 6 601780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.168 CLN5 Catherine Snow Classified gene: CLN5 as Green List (high evidence)
Retinal disorders v1.168 CLN5 Catherine Snow Gene: cln5 has been classified as Green List (High Evidence).
Retinal disorders v1.167 CLN5 Catherine Snow Mode of inheritance for gene: CLN5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.166 CLN5 Catherine Snow Phenotypes for gene: CLN5 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 5, 256731
Familial hypercholesterolaemia - targeted panel v0.2 Rebecca Foulger Panel status changed from internal to public
Retinal disorders v1.165 CLN5 Catherine Snow reviewed gene: CLN5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 5, 256731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial hypercholesterolaemia v1.26 Rebecca Foulger Panel types changed to Rare Disease 100K
Familial hypercholesterolaemia - targeted panel v0.1 PCSK9 Rebecca Foulger gene: PCSK9 was added
gene: PCSK9 was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: PCSK9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCSK9 were set to 16224054; 23433573
Phenotypes for gene: PCSK9 were set to Hypercholesterolemia, familial, 3, 603776; Familial Hypercholesterolaemia; Hypercholesterolemia; {Low density lipoprotein cholesterol level QTL 1}, 603776; Familial Hypercholesterolemia
Mode of pathogenicity for gene: PCSK9 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Familial hypercholesterolaemia - targeted panel v0.1 LDLRAP1 Rebecca Foulger gene: LDLRAP1 was added
gene: LDLRAP1 was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: LDLRAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDLRAP1 were set to 12417523
Phenotypes for gene: LDLRAP1 were set to Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia; Hypercholesterolemia, familial, 4, 603813
Familial hypercholesterolaemia - targeted panel v0.1 LDLR Rebecca Foulger gene: LDLR was added
gene: LDLR was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: LDLR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDLR were set to 17142622; 25414277; 23433573
Phenotypes for gene: LDLR were set to LDL cholesterol level QTL2, 143890; Familial Hypercholesterolaemia; Hypercholesterolemia; Familial Hypercholesterolemia; Hypercholesterolemia, familial, 1, 143890
Familial hypercholesterolaemia - targeted panel v0.1 APOE Rebecca Foulger gene: APOE was added
gene: APOE was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,Emory Genetics Laboratory,Expert Review Green
Mode of inheritance for gene: APOE was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: APOE were set to 11095479; 23433584; 24267230; 26802169; 16094309; 22481068; 22949395
Phenotypes for gene: APOE were set to Hyperlipoproteinemia, type III 617347
Familial hypercholesterolaemia - targeted panel v0.1 APOB Rebecca Foulger gene: APOB was added
gene: APOB was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: APOB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOB were set to 8141833; 25414277; 23433573
Phenotypes for gene: APOB were set to Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia, familial, 2, 144010; Hypercholesterolemia
Mode of pathogenicity for gene: APOB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Familial hypercholesterolaemia - targeted panel v0.0 Rebecca Foulger Added Panel Familial hypercholesterolaemia - targeted panel
Set panel types to: GMS Rare Disease
DDG2P v1.128 SOX11 alisdair mcneill reviewed gene: SOX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss alisdair mcneill reviewed Region: ISCA-37429-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 FLNA alisdair mcneill reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 CREBBP alisdair mcneill reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460469; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 ASAH1 alisdair mcneill reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SMA with myoclonic epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.352 ARID1B alisdair mcneill reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.1065 FBXW11 Catherine Snow Classified gene: FBXW11 as Green List (high evidence)
Intellectual disability v2.1065 FBXW11 Catherine Snow Gene: fbxw11 has been classified as Green List (High Evidence).
Intellectual disability v2.1064 FBXW11 Catherine Snow reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: 31402090, 16865294; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1064 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Intellectual disability v2.1064 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, support gene-disease association.
Intellectual disability v2.1064 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Intellectual disability v2.1063 SMPD4 Louise Daugherty Tag watchlist was removed from gene: SMPD4.
Intellectual disability v2.1063 SMPD4 Louise Daugherty Added comment: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Intellectual disability v2.1063 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Arthrogryposis v2.45 SMPD4 Louise Daugherty changed review comment from: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.; to: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases support gene-disease association.
Cerebellar hypoplasia v1.39 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Cerebellar hypoplasia v1.39 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, support gene-disease association.
Cerebellar hypoplasia v1.39 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.38 SMPD4 Louise Daugherty Added comment: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Cerebellar hypoplasia v1.38 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Arthrogryposis v2.45 SMPD4 Louise Daugherty changed review comment from: Comment on publications: Publication Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.; to: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Arthrogryposis v2.45 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Arthrogryposis v2.45 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Arthrogryposis v2.45 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Arthrogryposis v2.44 SMPD4 Louise Daugherty Tag watchlist was removed from gene: SMPD4.
Arthrogryposis v2.44 SMPD4 Louise Daugherty Added comment: Comment on publications: Publication Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Arthrogryposis v2.44 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Genetic epilepsy syndromes v1.352 KCNA1 Rebecca Foulger Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771
Genetic epilepsy syndromes v1.351 KCNA1 Rebecca Foulger edited their review of gene: KCNA1: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Genetic epilepsy syndromes v1.351 SCN9A Rebecca Foulger edited their review of gene: SCN9A: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Genetic epilepsy syndromes v1.351 FLNA Rebecca Foulger edited their review of gene: FLNA: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Undiagnosed monogenic disorder seen in a specialist genetics clinic v1.0 Ellen McDonagh promoted panel to version 1.0
Undiagnosed monogenic disorder seen in a specialist genetics clinic v0.4 Ellen McDonagh List of related panels changed from to
Panel status changed from internal to public
Ultra-rare undescribed monogenic disorders v1.0 Ellen McDonagh promoted panel to version 1.0
Ultra-rare undescribed monogenic disorders v0.5 Ellen McDonagh Panel status changed from internal to public
Genetic epilepsy syndromes v1.351 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
------------

[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature
Intellectual disability v2.1062 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949)
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
------------

[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1062 PCDH12 Konstantinos Varvagiannis reviewed gene: PCDH12: Rating: ; Mode of pathogenicity: None; Publications: 27164683, 28804758, 29556033, 30178464, 30459466, 18477666; Phenotypes: Microcephaly, seizures, spasticity, and brain calcification, 251280; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.1062 NKAP Konstantinos Varvagiannis reviewed gene: NKAP: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI: 10.1016/j.ajhg.2019.09.009; Phenotypes: Global developmental delay, Intellectual disability, Tall stature, Scoliosis, Pectus excavatum, Pectus carinatum, Arachnodactyly, Camptodactyly, Abnormality of the cardiovascular system, Abnormality of the genitourinary system, Abnormality of the face, Obesity; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.351 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to AMBER
Added comment: This gene was reviewed for the ID panel (details below).

It could be also be considered for inclusion in the epilepsy panel as amber/green.

[Seizures in 8/14 individuals (generalized tonic-clonic/myoclonic, onset 3m - 6yrs) although some individuals were too young when last examined (eg. 8m) and sibs in one family (F7) were discordant for this feature at the ages of 4y7m (+) and 6y (-). Lissencephaly is often associated with seizures which have occasionally been observed in Apc2-deficient mice (PMID cited: 22573669)].

-----

Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
Sources: Literature
Intellectual disability v2.1062 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
-----
In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes.
APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx).
-----
Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis changed review comment from: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature; to: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis gene: CDH2 was added
gene: CDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Phenotypes for gene: CDH2 were set to 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
Penetrance for gene: CDH2 were set to unknown
Review for gene: CDH2 was set to AMBER
Added comment: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Inborn errors of metabolism v1.339 PIGM Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.366 ISCA2 Sarah Leigh Classified gene: ISCA2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.366 ISCA2 Sarah Leigh Gene: isca2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.339 ISCA2 Sarah Leigh Classified gene: ISCA2 as Green List (high evidence)
Inborn errors of metabolism v1.339 ISCA2 Sarah Leigh Gene: isca2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.365 ISCA2 Sarah Leigh gene: ISCA2 was added
gene: ISCA2 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA2 were set to 25539947; 29359243
Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4 616370
Review for gene: ISCA2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two different ethinicities. Rated green based on review of Anna de Burca (Clinical Fellow, Genomic England).
Sources: Literature
Inborn errors of metabolism v1.338 ISCA2 Sarah Leigh Added comment: Comment on phenotypes: infantile neurodegenerative mitochondrial disorder
Inborn errors of metabolism v1.338 ISCA2 Sarah Leigh Phenotypes for gene: ISCA2 were changed from Multiple mitochondrial dysfunctions syndrome 4 616370 to Multiple mitochondrial dysfunctions syndrome 4 616370
Inborn errors of metabolism v1.337 ISCA2 Sarah Leigh Publications for gene: ISCA2 were set to 25539947; 29359243; 29122497
Intellectual disability v2.1062 MED25 Helen Brittain edited their review of gene: MED25: Added comment: There are now different variants (potentially each founders) in three populations, and several families, that have been reported in association with ID. Therefore the evidence for a green rating in terms of a gene:disease association now seems sufficient. To determine the extent of the phenotype, in terms of associated features, further cases would be beneficial. Therefore I would currently recommend a green rating for the ID panel.; Changed rating: GREEN; Changed phenotypes: Basel-Vanagait-Smirin-Yosef syndrome 616449; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy - teen and adult v1.77 MT-TI James Eden reviewed gene: MT-TI: Rating: AMBER; Mode of pathogenicity: None; Publications: 12767666; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Intellectual disability v2.1062 INTS1 Rebecca Foulger Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Intellectual disability v2.1061 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Genetic epilepsy syndromes v1.351 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Intellectual disability v2.1060 RAC3 Rebecca Foulger Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Intellectual disability v2.1059 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Genetic epilepsy syndromes v1.350 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Genetic epilepsy syndromes v1.349 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome
Intellectual disability v2.1058 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY to SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548
Intellectual disability v2.1057 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Genetic epilepsy syndromes v1.348 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Intellectual disability v2.1056 HNRNPR Catherine Snow Classified gene: HNRNPR as Green List (high evidence)
Intellectual disability v2.1056 HNRNPR Catherine Snow Gene: hnrnpr has been classified as Green List (High Evidence).
Intellectual disability v2.1055 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079900, 26795593; Phenotypes: Intellectual Disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1055 DDX6 Catherine Snow Classified gene: DDX6 as Green List (high evidence)
Intellectual disability v2.1055 DDX6 Catherine Snow Gene: ddx6 has been classified as Green List (High Evidence).
Intellectual disability v2.1054 DDX6 Catherine Snow reviewed gene: DDX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic cardiomyopathy v1.41 FLNC Ellen McDonagh Phenotypes for gene: FLNC were changed from to v
Arrhythmogenic cardiomyopathy v1.40 CDH2 Ellen McDonagh Classified gene: CDH2 as Amber List (moderate evidence)
Arrhythmogenic cardiomyopathy v1.40 CDH2 Ellen McDonagh Added comment: Comment on list classification: Was agreed by the GMS Cardiology Specialist Group that this should be Amber rating on a call on Thursday 3rd October 2019.
Arrhythmogenic cardiomyopathy v1.40 CDH2 Ellen McDonagh Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Dilated cardiomyopathy - adult and teen v0.50 LAMP2 Ellen McDonagh Classified gene: LAMP2 as Red List (low evidence)
Dilated cardiomyopathy - adult and teen v0.50 LAMP2 Ellen McDonagh Gene: lamp2 has been classified as Red List (Low Evidence).
Dilated cardiomyopathy - adult and teen v0.49 FLNC Ellen McDonagh Classified gene: FLNC as Red List (low evidence)
Dilated cardiomyopathy - adult and teen v0.49 FLNC Ellen McDonagh Gene: flnc has been classified as Red List (Low Evidence).
Dilated cardiomyopathy - adult and teen v0.48 DMD Ellen McDonagh Classified gene: DMD as Red List (low evidence)
Dilated cardiomyopathy - adult and teen v0.48 DMD Ellen McDonagh Gene: dmd has been classified as Red List (Low Evidence).
Dilated cardiomyopathy - adult and teen v0.47 BAG3 Ellen McDonagh Classified gene: BAG3 as Red List (low evidence)
Dilated cardiomyopathy - adult and teen v0.47 BAG3 Ellen McDonagh Gene: bag3 has been classified as Red List (Low Evidence).
Arrhythmogenic cardiomyopathy v1.39 CDH2 Ellen McDonagh Mode of inheritance for gene: CDH2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic cardiomyopathy v1.38 CDH2 Ellen McDonagh Publications for gene: CDH2 were set to
Arrhythmogenic cardiomyopathy v1.37 CDH2 Ellen McDonagh gene: CDH2 was added
gene: CDH2 was added to Arrhythmogenic cardiomyopathy. Sources: Expert list
Mode of inheritance for gene: CDH2 was set to Unknown
DDG2P v1.127 SNORD118 Rebecca Foulger Phenotypes for gene: SNORD118 were changed from Leukoencephalopathy with cerebral calcification & cysts to Leukoencephalopathy with cerebral calcification & cysts 614561
DDG2P v1.126 SNORD118 Rebecca Foulger changed review comment from: Original DDG2P rating: both DD and IF. ; to: Original DDG2P rating for Leukoencephalopathy with cerebral calcification & cysts: both DD and IF. DDG2P Mutation consequence: loss of function; DDG2P allelic requirement: biallelic.
Cardiomyopathies - including childhood onset v0.13 ACADVL James Eden reviewed gene: ACADVL: Rating: GREEN; Mode of pathogenicity: None; Publications: 24285112, 9973285; Phenotypes: VLCAD deficiency 201475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v1.126 SNORD118 Rebecca Foulger commented on gene: SNORD118: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is now 'both RD and IF' for Leukoencephalopathy with cerebral calcification & cysts.
DDG2P v1.126 MYH6 Rebecca Foulger changed review comment from: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is no 'RD and IF' for all three disorders: ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY DILATED TYPE 1EE; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14.; to: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is now 'RD and IF' for all three disorders: ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY DILATED TYPE 1EE; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14.
DDG2P v1.126 MYH6 Rebecca Foulger changed review comment from: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder).; to: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is no 'RD and IF' for all three disorders: ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY DILATED TYPE 1EE; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14.
DDG2P v1.126 MYH6 Rebecca Foulger Phenotypes for gene: MYH6 were changed from CARDIOMYOPATHY DILATED TYPE 1EE 613252; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14 613251; ATRIAL SEPTAL DEFECT TYPE 3 160710 to CARDIOMYOPATHY DILATED TYPE 1EE 613252; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14 613251; ATRIAL SEPTAL DEFECT TYPE 3 614089
DDG2P v1.125 MYH6 Rebecca Foulger commented on gene: MYH6: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder).
DDG2P v1.125 BRCA1 Rebecca Foulger commented on gene: BRCA1: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder).
DDG2P v1.125 BRCA1 Rebecca Foulger Phenotypes for gene: BRCA1 were changed from INTELLECTUAL DISABILITY to INTELLECTUAL DISABILITY 616579
DDG2P v1.124 KDM5B Rebecca Foulger Publications for gene: KDM5B were set to 24307393; 28720891
DDG2P v1.123 KDM5B Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of inheritance from 'monoallelic' to 'BOTH monoallelic and biallelic' to match the September 2019 DDG2P update.
DDG2P v1.123 KDM5B Rebecca Foulger Mode of inheritance for gene: KDM5B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.122 KDM5B Rebecca Foulger Classified gene: KDM5B as Amber List (moderate evidence)
DDG2P v1.122 KDM5B Rebecca Foulger Added comment: Comment on list classification: Updated rating of KDM5B from Red to Amber: A DDG2P update (September 2019) has changed the rating from 'possible' to 'probable'. The Mode of inheritance was also changed in the September 2019 update from monoallelic to both monoallelic and biallelic.
DDG2P v1.122 KDM5B Rebecca Foulger Gene: kdm5b has been classified as Amber List (Moderate Evidence).
DDG2P v1.121 KDM5B Rebecca Foulger changed review comment from: Original DDG2P rating: possible. ; to: Original DDG2P rating for Autism: possible. DDG2P Mutation consequence: loss of function. Mode of inheritance: monoallelic.
Genetic epilepsy syndromes v1.347 ACTL6B Rebecca Foulger commented on gene: ACTL6B: ACTL6B now has a 'confirmed' rating for 'EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE' in the DD panel of Gene2Phenotype (DDG2P update, 18/09/2019), supporting the Green rating of ACTL6B on this panel.
DDG2P v1.121 ACTL6B Rebecca Foulger Classified gene: ACTL6B as Green List (high evidence)
DDG2P v1.121 ACTL6B Rebecca Foulger Added comment: Comment on list classification: Updated rating of ACTL6B from Red to Green, to match 'confirmed' rating of new DDG2P disorder: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE.
DDG2P v1.121 ACTL6B Rebecca Foulger Gene: actl6b has been classified as Green List (High Evidence).
DDG2P v1.120 ACTL6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: Changed MOP from 'Other' to default, since the confirmed (EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE) disorder has loss of function listed as the DDG2P mutation consequence.
DDG2P v1.120 ACTL6B Rebecca Foulger Mode of pathogenicity for gene: ACTL6B was changed from Other - please provide details in the comments to None
DDG2P v1.119 ACTL6B Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from MONOALLELIC to BIALLELIC to match the MOI of the confirmed disorder. Only the new biallelic disorder (EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE) has a 'confirmed' rating. Both monoallelic disorders have 'possible' ratings.
DDG2P v1.119 ACTL6B Rebecca Foulger Mode of inheritance for gene: ACTL6B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathies - including childhood onset v0.13 ABCC9 James Eden reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: None; Publications: 15034580; Phenotypes: Atrial fibrillation, familial, 12 614050, Cardiomyopathy, dilated, 1O 608569, Hypertrichotic osteochondrodysplasia 239850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.118 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Two new gene:disorder associations added to DDG2P for ACTL6B, September 2019:

New gene:disorder association: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE. Disease confidence rating in DDG2P: confirmed. DDG2P mutation consequence: loss of function; DDG2P allelic requirement: biallelic.

New gene:disorder association: INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEVERE SPEECH AND AMBULATION DEFECTS. Disease confidence rating in DDG2P: possible. DDG2P mutation consequence: all missense/in frame; DDG2P allelic requirement: monoallelic.
DDG2P v1.118 ACTL6B Rebecca Foulger Publications for gene: ACTL6B were set to 28867141
DDG2P v1.117 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Unspecified Neurodevelopmental Disorder to Unspecified Neurodevelopmental Disorder; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE 618468; INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEVERE SPEECH AND AMBULATION DEFECTS 618470
DDG2P v1.116 ACTL6B Rebecca Foulger changed review comment from: Original DDG2P rating: possible. DDG2P mode of pathogenicity: all missense/in frame ; to: Original DDG2P rating for Unspecified Neurodevelopmental Disorder: possible. DDG2P mode of pathogenicity: all missense/in frame; DG2P allelic requirement: monoallelic.
DDG2P v1.116 FAT4 Rebecca Foulger commented on gene: FAT4: Two new gene:disorders added to DDG2P for FAT4, September 2019:

New gene:disorder association: HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2. Disease confidence rating in DDG2P: confirmed. DDG2P mutation consequence: uncertain; DDG2P allelic requirement: biallelic.

New gene:disorder association: VAN MALDERGEM SYNDROME. Disease confidence rating in DDG2P: confirmed. DDG2P mutation consequence: loss of function; DDG2P allelic requirement: biallelic.
DDG2P v1.116 FAT4 Rebecca Foulger Phenotypes for gene: FAT4 were changed from PERIVENTRICULAR NEURONAL HETEROTOPIA to PERIVENTRICULAR NEURONAL HETEROTOPIA; HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2 616006; VAN MALDERGEM SYNDROME 615546
Thoracic aortic aneurysm and dissection v0.32 COL9A3 James Eden reviewed gene: COL9A3: Rating: RED; Mode of pathogenicity: None; Publications: 24765306; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy 600969; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.115 FAT4 Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for PERIVENTRICULAR NEURONAL HETEROTOPIA: confirmed. DDG2P Mutation consequence: loss of function; DDG2P allelic requirement: biallelic.
Thoracic aortic aneurysm and dissection v0.32 COL9A2 James Eden reviewed gene: COL9A2: Rating: RED; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: ?Stickler syndrome, type V 614284, Epiphyseal dysplasia, multiple, 2 600204; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.115 KDM3B Rebecca Foulger commented on gene: KDM3B: New gene:disorder association added to DDG2P for KDM3B, September 2019: Intellectual Disability, Short Stature, and Facial Dysmorphism. Disease confidence rating in DDG2P: probable; DDG2P mutation consequence: loss of function; DDG2P mode of inheritance: monoallelic.
DDG2P v1.115 KDM3B Rebecca Foulger Phenotypes for gene: KDM3B were changed from KDM3B-related intellectual disability, short stature and facial dysmorphism to Intellectual Disability, Short Stature, and Facial Dysmorphism; KDM3B-related intellectual disability, short stature and facial dysmorphism
Thoracic aortic aneurysm and dissection v0.32 COL9A1 James Eden reviewed gene: COL9A1: Rating: RED; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: ?Epiphyseal dysplasia, multiple, 6 614135, Stickler syndrome, type IV 614134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.114 KMT2E Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for INTELLECTUAL DISABILITY: confirmed. DDG2P Mode of Pathogenicity/Mutation consequence: loss of function; DDG2P Mode of inheritance/allelic requirement: monoallelic.
Thoracic aortic aneurysm and dissection v0.32 COL4A1 James Eden reviewed gene: COL4A1: Rating: RED; Mode of pathogenicity: None; Publications: 20558831; Phenotypes: ?Retinal arteries, tortuosity of 180000, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps 611773, Brain small vessel disease with or without ocular anomalies 175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant 618564; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.114 KMT2E Rebecca Foulger commented on gene: KMT2E: New gene:disorder association added to DDG2P for KMT2E, September 2019: Neurodevelopmental disorder and Epilepsy. Disease confidence rating in DDG2P: possible; DDG2P mutation consequence: uncertain; DDG2P mode of inheritance: monoallelic.
DDG2P v1.114 KMT2E Rebecca Foulger Publications for gene: KMT2E were set to
DDG2P v1.113 KMT2E Rebecca Foulger Phenotypes for gene: KMT2E were changed from INTELLECTUAL DISABILITY to INTELLECTUAL DISABILITY 616579; Neurodevelopmental disorder and Epilepsy 618512
DDG2P v1.112 NBAS Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD: confirmed. DDG2P Mode of Pathogenicity: loss of function; DDG2P Mode of Inheritance: biallelic.
DDG2P v1.112 NBAS Rebecca Foulger commented on gene: NBAS: New gene:disorder association added to DDG2P for NBAS, September 2019: ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD; SHORT STATURE, OPTIC NERVE ATROPHY, AND PELGER-HUET ANOMALY. Disease confidence rating in DDG2P: confirmed; DDG2P mutation consequence: loss of function. DDG2P mode of inheritance: biallelic.
DDG2P v1.112 NBAS Rebecca Foulger Phenotypes for gene: NBAS were changed from ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD to ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD; ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD; SHORT STATURE, OPTIC NERVE ATROPHY, AND PELGER-HUET ANOMALY 616483
Thoracic aortic aneurysm and dissection v0.32 COL2A1 James Eden reviewed gene: COL2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Stickler syndrome, type I 108300, Spondyloperipheral dysplasia 271700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.111 CNOT1 Rebecca Foulger Phenotypes for gene: CNOT1 were changed from pancreatic agenesis and holoprosencephaly syndrome to pancreatic agenesis and holoprosencephaly syndrome; HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS 618500
DDG2P v1.110 CNOT1 Rebecca Foulger commented on gene: CNOT1: New gene:disorder association added to DDG2P for CNOT1, September 2019: HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS. Disease confidence rating in DDG2P: probable; DDG2P mutation consequence: all missense/in frame. DDG2P mode of inheritance: monoallelic.
Thoracic aortic aneurysm and dissection v0.32 COL11A2 James Eden reviewed gene: COL11A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal dominant 13 601868, Deafness, autosomal recessive 53 609706, Fibrochondrogenesis 2 614524, Otospondylomegaepiphyseal dysplasia, autosomal dominant 184840, Otospondylomegaepiphyseal dysplasia, autosomal recessive 215150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.110 SCN11A Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. DDG2P mode of pathogenicity: activating ; to: Original DDG2P rating for CONGENITAL INABILITY TO EXPERIENCE PAIN: confirmed. DDG2P mode of pathogenicity: activating. DDG2P mode of inheritance: monoallelic.
DDG2P v1.110 SCN11A Rebecca Foulger commented on gene: SCN11A: New gene:disorder association added to DDG2P for SCN11A, September 2019: EPISODIC PAIN SYNDROME, FAMILIAL. Disease confidence rating in DDG2P: both RD and IF; DDG2P mutation consequence: activating. DDG2P mode of inheritance: monoallelic.
Thoracic aortic aneurysm and dissection v0.32 COL11A1 James Eden reviewed gene: COL11A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Deafness, autosomal dominant 37 618533, Fibrochondrogenesis 1 228520, Marshall syndrome 154780, Stickler syndrome, type II 604841; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.110 SCN11A Rebecca Foulger Phenotypes for gene: SCN11A were changed from CONGENITAL INABILITY TO EXPERIENCE PAIN to CONGENITAL INABILITY TO EXPERIENCE PAIN; EPISODIC PAIN SYNDROME, FAMILIAL 615552
DDG2P v1.109 FLNA Rebecca Foulger commented on gene: FLNA: New gene:disorder association added to DDG2P, September 2019: PERIVENTRICULAR NODULAR HETEROTOPIA 1. Disease confidence rating in DDG2P: confirmed; DDG2P mutation consequence: loss of function. DDG2P mode of inheritance: x-linked dominant.
DDG2P v1.109 FLNA Rebecca Foulger Phenotypes for gene: FLNA were changed from FRONTOMETAPHYSEAL DYSPLASIA 305620; FG SYNDROME TYPE 2 300321; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION 300048; MELNICK-NEEDLES SYNDROME 309350; Childhood Interstitial Lung Disease; EPILEPTIC ENCEPHALOPATHY; OTOPALATODIGITAL SYNDROME TYPE 1 311300; OTOPALATODIGITAL SYNDROME TYPE 2 304120; TERMINAL OSSEOUS DYSPLASIA 300244 to PERIVENTRICULAR NODULAR HETEROTOPIA 1 300049; FRONTOMETAPHYSEAL DYSPLASIA 305620; FG SYNDROME TYPE 2 300321; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION 300048; MELNICK-NEEDLES SYNDROME 309350; Childhood Interstitial Lung Disease; EPILEPTIC ENCEPHALOPATHY; OTOPALATODIGITAL SYNDROME TYPE 1 311300; OTOPALATODIGITAL SYNDROME TYPE 2 304120; TERMINAL OSSEOUS DYSPLASIA 300244
DDG2P v1.108 CLIC2 Rebecca Foulger Phenotypes for gene: CLIC2 were changed from Mental retardation, X-linked, syndromic 32 to Mental retardation, X-linked, syndromic 32 300886
DDG2P v1.107 DKC1 Rebecca Foulger Phenotypes for gene: DKC1 were changed from DYSKERATOSIS CONGENITA, X-LINKED; DKC1-RELATED DYSKERATOSIS CONGENITA 314912 to DYSKERATOSIS CONGENITA, X-LINKED, 305000; DKC1-RELATED DYSKERATOSIS CONGENITA 314912
DDG2P v1.106 GDI1 Rebecca Foulger Phenotypes for gene: GDI1 were changed from MENTAL RETARDATION X-LINKED TYPE 48 300104; MENTAL RETARDATION X-LINKED TYPE 41 300104 to MENTAL RETARDATION X-LINKED TYPE 48 300849; MENTAL RETARDATION X-LINKED TYPE 41 300849
Limb disorders v1.61 HDAC4 Eleanor Williams Classified gene: HDAC4 as Amber List (moderate evidence)
Limb disorders v1.61 HDAC4 Eleanor Williams Added comment: Comment on list classification: Changing rating from green to amber, as there are only 2 cases where patients with variants in this gene have a reported brachydactyly phenotype. But the CNV covering this region has been added to the panel - ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss) as there is more evidence that loss of the region results in a relevant phenotype.
Limb disorders v1.61 HDAC4 Eleanor Williams Gene: hdac4 has been classified as Amber List (Moderate Evidence).
Limb disorders v1.60 ISCA-37394-Loss Eleanor Williams Classified Region: ISCA-37394-Loss as Green List (high evidence)
Limb disorders v1.60 ISCA-37394-Loss Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. Sufficient evidence that CNVs covering this region (HDAC4 in particular) result in a brachydactyly phenotype (PMID: 25329715, PMID: 24715439, PMID: 25402011)
Limb disorders v1.60 ISCA-37394-Loss Eleanor Williams Region: isca-37394-loss has been classified as Green List (High Evidence).
Limb disorders v1.59 ISCA-37394-Loss Eleanor Williams Region: ISCA-37394-Loss was added
Region: ISCA-37394-Loss was added to Limb disorders. Sources: ClinGen
Mode of inheritance for Region: ISCA-37394-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37394-Loss were set to 2q37 deletion syndrome is a condition that can affect many parts of the body. This condition is characterized by weak muscle tone (hypotonia) in infancy, mild to severe intellectual disability and developmental delay, behavioral problems, characteristic facial features, and other physical abnormalities. PMID 23188045 brachydactyly-mental retardation syndrome, Albright hereditary osteodystrophy-like syndrome, developmental delay and behavioural abnormalities in combination; 600430
Review for Region: ISCA-37394-Loss was set to GREEN
Added comment: Adding this CNV as is associated with brachydactyly. The CNV is also on the skeletal dsyplasia panel
Sources: ClinGen
Pain syndromes v1.6 PRDM12 Tomislav Kokotovic reviewed gene: PRDM12: Rating: GREEN; Mode of pathogenicity: None; Publications: 25891934; Phenotypes: HSAN VIII, insensitivity to pain; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams changed review comment from: Comment on list classification: After review with members of the GMS Musculoskeletal specialist test group and Genomics England Clinicians it was decided to rate the HDAC4 gene amber for SNVs, but to keep the region
ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss) green.; to: Comment on list classification: After review with members of the GMS Musculoskeletal specialist test group and Genomics England Clinicians it was decided to rate the HDAC4 gene amber for SNVs, but to keep the region covering this gene green (ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss))
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams Classified gene: HDAC4 as Amber List (moderate evidence)
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams Added comment: Comment on list classification: After review with members of the GMS Musculoskeletal specialist test group and Genomics England Clinicians it was decided to rate the HDAC4 gene amber for SNVs, but to keep the region
ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss) green.
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams Gene: hdac4 has been classified as Amber List (Moderate Evidence).
DDG2P v1.105 TUBB Rebecca Foulger Phenotypes for gene: TUBB were changed from Circumferential Skin Creases Kunze Type; CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6 615771 to Circumferential Skin Creases Kunze Type 156610; CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6 615771
DDG2P v1.104 TPM2 Rebecca Foulger Phenotypes for gene: TPM2 were changed from ARTHROGRYPOSIS, DISTAL, TYPE 1 to ARTHROGRYPOSIS, DISTAL, TYPE 1 108120
DDG2P v1.103 TGFB3 Rebecca Foulger Phenotypes for gene: TGFB3 were changed from LOEYS-DIETZ SYNDROME to LOEYS-DIETZ SYNDROME 615582
DDG2P v1.102 TGFBR1 Rebecca Foulger Phenotypes for gene: TGFBR1 were changed from LOEYS-DIETZ SYNDROME TYPE 2A 608967; LOEYS-DIETZ SYNDROME TYPE 1A 609192; AORTIC ANEURYSM FAMILIAL THORACIC TYPE 5 608967 to LOEYS-DIETZ SYNDROME TYPE 2A 608967; LOEYS-DIETZ SYNDROME TYPE 1A 609192; AORTIC ANEURYSM FAMILIAL THORACIC TYPE 5 609192
DDG2P v1.101 ABL1 Rebecca Foulger Phenotypes for gene: ABL1 were changed from Congenital heart defects and skeletal malformations to Congenital heart defects and skeletal malformations 617602
DDG2P v1.100 POLG Rebecca Foulger Phenotypes for gene: POLG were changed from MITOCHONDRIAL DNA DEPLETION SYNDROME 4A 607459 to MITOCHONDRIAL DNA DEPLETION SYNDROME 4A 203700
DDG2P v1.99 PAX9 Rebecca Foulger Phenotypes for gene: PAX9 were changed from TOOTH AGENESIS, SELECTIVE, 3 318869 to TOOTH AGENESIS, SELECTIVE, 3 604625
DDG2P v1.98 GLI3 Rebecca Foulger Phenotypes for gene: GLI3 were changed from PREAXIAL POLYDACTYLY TYPE IV 269157; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME 175700; POSTAXIAL POLYDACTYLY TYPE A 149847; PALLISTER-HALL SYNDROME 146510 to PREAXIAL POLYDACTYLY TYPE IV 269157; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME 175700; POSTAXIAL POLYDACTYLY TYPE A 174200; PALLISTER-HALL SYNDROME 146510
DDG2P v1.97 MYH9 Rebecca Foulger Phenotypes for gene: MYH9 were changed from DEAFNESS AUTOSOMAL DOMINANT TYPE 17 603622; SEBASTIAN SYNDROME 605249; MACROTHROMBOCYTOPENIA WITH PROGRESSIVE SENSORINEURAL DEAFNESS 600208; EPSTEIN SYNDROME 153650; MAY-HEGGLIN ANOMALY 155100; FECHTNER SYNDROME 153640 to DEAFNESS AUTOSOMAL DOMINANT TYPE 17 603622; SEBASTIAN SYNDROME 155100; MACROTHROMBOCYTOPENIA WITH PROGRESSIVE SENSORINEURAL DEAFNESS 155100; EPSTEIN SYNDROME 155100; MAY-HEGGLIN ANOMALY 155100; FECHTNER SYNDROME 155100
DDG2P v1.96 MITF Rebecca Foulger Phenotypes for gene: MITF were changed from Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness; WAARDENBURG SYNDROME TYPE 2 WITH OCULAR ALBINISM 103470; TIETZ SYNDROME 103500; WAARDENBURG SYNDROME TYPE 2A 193510 to Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness 617306; WAARDENBURG SYNDROME TYPE 2 WITH OCULAR ALBINISM 103470; TIETZ SYNDROME 103500; WAARDENBURG SYNDROME TYPE 2A 193510
DDG2P v1.95 LAMA1 Rebecca Foulger Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY; AUTOSOMAL RECESSIVE MENTAL RETARDATION to CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY 615960; AUTOSOMAL RECESSIVE MENTAL RETARDATION
DDG2P v1.94 ITPR1 Rebecca Foulger Phenotypes for gene: ITPR1 were changed from SPINOCEREBELLAR ATAXIA TYPE15 606658; SPINOCEREBELLAR ATAXIA 29, CONGENITAL NONPROGRESSIVE 117360; Gillespie Syndrome to SPINOCEREBELLAR ATAXIA TYPE15 606658; SPINOCEREBELLAR ATAXIA 29, CONGENITAL NONPROGRESSIVE 117360; Gillespie Syndrome 206700
DDG2P v1.93 SLC2A2 Rebecca Foulger Phenotypes for gene: SLC2A2 were changed from FANCONI-BICKEL SYNDROME 269871 to FANCONI-BICKEL SYNDROME 227810
DDG2P v1.92 FGFR1 Rebecca Foulger Phenotypes for gene: FGFR1 were changed from PFEIFFER SYNDROME 101600; OSTEOGLOPHONIC DYSPLASIA 166250; Hartsfield syndrome; KALLMANN SYNDROME TYPE 2 147950; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM 146110; Encephalocraniocutaneous lipomatosis to PFEIFFER SYNDROME 101600; OSTEOGLOPHONIC DYSPLASIA 166250; Hartsfield syndrome 615465; KALLMANN SYNDROME TYPE 2 147950; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM 146110; Encephalocraniocutaneous lipomatosis 613001
DDG2P v1.91 FN1 Rebecca Foulger Phenotypes for gene: FN1 were changed from Spondylometaphyseal Dysplasia with Corner Fractures to Spondylometaphyseal Dysplasia with Corner Fractures 184255
DDG2P v1.90 EDNRA Rebecca Foulger Phenotypes for gene: EDNRA were changed from MANDIBULOFACIAL DYSOSTOSIS WITH ALOPECIA to MANDIBULOFACIAL DYSOSTOSIS WITH ALOPECIA 616367
DDG2P v1.89 ERCC1 Rebecca Foulger Phenotypes for gene: ERCC1 were changed from FANCONI ANEMIA 229154; CEREBROOCULOFACIOSKELETAL SYNDROME 4 298956 to FANCONI ANEMIA 229154; CEREBROOCULOFACIOSKELETAL SYNDROME 4 610758
DDG2P v1.88 DSG1 Rebecca Foulger Phenotypes for gene: DSG1 were changed from SEVERE DERMATITIS, MULTIPLE ALLERGIES AND METABOLIC WASTING to SEVERE DERMATITIS, MULTIPLE ALLERGIES AND METABOLIC WASTING, 615508
DDG2P v1.87 CRYGD Rebecca Foulger Phenotypes for gene: CRYGD were changed from CATARACT CONGENITAL CERULEAN TYPE 3 608983; CATARACT AUTOSOMAL DOMINANT 604219; CATARACT CONGENITAL NON-NUCLEAR POLYMORPHIC AUTOSOMAL DOMINANT 123690; CATARACT CRYSTALLINE ACULEIFORM 115700 to CATARACT CONGENITAL CERULEAN TYPE 3 115700; CATARACT AUTOSOMAL DOMINANT 604219; CATARACT CONGENITAL NON-NUCLEAR POLYMORPHIC AUTOSOMAL DOMINANT 123690; CATARACT CRYSTALLINE ACULEIFORM 115700
DDG2P v1.86 CRYAA Rebecca Foulger Phenotypes for gene: CRYAA were changed from CATARACT, NUCLEAR 123580; CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 1 123580 to CATARACT, NUCLEAR 123580; CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 1 604219
DDG2P v1.85 COL18A1 Rebecca Foulger Phenotypes for gene: COL18A1 were changed from KNOBLOCH SYNDROME TYPE I 315926 to KNOBLOCH SYNDROME TYPE I 267750
DDG2P v1.84 COL11A2 Rebecca Foulger Phenotypes for gene: COL11A2 were changed from WEISSENBACHER-ZWEYMUELLER SYNDROME 277610; AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA 215150; DEAFNESS AUTOSOMAL DOMINANT TYPE 13 601868; STICKLER SYNDROME TYPE 3 184840; DEAFNESS AUTOSOMAL RECESSIVE TYPE 53 609706 to WEISSENBACHER-ZWEYMUELLER SYNDROME 184840; AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA 215150; DEAFNESS AUTOSOMAL DOMINANT TYPE 13 601868; STICKLER SYNDROME TYPE 3 184840; DEAFNESS AUTOSOMAL RECESSIVE TYPE 53 609706
DDG2P v1.83 CDH3 Rebecca Foulger Phenotypes for gene: CDH3 were changed from EEM SYNDROME 280238; HYPOTRICHOSIS, CONGENITAL, WITH JUVENILE MACULAR DYSTROPHY 601553 to EEM SYNDROME 225280; HYPOTRICHOSIS, CONGENITAL, WITH JUVENILE MACULAR DYSTROPHY 601553
DDG2P v1.82 ACTA1 Rebecca Foulger Phenotypes for gene: ACTA1 were changed from NEMALINE MYOPATHY 3 to NEMALINE MYOPATHY 3, 161800
Thoracic aortic aneurysm and dissection v0.32 CHST14 James Eden reviewed gene: CHST14: Rating: RED; Mode of pathogenicity: None; Publications: 26373698; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 ZNF469 James Eden reviewed gene: ZNF469: Rating: RED; Mode of pathogenicity: None; Publications: 24895405; Phenotypes: Brittle cornea syndrome 1 229200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 TNXB James Eden reviewed gene: TNXB: Rating: RED; Mode of pathogenicity: None; Publications: 23830591; Phenotypes: Ehlers-Danlos syndrome, classic-like, 1 606408, Vesicoureteral reflux 8 615963; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 PKD2 James Eden reviewed gene: PKD2: Rating: RED; Mode of pathogenicity: None; Publications: 10615132, 12874107; Phenotypes: Polycystic kidney disease 2 613095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 PKD1 James Eden reviewed gene: PKD1: Rating: RED; Mode of pathogenicity: None; Publications: 17656674, 18679710; Phenotypes: Polycystic kidney disease 1 173900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 LTBP2 James Eden reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: 20179738; Phenotypes: ?Weill-Marchesani syndrome 3, recessive 614819, Glaucoma 3, primary congenital, D 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma 251750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 KCNN1 James Eden reviewed gene: KCNN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thoracic aortic aneurysm and dissection v0.32 HNRNPK James Eden reviewed gene: HNRNPK: Rating: RED; Mode of pathogenicity: None; Publications: 29904177; Phenotypes: Au-Kline syndrome 616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 SLC39A13 James Eden reviewed gene: SLC39A13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, spondylodysplastic type, 3 612350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 B4GALT7 James Eden commented on gene: B4GALT7: Not significantly associated with aortopathy.
Thoracic aortic aneurysm and dissection v0.32 B4GALT7 James Eden reviewed gene: B4GALT7: Rating: RED; Mode of pathogenicity: None; Publications: 26940150, 28882145; Phenotypes: Ehlers-Danlos syndrome, spondylodysplastic type, 1 130070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v0.92 FKRP Ivone Leong Classified gene: FKRP as Amber List (moderate evidence)
Structural eye disease v0.92 FKRP Ivone Leong Gene: fkrp has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm and dissection v0.32 ATP7A James Eden reviewed gene: ATP7A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Menkes disease 309400, Occipital horn syndrome 304150, Spinal muscular atrophy, distal, X-linked 3 300489; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Structural eye disease v0.91 MYRF Nicola Ragge reviewed gene: MYRF: Rating: GREEN; Mode of pathogenicity: ; Publications: 31266062; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 CSPP1 Nicola Ragge reviewed gene: CSPP1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 WNT3 Nicola Ragge reviewed gene: WNT3: Rating: RED; Mode of pathogenicity: ; Publications: 14872406; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 TUBB Nicola Ragge reviewed gene: TUBB: Rating: AMBER; Mode of pathogenicity: ; Publications: 26637975; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 SNX3 Nicola Ragge reviewed gene: SNX3: Rating: RED; Mode of pathogenicity: ; Publications: 12471201; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 SMO Nicola Ragge edited their review of gene: SMO: Added comment: Twigg 2016: 8 individuals with somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]). 4 of the individuals present coloboma and/microphthalmia. ; Set current diagnostic: yes
Structural eye disease v0.91 SMG9 Nicola Ragge reviewed gene: SMG9: Rating: AMBER; Mode of pathogenicity: ; Publications: 27018474; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 SLC25A24 Nicola Ragge reviewed gene: SLC25A24: Rating: AMBER; Mode of pathogenicity: ; Publications: 29100093; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 TMEM5 Nicola Ragge reviewed gene: TMEM5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 RIPK4 Nicola Ragge reviewed gene: RIPK4: Rating: GREEN; Mode of pathogenicity: ; Publications: 23074676, 22197488, 22197489 ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 RERE Nicola Ragge reviewed gene: RERE: Rating: GREEN; Mode of pathogenicity: ; Publications: 27087320, 29330883 ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 POMT2 Nicola Ragge edited their review of gene: POMT2: Added comment: Van Reeuwijk, three families with Walker-Warburg syndrome, one case with Peter's anomaly, congenital cataract and microphthalmia and homozygous nonsense variant. The other cases had congenital cataract (homozygous splice site variant) and cataract/buphthalmos (homozygous frameshift). Nabhan family of four diseased siblings with Walker/Warburg syndrome, oldest sibling had microphthalmia, all siblings have homozygous missense. ; Changed rating: GREEN; Changed publications: 15894594, 28815891; Set current diagnostic: yes
Structural eye disease v0.91 POMT1 Nicola Ragge edited their review of gene: POMT1: Added comment: Bernabe 3 families with microphthalmia among 7 families with Walker-Warburg syndrome, one with homozygous missense, one with homozygous nonsense, one with compound het missense/frameshift. Three other families described have buphthalmos, lens opacities and/or cataracts. All variants segregate. Kim one case with microphthalmia with homozygous in-frame deletion.; Changed publications: 12369018, 15037715; Set current diagnostic: yes
Structural eye disease v0.91 POMGNT2 Nicola Ragge reviewed gene: POMGNT2: Rating: AMBER; Mode of pathogenicity: ; Publications: 22958903; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 POMGNT1 Nicola Ragge reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19679478, 19452620, 28765568, 11709191, 0961548; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCL Nicola Ragge reviewed gene: FANCL: Rating: AMBER; Mode of pathogenicity: ; Publications: 25754594; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 OLFM2 Nicola Ragge edited their review of gene: OLFM2: Added comment: Holt reports two cases, one with a de novo CNV involving an additional gene and one with a 5' UTR variant which is inherited from an unaffected parent.; Changed publications: 27844144, 17122126; Set current diagnostic: yes
Structural eye disease v0.91 NDUFB11 Nicola Ragge reviewed gene: NDUFB11: Rating: RED; Mode of pathogenicity: ; Publications: 25772934; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 MITF Nicola Ragge edited their review of gene: MITF: Added comment: Dominant variants are associated with Waardenburg syndrome, however George et al reported two cases with compound het changes and a new syndrome including microphthalmia (COMMAD syndrome): one case with compound heterozygous changes for missense/in-frame deletion segregating in parents - inframe deletion was previously shown to lack DNA binding or regulate target-gene promotors in mice (Grill paper), another unrelated case with missense and splice site variant segregating in parents plus convincing evidence in mouse and cell models that these variants are pathogenic. Steingrimsson published first paper on MITF variants causing microphthalmia in mice ; Changed publications: 27889061, 23787126, 7874168; Set current diagnostic: yes
Structural eye disease v0.91 MAPRE2 Nicola Ragge reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26637975; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 KIF11 Nicola Ragge reviewed gene: KIF11: Rating: AMBER; Mode of pathogenicity: ; Publications: 27212378; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 KDM6A Nicola Ragge reviewed gene: KDM6A: Rating: AMBER; Mode of pathogenicity: ; Publications: 29617172, 29300383; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 ISPD Nicola Ragge edited their review of gene: ISPD: Added comment: Roscioli: six Walker-Warburg cases with microphthalmia and one with Peter's anomaly, full segregation of homozygous or compound heterozygous variants. Morpholino treated zebrafish have significantly smaller eyes.; Set current diagnostic: yes
Structural eye disease v0.91 IKBKG Nicola Ragge reviewed gene: IKBKG: Rating: RED; Mode of pathogenicity: ; Publications: 31119873, 20499493, 30905793 ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 GLI2 Nicola Ragge edited their review of gene: GLI2: Added comment: Rahimov one family with anophthalmia,segregation unknown; Bertolacini one case with anophthalmia with de novo missense now benign in Clinvar ; Changed publications: 17096318, 21204792; Set current diagnostic: yes
Structural eye disease v0.91 FKTN Nicola Ragge reviewed gene: FKTN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 FKRP Nicola Ragge edited their review of gene: FKRP: Added comment: Van reeuwijk: one family with Walker -Warburg syndrome and microphthalmia with homozygous variant in start codon segregating in parents; Bernabe one case with microphthalmia and coloboma with homozygous missense, segregation unknown; Kawahara zebrafish model; Chan: mouse model. ; Changed rating: AMBER; Changed publications: 20236121, 15121789, 19955119, 20675713 ; Set current diagnostic: yes
Structural eye disease v0.91 FANCI Nicola Ragge reviewed gene: FANCI: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCE Nicola Ragge reviewed gene: FANCE: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCD2 Nicola Ragge reviewed gene: FANCD2: Rating: RED; Mode of pathogenicity: ; Publications: 12893777; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCA Nicola Ragge reviewed gene: FANCA: Rating: RED; Mode of pathogenicity: ; Publications: 12913077, 8502512; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 ESCO2 Nicola Ragge reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: ; Publications: 16380922, 19574259; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 DOCK6 Nicola Ragge reviewed gene: DOCK6: Rating: GREEN; Mode of pathogenicity: ; Publications: 25824905; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 DAG1 Nicola Ragge reviewed gene: DAG1: Rating: AMBER; Mode of pathogenicity: ; Publications: 24052401, 25934851; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 C5orf42 Nicola Ragge edited their review of gene: C5orf42: Added comment: Lopez: one case with microphthalmia among 11 families, compound het for missense and frameshift, parents not available; Set current diagnostic: yes
Structural eye disease v0.91 COX7B Nicola Ragge reviewed gene: COX7B: Rating: AMBER; Mode of pathogenicity: ; Publications: 23122588; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 B3GALNT2 Nicola Ragge reviewed gene: B3GALNT2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23453667; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 ALX3 Nicola Ragge reviewed gene: ALX3: Rating: RED; Mode of pathogenicity: ; Publications: 19409524; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 ALX1 Nicola Ragge reviewed gene: ALX1: Rating: AMBER; Mode of pathogenicity: ; Publications: 20451171, 23059813; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm and dissection v0.32 ATP6V0A2 James Eden commented on gene: ATP6V0A2: No significant association with aortopathy.
Thoracic aortic aneurysm and dissection v0.32 ATP6V0A2 James Eden reviewed gene: ATP6V0A2: Rating: RED; Mode of pathogenicity: None; Publications: 19321599; Phenotypes: Cutis laxa, autosomal recessive, type IIA 219200, Wrinkly skin syndrome 278250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 ALDH18A1 James Eden reviewed gene: ALDH18A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cutis laxa, autosomal dominant 3 616603, Cutis laxa, autosomal recessive, type IIIA 219150, Spastic paraplegia 9A, autosomal dominant 601162, Spastic paraplegia 9B, autosomal recessive 616586; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 ADAMTS2 James Eden reviewed gene: ADAMTS2: Rating: RED; Mode of pathogenicity: None; Publications: 26765342; Phenotypes: Ehlers-Danlos syndrome, dermatosparaxis typen 225410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 ACVR1 James Eden reviewed gene: ACVR1: Rating: RED; Mode of pathogenicity: None; Publications: 22536403; Phenotypes: Fibrodysplasia ossificans progressiva 135100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 EMILIN1 James Eden reviewed gene: EMILIN1: Rating: RED; Mode of pathogenicity: None; Publications: 26462740; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 SMAD6 James Eden reviewed gene: SMAD6: Rating: AMBER; Mode of pathogenicity: None; Publications: 30796334, 28659821, 30963242; Phenotypes: Aortic valve disease 2 614823; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 COL1A1 James Eden reviewed gene: COL1A1: Rating: RED; Mode of pathogenicity: None; Publications: 14630726; Phenotypes: Caffey disease 114000, Ehlers-Danlos syndrome, arthrochalasia type, 1 130060, Osteogenesis imperfecta, types I-IV; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.32 MYLK2 James Eden reviewed gene: MYLK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, hypertrophic, 1, digenic 192600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cataracts v2.0 Ivone Leong promoted panel to version 2.0
Cataracts v1.37 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Bardet Biedl syndrome v1.0 Ivone Leong promoted panel to version 1.0
Bardet Biedl syndrome v0.25 Ivone Leong Panel types changed to GMS Rare Disease; GMS signed-off
Bardet Biedl syndrome v0.24 IFT27 Ivone Leong reviewed gene: IFT27: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bardet Biedl syndrome v0.24 MKS1 Ivone Leong reviewed gene: MKS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bardet Biedl syndrome v0.24 LZTFL1 Ivone Leong reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Optic neuropathy v2.0 Ivone Leong promoted panel to version 2.0
Optic neuropathy v1.121 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Leber hereditary optic neuropathy v1.0 Ivone Leong promoted panel to version 1.0
Leber hereditary optic neuropathy v0.8 Ivone Leong Panel types changed to GMS Rare Disease; GMS signed-off
Primary lymphoedema v2.0 Ivone Leong promoted panel to version 2.0
Primary lymphoedema v1.123 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Cataracts v1.36 KIAA1109 Ivone Leong Classified gene: KIAA1109 as Red List (low evidence)
Cataracts v1.36 KIAA1109 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Red. KIAA1109 is associated with Alkuraya-Kucinskas syndrome and cataracts are a minor feature. As we are not aware of any cases of variants in this gene associated with isolated cataracts, it has been demoted to Red.
Cataracts v1.36 KIAA1109 Ivone Leong Gene: kiaa1109 has been classified as Red List (Low Evidence).
Cataracts v1.35 LONP1 Ivone Leong Classified gene: LONP1 as Green List (high evidence)
Cataracts v1.35 LONP1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on previous review.
Cataracts v1.35 LONP1 Ivone Leong Gene: lonp1 has been classified as Green List (High Evidence).
Cataracts v1.34 GEMIN4 Ivone Leong Classified gene: GEMIN4 as Green List (high evidence)
Cataracts v1.34 GEMIN4 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on previous review.
Cataracts v1.34 GEMIN4 Ivone Leong Gene: gemin4 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy - teen and adult v1.77 MYH6 Ellen McDonagh Publications for gene: MYH6 were set to 27532257; 22194935
Thoracic aortic aneurysm and dissection v0.32 FKBP14 James Eden reviewed gene: FKBP14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22265013; Phenotypes: Ehlers-Danlos syndrome, kyphoscoliotic type, 2 614557; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 FBLN5 James Eden changed review comment from: Gene is associated with cutis laxa, which includes aortic symptoms.; to: Gene is associated with cutis laxa, which includes aortic symptoms. Also associated with age-related macular degeneration and autistic spectrum disorder in HGMD.
Thoracic aortic aneurysm and dissection v0.32 FBLN5 James Eden reviewed gene: FBLN5: Rating: AMBER; Mode of pathogenicity: None; Publications: 12189163, 27089918; Phenotypes: ?Cutis laxa, autosomal dominant 2 614434, Cutis laxa, autosomal recessive, type IA 219100, Macular degeneration, age-related, 3 608895, Neuropathy, hereditary, with or without age-related macular degeneration 608895; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 ABCC6 James Eden reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: 28102862; Phenotypes: Pseudoxanthoma elasticum 264800, Pseudoxanthoma elasticum, forme fruste 177850, Arterial calcification, generalized, of infancy, 2 614473; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.32 FLNA Ivone Leong Added comment: Comment on mode of inheritance: MOI has been corrected.
Thoracic aortic aneurysm and dissection v0.32 FLNA Ivone Leong Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm and dissection v0.31 BGN Ivone Leong Added comment: Comment on mode of inheritance: MOI has been corrected.
Thoracic aortic aneurysm and dissection v0.31 BGN Ivone Leong Mode of inheritance for gene: BGN was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm and dissection v0.30 SMAD4 James Eden reviewed gene: SMAD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 29392890; Phenotypes: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 175050, Myhre syndrome 139210, Pancreatic cancer, somatic 260350, Polyposis, juvenile intestinal 174900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 PRKG1 James Eden reviewed gene: PRKG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910461, 30577811; Phenotypes: Aortic aneurysm, familial thoracic 8 615436; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 NOTCH1 James Eden reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29907982, 18593716; Phenotypes: Aortic valve disease 1 109730, Adams-Oliver syndrome 5 616028; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 MFAP5 James Eden reviewed gene: MFAP5: Rating: AMBER; Mode of pathogenicity: None; Publications: 25434006; Phenotypes: Aortic aneurysm, familial thoracic 9 616166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 MED12 James Eden reviewed gene: MED12: Rating: RED; Mode of pathogenicity: None; Publications: 28724790; Phenotypes: Lujan-Fryns syndrome 309520, Ohdo syndrome, X-linked 300895, Opitz-Kaveggia syndrome 305450; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Catecholaminergic polymorphic VT v1.25 CALM3 Ellen McDonagh Publications for gene: CALM3 were set to
Thoracic aortic aneurysm and dissection v0.30 LOX James Eden reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 26838787, 27432961; Phenotypes: Aortic aneurysm, familial thoracic 10 617168; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 FOXE3 James Eden reviewed gene: FOXE3: Rating: AMBER; Mode of pathogenicity: None; Publications: 26854927; Phenotypes: Aortic aneurysm, familial thoracic 11, (susceptibility to) 617349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 EFEMP2 James Eden reviewed gene: EFEMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868310, 22440127; Phenotypes: Cutis laxa, autosomal recessive, type IB 614437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.30 COL5A2 James Eden reviewed gene: COL5A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868310; Phenotypes: Ehlers-Danlos syndrome, classic type, 2 130010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 COL5A1 James Eden reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868310; Phenotypes: Ehlers-Danlos syndrome, classic type, 1 130000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm and dissection v0.30 SLC2A10 James Eden reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16550171, 17935213; Phenotypes: Arterial tortuosity syndrome 208050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm and dissection v0.30 FBN2 James Eden reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25944730, 29907982; Phenotypes: Contractural arachnodactyly, congenital 121050, Macular degeneration, early-onset 616118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection v1.103 ADAMTS2 Ellen McDonagh Phenotypes for gene: ADAMTS2 were changed from to 225410 Ehlers-Danlos syndrome, type VIIC
Thoracic aortic aneurysm or dissection v1.102 ADAMTS2 Ellen McDonagh Publications for gene: ADAMTS2 were set to
Thoracic aortic aneurysm or dissection v1.101 ADAMTS2 Ellen McDonagh Mode of inheritance for gene: ADAMTS2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection v1.100 ABCC6 Ellen McDonagh Phenotypes for gene: ABCC6 were changed from to #614473- Arterial calcification, generalized, of infancy, 2; #264800- Pseudoxanthoma elasticum; #177850- Pseudoxanthoma elasticum, forme fruste
Thoracic aortic aneurysm or dissection v1.99 ABCC6 Ellen McDonagh Publications for gene: ABCC6 were set to
Cardiomyopathies - including childhood onset v0.13 ABCC9 Matthew Edwards reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: OMIM#239850:Cantu Syndrome; Mode of inheritance: None; Current diagnostic: yes
Thoracic aortic aneurysm or dissection v1.98 SLC2A10 Ellen McDonagh edited their review of gene: SLC2A10: Added comment: Biallelic mode of inheritance is correct.; Changed publications: 22001912, doi:10.​1007/​s12265-016-9673-5; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Progressive cardiac conduction disease v0.28 KCNK17 James Eden reviewed gene: KCNK17: Rating: RED; Mode of pathogenicity: None; Publications: 24972929; Phenotypes: ; Mode of inheritance: Unknown
Thoracic aortic aneurysm or dissection v1.98 MYH11 Ellen McDonagh Publications for gene: MYH11 were set to 27081537
Progressive cardiac conduction disease v0.28 ANK2 James Eden edited their review of gene: ANK2: Changed rating: RED; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 ANK2 James Eden changed review comment from: Little literature associating this gene with conduction disease in particular.; to: Little literature associating this gene with conduction disease in particular.
Progressive cardiac conduction disease v0.28 ANK2 James Eden reviewed gene: ANK2: Rating: ; Mode of pathogenicity: None; Publications: 30929919; Phenotypes: Cardiac arrhythmia, ankyrin-B-related 600919, Long QT syndrome 4 600919; Mode of inheritance: None
Progressive cardiac conduction disease v0.28 GJA5 James Eden reviewed gene: GJA5: Rating: RED; Mode of pathogenicity: None; Publications: 22247482; Phenotypes: Atrial fibrillation, familial, 11 614049, Atrial standstill, digenic (GJA5/SCN5A) 108770; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 TBX3 James Eden reviewed gene: TBX3: Rating: RED; Mode of pathogenicity: None; Publications: 30820409; Phenotypes: Ulnar-mammary syndrome 181450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 PRKAG2 James Eden reviewed gene: PRKAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26729852, 12015471; Phenotypes: Cardiomyopathy, hypertrophic 6 600858, Glycogen storage disease of heart, lethal congenital 261740, Wolff-Parkinson-White syndrome 194200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Progressive cardiac conduction disease v0.28 TNNI3K James Eden reviewed gene: TNNI3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 25791106, 24925317, 30010057; Phenotypes: Cardiac conduction disease with or without dilated cardiomyopathy 616117; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurological ciliopathies v0.7 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Neurological ciliopathies v0.7 FAM149B1 Eleanor Williams Added comment: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Neurological ciliopathies v0.7 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v0.6 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Ophthalmological ciliopathies v0.11 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Ophthalmological ciliopathies v0.11 FAM149B1 Eleanor Williams Added comment: Comment on list classification: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Ophthalmological ciliopathies v0.11 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v0.10 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Ophthalmological ciliopathies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Inborn errors of metabolism v1.336 ISCA2 Sarah Leigh Classified gene: ISCA2 as Green List (high evidence)
Inborn errors of metabolism v1.336 ISCA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two different ethinicities.
Rated green based on review of Anna de Burca (Clinical Fellow, Genomic England).
Inborn errors of metabolism v1.336 ISCA2 Sarah Leigh Gene: isca2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.335 ISCA2 Sarah Leigh Added comment: Comment on phenotypes: infantile neurodegenerative mitochondrial disorder
Inborn errors of metabolism v1.335 ISCA2 Sarah Leigh Phenotypes for gene: ISCA2 were changed from infantile neurodegenerative mitochondrial disorder to Multiple mitochondrial dysfunctions syndrome 4 616370
Inborn errors of metabolism v1.334 ISCA2 Sarah Leigh Publications for gene: ISCA2 were set to PMID: 25539947
Mitochondrial disorders v2.1 ISCA2 Sarah Leigh Publications for gene: ISCA2 were set to PMID: 25539947
Inborn errors of metabolism v1.333 DNM2 Sarah Leigh Publications for gene: DNM2 were set to 18560793; 17932957; 17636067; 17008356; 16227997; 15731758
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Classified gene: DNM2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Added comment: Comment on list classification: This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 1 case with multiple deletions and COX negative fibres; 5 cases presented in a poster with dominant DMN2 variants (had COX deficient muscle fibres, one case with the p.Arg369Trp revealed disruption of the dynamic mitochondrial network, https://doi.org/10.1016/j.nmd.2012.06.124). From panels: Possible mitochondrial disorder - nuclear genes (Version 0.187) and Mitochondrial DNA maintenance disorder (Version 0.8).
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Gene: dnm2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.332 DNM2 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity
Inborn errors of metabolism v1.332 DNM2 Sarah Leigh Phenotypes for gene: DNM2 were changed from Disorders of mitochondrial DNA maintenance and integrity to Centronuclear myopathy 1 160150; Charcot-Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.363 DNM2 Sarah Leigh Publications for gene: DNM2 were set to
Undiagnosed metabolic disorders v1.362 DNM2 Sarah Leigh Phenotypes for gene: DNM2 were changed from Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482 to Centronuclear myopathy 1 160150; Charcot-Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams changed review comment from: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.; to: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported. However, the skeletal phenotypes are polydactyly/clinodactyly only.
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams Added comment: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v0.14 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Clefting v1.59 ALX1 Eleanor Williams commented on gene: ALX1: Amber rating confirmed by Genomics England clinical team.
Paroxysmal central nervous system disorders v0.168 NKX2-1 Rebecca Foulger Publications for gene: NKX2-1 were set to 24555207
Paroxysmal central nervous system disorders v0.167 ISCA-37468-Loss Rebecca Foulger Classified Region: ISCA-37468-Loss as Red List (low evidence)
Paroxysmal central nervous system disorders v0.167 ISCA-37468-Loss Rebecca Foulger Added comment: Comment on list classification: Demoted CNV from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.167 ISCA-37468-Loss Rebecca Foulger Region: isca-37468-loss has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.166 TBP_CAG Rebecca Foulger Classified STR: TBP_CAG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.166 TBP_CAG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.166 TBP_CAG Rebecca Foulger Str: tbp_cag has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.165 DMPK_CTG Rebecca Foulger Classified STR: DMPK_CTG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.165 DMPK_CTG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.165 DMPK_CTG Rebecca Foulger Str: dmpk_ctg has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.164 CSTB_CCCCGCCCCGCG Rebecca Foulger Classified STR: CSTB_CCCCGCCCCGCG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.164 CSTB_CCCCGCCCCGCG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.164 CSTB_CCCCGCCCCGCG Rebecca Foulger Str: cstb_ccccgccccgcg has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.163 CACNA1A_CAG Rebecca Foulger Classified STR: CACNA1A_CAG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.163 CACNA1A_CAG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.163 CACNA1A_CAG Rebecca Foulger Str: cacna1a_cag has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.162 ATN1_CAG Rebecca Foulger Classified STR: ATN1_CAG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.162 ATN1_CAG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.162 ATN1_CAG Rebecca Foulger Str: atn1_cag has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.161 ATAD1 Rebecca Foulger Classified gene: ATAD1 as Green List (high evidence)
Paroxysmal central nervous system disorders v0.161 ATAD1 Rebecca Foulger Added comment: Comment on list classification: Upgraded ATAD1 from Amber to Green to match Green rating of other Hyperkeplexia genes (GLRA1, GLRB, SLC6A5). A comment from Robyn Labrum (University College London Hospitals) on behalf of London North GLH for the GMS Neurology specialist test group (received via email, September 30th 2019) notes that Hyperkeplexia genes should be included on the panel if the clinicians agree.
Paroxysmal central nervous system disorders v0.161 ATAD1 Rebecca Foulger Gene: atad1 has been classified as Green List (High Evidence).
Paroxysmal central nervous system disorders v0.160 VAMP2 Rebecca Foulger commented on gene: VAMP2: Review from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. This is a gene that was re-reviewed to reach a consensus- The comment by Robyn Labrum was expanded from previous comment. No new rating was submitted so the suggested rating remains as Green.
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Marked gene: KCNK18 as ready
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Gene: kcnk18 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Classified gene: KCNK18 as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber based on consensus of GLH review.
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Gene: kcnk18 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.159 KCNK18 Rebecca Foulger commented on gene: KCNK18: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Suggested rating: Amber. This is a gene that was re-reviewed to reach a consensus, and therefore the rating by Robyn Labrum has changed from Red to Amber.
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Marked gene: MOG as ready
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Gene: mog has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Classified gene: MOG as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber based on consensus GLH review- insufficient evidence for Green rating.
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Gene: mog has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.158 MOG Rebecca Foulger commented on gene: MOG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Suggested rating: None submitted but comment suggests Amber. This is a gene that was re-reviewed to reach a consensus, and therefore the rating by Robyn Labrum has changed from Green to Amber in PanelApp.
Paroxysmal central nervous system disorders v0.158 CACNB4 Rebecca Foulger Marked gene: CACNB4 as ready
Paroxysmal central nervous system disorders v0.158 CACNB4 Rebecca Foulger Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.158 CACNB4 Rebecca Foulger commented on gene: CACNB4: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Suggested rating: ? Amber. This review agrees with the recent downgrading of CACNB4 to Amber.
Paroxysmal central nervous system disorders v0.158 VAMP2 Robyn Labrum commented on gene: VAMP2: Recent publication (Salpietro et al. Am J Hum Genet. 2019 Apr 4;104(4):721-730) de novo mutations in 5 unrelated individuals phenotype neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. More severe phenotype includes additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. ?Better on intellectual disability or neurodevelopmental panel. Needs clinical input.
Paroxysmal central nervous system disorders v0.158 KCNK18 Robyn Labrum edited their review of gene: KCNK18: Added comment: Phenotype is migraine with aura in one family - amber.; Changed rating: AMBER
Paroxysmal central nervous system disorders v0.158 MOG Robyn Labrum edited their review of gene: MOG: Added comment: In a single large Spanish family across 4 generations. All 11 affected members studied and 1 who did not completely fulfill the diagnostic criteria for narcolepsy carried the mutation, whereas all 14 unaffected family members studied did not have the mutation. Is this sufficient evidence? If not then it should be amber.; Changed rating: AMBER
Paroxysmal central nervous system disorders v0.158 CACNB4 Robyn Labrum reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Catecholaminergic polymorphic VT v1.24 TECRL Ivone Leong Phenotypes for gene: TECRL were changed from to Ventricular tachycardia, catecholaminergic polymorphic, 3 614021
Catecholaminergic polymorphic VT v1.23 TECRL Ivone Leong Publications for gene: TECRL were set to
Paroxysmal central nervous system disorders v0.157 TBP_CAG Rebecca Foulger commented on STR: TBP_CAG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: TBP_CAG. Suggested rating: ?; Comments provided: Triplet repeat.
Paroxysmal central nervous system disorders v0.157 DMPK_CTG Rebecca Foulger commented on STR: DMPK_CTG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: DMPK_CTG. Suggested rating: ?; Comments provided: Triplet repeat.
Paroxysmal central nervous system disorders v0.157 CSTB_CCCCGCCCCGCG Rebecca Foulger commented on STR: CSTB_CCCCGCCCCGCG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: CSTB_CCCCGCCCCGCG. Suggested rating: ?; Comments provided: STR.
Paroxysmal central nervous system disorders v0.157 CACNA1A_CAG Rebecca Foulger commented on STR: CACNA1A_CAG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: CACNA1A_CAG. Suggested rating: ?; Comments provided: Triplet repeat. Primarily an ataxia gene.
Paroxysmal central nervous system disorders v0.157 ATN1_CAG Rebecca Foulger commented on STR: ATN1_CAG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: ATN1_CAG. Suggested rating: ?; Comments provided: Triplet repeat. Primarily an ataxia gene. Also ataxia is not episodic/paroxysmal in nature.
Disorders of sex development v2.1 MYRF Ivone Leong Classified gene: MYRF as Red List (low evidence)
Disorders of sex development v2.1 MYRF Ivone Leong Added comment: Comment on list classification: New gene added by reviewer. I have given this gene a Red rating as this was added after the panel has been signed-off by the GMS specialist group.
Disorders of sex development v2.1 MYRF Ivone Leong Gene: myrf has been classified as Red List (Low Evidence).
Structural eye disease v0.90 MYRF Ivone Leong Phenotypes for gene: MYRF were changed from to Nanophthalmos
Structural eye disease v0.89 MYRF Ivone Leong gene: MYRF was added
gene: MYRF was added to Structural eye disease. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYRF were set to 31266062
Structural eye disease v0.89 CSPP1 Ivone Leong Source NHS GMS was added to CSPP1.
Source Expert Review Red was added to CSPP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 WNT3 Ivone Leong Source NHS GMS was added to WNT3.
Source Expert Review Red was added to WNT3.
Publications for gene WNT3 were changed from to 14872406
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 TUBB Ivone Leong Source NHS GMS was added to TUBB.
Publications for gene TUBB were changed from to 26637975
Structural eye disease v0.89 SNX3 Ivone Leong Source NHS GMS was added to SNX3.
Source Expert Review Red was added to SNX3.
Publications for gene SNX3 were changed from to 12471201
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 SMG9 Ivone Leong Source NHS GMS was added to SMG9.
Publications for gene SMG9 were changed from to 27018474
Structural eye disease v0.89 SLC25A24 Ivone Leong Source NHS GMS was added to SLC25A24.
Publications for gene SLC25A24 were changed from to 29100093
Structural eye disease v0.89 TMEM5 Ivone Leong Source NHS GMS was added to TMEM5.
Source Expert Review Red was added to TMEM5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 RIPK4 Ivone Leong Source Expert Review Green was added to RIPK4.
Source NHS GMS was added to RIPK4.
Publications for gene RIPK4 were changed from to 22197489; 23074676; 22197488
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 RERE Ivone Leong Source Expert Review Green was added to RERE.
Source NHS GMS was added to RERE.
Publications for gene RERE were changed from to 27087320; 29330883
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 POMT2 Ivone Leong Source Expert Review Green was added to POMT2.
Publications for gene POMT2 were changed from 28815891; 15894594 to 15894594; 28815891
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 POMT1 Ivone Leong Publications for gene POMT1 were changed from 15037715; 12369018 to 12369018; 15037715
Structural eye disease v0.89 POMGNT2 Ivone Leong Source NHS GMS was added to POMGNT2.
Publications for gene POMGNT2 were changed from to 22958903
Structural eye disease v0.89 POMGNT1 Ivone Leong Source Expert Review Green was added to POMGNT1.
Source NHS GMS was added to POMGNT1.
Publications for gene POMGNT1 were changed from to 0961548; 19452620; 28765568; 11709191; 19679478
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 FANCL Ivone Leong Source NHS GMS was added to FANCL.
Publications for gene FANCL were changed from to 25754594
Structural eye disease v0.89 OLFM2 Ivone Leong Publications for gene OLFM2 were changed from 27844144 to 27844144; 17122126
Structural eye disease v0.89 NDUFB11 Ivone Leong Source NHS GMS was added to NDUFB11.
Source Expert Review Red was added to NDUFB11.
Publications for gene NDUFB11 were changed from to 25772934
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 MITF Ivone Leong Publications for gene MITF were changed from 27889061 to 7874168; 27889061; 23787126
Structural eye disease v0.89 MAPRE2 Ivone Leong Source Expert Review Green was added to MAPRE2.
Source NHS GMS was added to MAPRE2.
Publications for gene MAPRE2 were changed from to 26637975
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 KIF11 Ivone Leong Source NHS GMS was added to KIF11.
Publications for gene KIF11 were changed from to 27212378
Structural eye disease v0.89 KDM6A Ivone Leong Source NHS GMS was added to KDM6A.
Publications for gene KDM6A were changed from to 29617172; 29300383
Structural eye disease v0.89 IKBKG Ivone Leong Source NHS GMS was added to IKBKG.
Source Expert Review Red was added to IKBKG.
Publications for gene IKBKG were changed from to 31119873; 20499493; 30905793
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 GLI2 Ivone Leong Publications for gene GLI2 were changed from 17096318; 21204792 to 21204792; 17096318
Structural eye disease v0.89 FKTN Ivone Leong Source Expert Review Green was added to FKTN.
Source NHS GMS was added to FKTN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 FKRP Ivone Leong Publications for gene FKRP were changed from 20675713; 19955119; 20236121; 15121789 to 15121789; 20675713; 19955119; 20236121
Structural eye disease v0.89 FANCI Ivone Leong Source NHS GMS was added to FANCI.
Source Expert Review Red was added to FANCI.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 FANCE Ivone Leong Source NHS GMS was added to FANCE.
Source Expert Review Red was added to FANCE.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 FANCD2 Ivone Leong Source NHS GMS was added to FANCD2.
Source Expert Review Red was added to FANCD2.
Publications for gene FANCD2 were changed from to 12893777
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 FANCA Ivone Leong Source NHS GMS was added to FANCA.
Source Expert Review Red was added to FANCA.
Publications for gene FANCA were changed from to 8502512; 12913077
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 ESCO2 Ivone Leong Source Expert Review Green was added to ESCO2.
Source NHS GMS was added to ESCO2.
Publications for gene ESCO2 were changed from to 16380922; 19574259
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 DOCK6 Ivone Leong Source Expert Review Green was added to DOCK6.
Source NHS GMS was added to DOCK6.
Publications for gene DOCK6 were changed from to 25824905
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 DAG1 Ivone Leong Source NHS GMS was added to DAG1.
Publications for gene DAG1 were changed from to 25934851; 24052401
Structural eye disease v0.89 COX7B Ivone Leong Source NHS GMS was added to COX7B.
Publications for gene COX7B were changed from to 23122588
Structural eye disease v0.89 B3GALNT2 Ivone Leong Source Expert Review Green was added to B3GALNT2.
Source NHS GMS was added to B3GALNT2.
Publications for gene B3GALNT2 were changed from to 23453667
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 ALX3 Ivone Leong Source NHS GMS was added to ALX3.
Source Expert Review Red was added to ALX3.
Publications for gene ALX3 were changed from to 19409524
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 ALX1 Ivone Leong Source NHS GMS was added to ALX1.
Publications for gene ALX1 were changed from to 20451171; 23059813
Familial hypercholesterolaemia v1.25 APOB Sarah Leigh commented on gene: APOB
Additional findings health related v0.55 APOB Sarah Leigh edited their review of gene: APOB: Added comment: Familial Hypercholesterolemia 2, Familial ligand-defective apolipoprotein B-100 (FDB)
• Monoallelic
• Mostly missense variants
• Terminating variants unlikely to be involved
• Prevents the LDL particle from binding with cell surface receptors (LDLR)
• Increased levels of cholesterol in blood; Changed rating: GREEN
Genetic epilepsy syndromes v1.347 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.347 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted ALKBH8 from Green to Amber following review from Helen Lord on behalf of West Midlands, Oxford and Wessex GLH, and agreement from Richard Scott (Genomics England clinical team).
Genetic epilepsy syndromes v1.347 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.346 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Genetic epilepsy syndromes v1.345 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Genetic epilepsy syndromes v1.344 POLG2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept rating as Amber to match Helen Lord's review, but changed MOI from biallelic to 'BOTH biallelic and monoallelic' since (as Helen Lord notes) Young et al 2011 (PMID:21555342) report 4/11 patients with seizures as part of their phenotype and heterozygous variants in POLG2.
Genetic epilepsy syndromes v1.344 POLG2 Rebecca Foulger Mode of inheritance for gene: POLG2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Classified gene: SLC2A1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. SLC2A1 is associated with GLUT1 deficiency syndrome 1 and GLUT1 deficiency syndrome 2 on OMIM and Gene2Phenotype. There are >3 unrelated cases reported on OMIM. Therefore, there is enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Gene: slc2a1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.331 SLC2A1 Ivone Leong Classified gene: SLC2A1 as Green List (high evidence)
Inborn errors of metabolism v1.331 SLC2A1 Ivone Leong Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. SLC2A1 is associated with GLUT1 deficiency syndrome 1 and GLUT1 deficiency syndrome 2 on OMIM and Gene2Phenotype. There are >3 unrelated cases reported on OMIM. Therefore, there is enough evidence for this gene to be promoted to Green status.
Inborn errors of metabolism v1.331 SLC2A1 Ivone Leong Gene: slc2a1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Tag watchlist tag was added to gene: PIGP.
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Classified gene: PIGP as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and GLH-review by Helen Lord. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Gene: pigp has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Classified gene: TIMM50 as Green List (high evidence)
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Added comment: Comment on list classification: TIMM50 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but upgraded rating from Grey to Green following review of literature evidence. PMID:27573165 and PMID:31058414 report 5 patients from 3 families with a consistent ID and epilepsy phenotype accompanied by 3-methylglutaconic aciduria. In addition, PMID:30190335 report pyschomotor regression in their patient, and a conference abstract (Serajee et al. 2015) adds an additional case of developmental delay. Therefore ID appears a consistent phenotype of 3-methylglutaconic aciduria and with sufficient reported cases, a Green rating is appropriate.
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Gene: timm50 has been classified as Green List (High Evidence).
Intellectual disability v2.1053 TIMM50 Rebecca Foulger commented on gene: TIMM50
Additional findings health related v0.55 RET Ellen McDonagh Source Additional Findings was removed from RET.
Source ACMG was removed from RET.
Source Other was added to RET.
Mode of pathogenicity for gene RET 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
Additional findings health related v0.51 APOB Ellen McDonagh Source Additional Findings was removed from APOB.
Source ACMG was removed from APOB.
Source Other was added to APOB.
Mode of pathogenicity for gene APOB 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
Undiagnosed metabolic disorders v1.360 HSPA9 Sarah Leigh Classified gene: HSPA9 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.360 HSPA9 Sarah Leigh Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.359 HSPA9 Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants reported in Anemia, sideroblastic, 4 182170.
Undiagnosed metabolic disorders v1.359 HSPA9 Sarah Leigh Phenotypes for gene: HSPA9 were changed from Even-plus syndrome 616854 to Even-plus syndrome 616854
Undiagnosed metabolic disorders v1.358 HSPA9 Sarah Leigh gene: HSPA9 was added
gene: HSPA9 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328
Phenotypes for gene: HSPA9 were set to Even-plus syndrome 616854
Review for gene: HSPA9 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated cases.
Sources: Literature
Intellectual disability v2.1053 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX (MIM 617698) to 3-methylglutaconic aciduria, type IX, 617698
Inborn errors of metabolism v1.330 HSPA9 Sarah Leigh Added comment: Comment on phenotypes: EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia;Epiphyseal, Vertebral, Ear, Nose, plus associated findings.
Monoallelic variants reported in Anemia, sideroblastic, 4 182170.
Inborn errors of metabolism v1.330 HSPA9 Sarah Leigh Phenotypes for gene: HSPA9 were changed from EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia; Epiphyseal, Vertebral, Ear, Nose, plus associated findings to Even-plus syndrome 616854
Inborn errors of metabolism v1.329 HSPA9 Sarah Leigh Classified gene: HSPA9 as Amber List (moderate evidence)
Inborn errors of metabolism v1.329 HSPA9 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated cases.
Inborn errors of metabolism v1.329 HSPA9 Sarah Leigh Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Classified gene: FDX2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Added comment: Comment on list classification: Based on reviews from Carl Fratter and Zornitza Stark (below).
This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 3 unrelated familties; iron sulfur pathway. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Promoted from red to amber, based on the expert review by Zornitza Stark (Australian Genomics) and the literature. FDX2 is associated with a phenotype in OMIM and not Gene2Phenotype. PMID: 24281368 describes a patient born of consanguineous Jewish Moroccan patents with episodic mitochondrial myopathy without optic atrophy or reversible leukoencephalopathy. The authors identified a homozygous missense variant in this gene (M1L). PMID: 30010796 describes 6 patients from 2 apparently unrelated Brazilian familes from the same geographical region with episodic mitochondrial myopathy. All affected individuals had the same homozygous variant (P144L). No haplotype analysis was performed. As there are only 2 different variants reported in this gene and no haplotype analysis was performed in PMID: 30010796 it was decided that there is currently not enough evidence to promote this gene to green status.
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Gene: fdx2 has been classified as Green List (High Evidence).
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence)
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green following advice from Genomics England clinical team. The case reported in PMID:29961870 (Butler et al 2018) had delayed milestones and is reported to be non-verbal, which is a relevant phenotype for this panel. Overall 3 unrelated cases from 2 papers.
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.356 FDX2 Sarah Leigh gene: FDX2 was added
gene: FDX2 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: FDX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDX2 were set to 24281368; 28803783; 30010796
Phenotypes for gene: FDX2 were set to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy 251900
Review for gene: FDX2 was set to GREEN
Added comment: Sources: Literature
Inborn errors of metabolism v1.328 FDX2 Sarah Leigh Classified gene: FDX2 as Green List (high evidence)
Inborn errors of metabolism v1.328 FDX2 Sarah Leigh Added comment: Comment on list classification: Based on reviews from Carl Fratter and Zornitza Stark.
Inborn errors of metabolism v1.328 FDX2 Sarah Leigh Gene: fdx2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.327 FDX2 Sarah Leigh Phenotypes for gene: FDX2 were changed from No OMIM phenotype?Mitochondrial myopathy with lactic acidosis, association with, 255125 to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy 251900
Long QT syndrome v1.42 SCN5A Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Long QT syndrome v1.42 SCN5A Ivone Leong Mode of inheritance for gene: SCN5A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Long QT syndrome v1.41 KCNQ1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Long QT syndrome v1.41 KCNQ1 Ivone Leong Mode of inheritance for gene: KCNQ1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Long QT syndrome v1.40 KCNE1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Long QT syndrome v1.40 KCNE1 Ivone Leong Mode of inheritance for gene: KCNE1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Inborn errors of metabolism v1.326 FDX2 Sarah Leigh Publications for gene: FDX2 were set to
Inborn errors of metabolism v1.325 FDX2 Sarah Leigh Mode of inheritance for gene: FDX2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - childhood onset v1.179 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia to Childhood onset hereditary spastic paraplegia;R61
Hereditary spastic paraplegia - adult onset v0.156 Louise Daugherty List of related panels changed from to R60
Hydrocephalus v1.38 Louise Daugherty List of related panels changed from Hydrocephalus to Hydrocephalus;R86
Holoprosencephaly v1.23 Louise Daugherty List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85
Hypertrophic cardiomyopathy - teen and adult v1.76 TNNI3 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Hypertrophic cardiomyopathy - teen and adult v1.76 TNNI3 Ivone Leong Mode of inheritance for gene: TNNI3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy - teen and adult v1.75 GLA Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Hypertrophic cardiomyopathy - teen and adult v1.75 GLA Ivone Leong Mode of inheritance for gene: GLA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Short QT syndrome v1.23 CACNB2 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Short QT syndrome v1.23 CACNB2 Ivone Leong Mode of inheritance for gene: CACNB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.22 CACNA2D1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Short QT syndrome v1.22 CACNA2D1 Ivone Leong Mode of inheritance for gene: CACNA2D1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.21 SLC22A5 Ivone Leong Added comment: Comment on mode of inheritance: Phenotype changed due to expert reviews.
Short QT syndrome v1.21 SLC22A5 Ivone Leong Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Catecholaminergic polymorphic VT v1.22 RYR2 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Catecholaminergic polymorphic VT v1.22 RYR2 Ivone Leong Mode of inheritance for gene: RYR2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.63 TTN Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.63 TTN Ivone Leong Mode of inheritance for gene: TTN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.62 TCAP Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.62 TCAP Ivone Leong Mode of inheritance for gene: TCAP was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.61 SCN5A Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.61 SCN5A Ivone Leong Mode of inheritance for gene: SCN5A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.60 MYH7 Ivone Leong commented on gene: MYH7
Dilated Cardiomyopathy and conduction defects v1.60 MYH7 Ivone Leong Mode of inheritance for gene: MYH7 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.59 LMNA Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.59 LMNA Ivone Leong Mode of inheritance for gene: LMNA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.58 DES Ivone Leong commented on gene: DES
Additional findings health related v0.50 Ellen McDonagh Panel name changed from Genomics England Secondary Findings to Genomics England Additional Findings
Dilated Cardiomyopathy and conduction defects v1.58 DES Ivone Leong Mode of inheritance for gene: DES was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inborn errors of metabolism v1.324 DNM2 Sarah Leigh Publications for gene: DNM2 were set to
Undiagnosed metabolic disorders v1.351 DNM2 Sarah Leigh gene: DNM2 was added
gene: DNM2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DNM2 were set to Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.351 DNM2 Sarah Leigh gene: DNM2 was added
gene: DNM2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DNM2 were set to Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Hereditary ataxia and cerebellar anomalies - childhood onset v3.390 Louise Daugherty Changed child panels to: Congenital disorders of glycosylation; Ataxia and cerebellar anomalies - narrow panel
Thoracic aortic aneurysm or dissection v1.97 FLNA Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Thoracic aortic aneurysm or dissection v1.97 FLNA Ivone Leong Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm or dissection v1.96 COL3A1 Ivone Leong commented on gene: COL3A1
Thoracic aortic aneurysm or dissection v1.96 COL1A2 Ivone Leong commented on gene: COL1A2
Thoracic aortic aneurysm or dissection v1.96 BGN Ivone Leong commented on gene: BGN
Thoracic aortic aneurysm or dissection v1.96 COL3A1 Ivone Leong Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection v1.95 COL1A2 Ivone Leong Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection v1.94 BGN Ivone Leong Mode of inheritance for gene: BGN was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Inborn errors of metabolism v1.323 COX8A Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 variant reported in a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex I deficiency.
No further variants reported to date (30/09/2019).; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 variant reported in a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex I deficiency. The proband died from cardiorespiratory failure associated with infection and metabolic crisis at 12.5 years. No further variants reported to date (30/09/2019).
Undiagnosed metabolic disorders v1.350 COX8A Sarah Leigh gene: COX8A was added
gene: COX8A was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: COX8A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX8A were set to 26685157
Phenotypes for gene: COX8A were set to ?Mitochondrial complex IV deficiency 220110
Review for gene: COX8A was set to RED
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 variant reported in a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex I deficiency. The proband died from cardiorespiratory failure associated with infection and metabolic crisis at 12.5 years. No further variants reported to date (30/09/2019).
Sources: Literature
Intellectual disability v2.1051 KCNMA1 Catherine Snow Phenotypes for gene: KCNMA1 were changed from GENERALIZED EPILEPSY AND PAROXYSMAL DYSKINESIA to Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446
Inborn errors of metabolism v1.323 COX8A Sarah Leigh Classified gene: COX8A as Red List (low evidence)
Inborn errors of metabolism v1.323 COX8A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 variant reported in a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex I deficiency.
No further variants reported to date (30/09/2019).
Inborn errors of metabolism v1.323 COX8A Sarah Leigh Gene: cox8a has been classified as Red List (Low Evidence).
Intellectual disability v2.1050 KCNMA1 Catherine Snow Publications for gene: KCNMA1 were set to 15937479
Inborn errors of metabolism v1.322 COX8A Sarah Leigh Added comment: Comment on phenotypes: Leigh-like syndrome and epilepsy
Inborn errors of metabolism v1.322 COX8A Sarah Leigh Phenotypes for gene: COX8A were changed from Leigh-like syndrome and epilepsy to ?Mitochondrial complex IV deficiency 220110
Intellectual disability v2.1049 KCNMA1 Catherine Snow Mode of inheritance for gene: KCNMA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.1048 KCNMA1 Catherine Snow Classified gene: KCNMA1 as Amber List (moderate evidence)
Intellectual disability v2.1048 KCNMA1 Catherine Snow Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1047 KCNMA1 Catherine Snow reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31427379, 31152168; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, 617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inborn errors of metabolism v1.321 COQ7 Sarah Leigh Classified gene: COQ7 as Green List (high evidence)
Inborn errors of metabolism v1.321 COQ7 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies.
Inborn errors of metabolism v1.321 COQ7 Sarah Leigh Gene: coq7 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.349 COQ7 Sarah Leigh Classified gene: COQ7 as Green List (high evidence)
Undiagnosed metabolic disorders v1.349 COQ7 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies.
Undiagnosed metabolic disorders v1.349 COQ7 Sarah Leigh Gene: coq7 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.348 COQ7 Sarah Leigh gene: COQ7 was added
gene: COQ7 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to 26084283; 28409910
Phenotypes for gene: COQ7 were set to ?Coenzyme Q10 deficiency, primary, 8 616733
Review for gene: COQ7 was set to GREEN
Added comment: This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 3 unrelated individuals and functional studies. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Sources: Literature
Inborn errors of metabolism v1.320 COQ7 Sarah Leigh Added comment: Comment on phenotypes: complex multisystem presentation;primary coenzyme Q10 deficiency
Inborn errors of metabolism v1.320 COQ7 Sarah Leigh Phenotypes for gene: COQ7 were changed from complex multisystem presentation; primary coenzyme Q10 deficiency to ?Coenzyme Q10 deficiency, primary, 8 616733
Inborn errors of metabolism v1.319 COQ7 Sarah Leigh Publications for gene: COQ7 were set to PMID: 26084283
Possible mitochondrial disorder - nuclear genes v1.12 COQ7 Sarah Leigh reviewed gene: COQ7: Rating: ; Mode of pathogenicity: None; Publications: 26084283, 28409910; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v2.0 COQ7 Sarah Leigh edited their review of gene: COQ7: Changed publications: 28409910, 26084283
Inborn errors of metabolism v1.318 MT-CO3 Louise Daugherty Phenotypes for gene: MT-CO3 were changed from to LEBER OPTIC ATROPHY; SEIZURES AND LACTIC ACIDOSIS; MITOCHONDRIAL COMPLEX IV DEFICIENCY
Inborn errors of metabolism v1.317 CEP89 Sarah Leigh reviewed gene: CEP89: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inborn errors of metabolism v1.317 MT-CO3 Louise Daugherty Publications for gene: MT-CO3 were set to LEBER OPTIC ATROPHY; SEIZURES AND LACTIC ACIDOSIS; MITOCHONDRIAL COMPLEX IV DEFICIENCY
Optic neuropathy v1.120 TMEM126A Sarah Leigh reviewed gene: TMEM126A: Rating: ; Mode of pathogenicity: None; Publications: 31119195; Phenotypes: ; Mode of inheritance: None
Optic neuropathy v1.120 TMEM126A Sarah Leigh Publications for gene: TMEM126A were set to 19327736; 20405026; 22815638; 30961538
Inborn errors of metabolism v1.316 TMEM126A Sarah Leigh Added comment: Comment on phenotypes: Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Inborn errors of metabolism v1.316 TMEM126A Sarah Leigh Phenotypes for gene: TMEM126A were changed from Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Optic atrophy-7, 612989; Optic atrophy 7; 612989 to Optic atrophy 7 612989
Inborn errors of metabolism v1.315 TMEM126A Sarah Leigh Classified gene: TMEM126A as Red List (low evidence)
Inborn errors of metabolism v1.315 TMEM126A Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Associated with the phenotype Optic atrophy 7 612989 in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in unrelated cases. The red rating is based on Helen Britain's opinion that, the phenotype of Optic atrophy 7 612989 will not present via a metabolic team. TMEM126A is green on the Optic neuropathy panel
Inborn errors of metabolism v1.315 TMEM126A Sarah Leigh Gene: tmem126a has been classified as Red List (Low Evidence).
Undiagnosed metabolic disorders v1.347 TMEM126A Sarah Leigh Classified gene: TMEM126A as Red List (low evidence)
Undiagnosed metabolic disorders v1.347 TMEM126A Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with the phenotype Optic atrophy 7 612989 in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in unrelated cases.
The red rating is based on Helen Britain's opinion that, the phenotype of Optic atrophy 7 612989 will not present via a metabolic team. TMEM126A is green on the Optic neuropathy panel.
Undiagnosed metabolic disorders v1.347 TMEM126A Sarah Leigh Gene: tmem126a has been classified as Red List (Low Evidence).
Undiagnosed metabolic disorders v1.346 TMEM126A Sarah Leigh Added comment: Comment on phenotypes: Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Undiagnosed metabolic disorders v1.346 TMEM126A Sarah Leigh Phenotypes for gene: TMEM126A were changed from Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Optic atrophy 7; 612989 to Optic atrophy 7 612989
Inborn errors of metabolism v1.314 TMEM126A Sarah Leigh Publications for gene: TMEM126A were set to 27604308
Undiagnosed metabolic disorders v1.345 TMEM126A Sarah Leigh Publications for gene: TMEM126A were set to 27604308
Additional findings health related v0.49 Ellen McDonagh Panel status changed from internal to public
Paroxysmal central nervous system disorders v0.157 CACNB4 Rebecca Foulger Classified gene: CACNB4 as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v0.157 CACNB4 Rebecca Foulger Added comment: Comment on list classification: Downgraded CACNB4 rating from Green to Amber based on GLH review. The most recent comments from Andrea Nemeth and Jonathan William agree that there is only weak evidence to support a gene:disease association. The current evidence comes from PMID:10762541 which reports 1 family (plus another family with epilepsy), and a mouse model.
Paroxysmal central nervous system disorders v0.157 CACNB4 Rebecca Foulger Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.156 CACNB4 Rebecca Foulger commented on gene: CACNB4: Reviews by Andrea Nemeth and Jonathan William were uploaded (September 29th 2019) on their behalf based on email discussion of these genes to reach a consensus on the rating. Comments were received over email, and I uploaded an Amber review based on their comments.
Paroxysmal central nervous system disorders v0.156 CACNB4 Jonathan Williams reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Paroxysmal central nervous system disorders v0.155 CACNB4 Andrea Nemeth reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Movement disorders - childhood onset v4.388 Louise Daugherty Changed child panels to: Dystonia - childhood onset; Neurological ciliopathies
Intellectual disability v2.1047 SMG9 Konstantinos Varvagiannis reviewed gene: SMG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 27018474, 31390136; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset movement disorder v0.125 PDE2A Louise Daugherty changed review comment from: Review and rating submitted by James Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group. ; to: Review and rating submitted by James Polke, unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.
Adult onset movement disorder v0.125 VAMP2 Louise Daugherty changed review comment from: Review and rating submitted by James Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group. ; to: Review and rating submitted by James Polke, unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.
Adult onset movement disorder v0.125 TIMM8A Louise Daugherty Mode of inheritance for gene: TIMM8A was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset movement disorder v0.124 TBK1 Louise Daugherty Mode of inheritance for gene: TBK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset movement disorder v0.123 TBK1 Louise Daugherty Phenotypes for gene: TBK1 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 4, 616439
Adult onset movement disorder v0.122 RNF216 Louise Daugherty Mode of inheritance for gene: RNF216 was changed from to BIALLELIC, autosomal or pseudoautosomal
Adult onset movement disorder v0.121 RNF216 Louise Daugherty Phenotypes for gene: RNF216 were changed from to Cerebellar ataxia and hypogonadotropic hypogonadism, 212840
Adult onset movement disorder v0.120 GTPBP2 Louise Daugherty Mode of inheritance for gene: GTPBP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Adult onset movement disorder v0.120 GTPBP2 Louise Daugherty Mode of inheritance for gene: GTPBP2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Adult onset movement disorder v0.119 GTPBP2 Louise Daugherty Phenotypes for gene: GTPBP2 were changed from to Jaberi-Elahi syndrome, 617988; Dystonia
Adult onset movement disorder v0.118 AFG3L2 Louise Daugherty Mode of inheritance for gene: AFG3L2 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset movement disorder v0.117 AFG3L2 Louise Daugherty Phenotypes for gene: AFG3L2 were changed from Dystonia to Dystonia; Spastic ataxia 5, autosomal recessive, 614487; Spinocerebellar ataxia 28, 610246
Adult onset movement disorder v0.116 ACTB Louise Daugherty Mode of inheritance for gene: ACTB was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset movement disorder v0.115 ACTB Louise Daugherty Phenotypes for gene: ACTB were changed from Dystonia, juvenile-onset, 607371Baraitser-Winter syndrome 1, 243310 to Dystonia, juvenile-onset, 607371; Baraitser-Winter syndrome 1, 243310
Intellectual disability v2.1047 METTL5 Konstantinos Varvagiannis edited their review of gene: METTL5: Set current diagnostic: yes
Intellectual disability v2.1047 METTL5 Konstantinos Varvagiannis gene: METTL5 was added
gene: METTL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Phenotypes for gene: METTL5 were set to Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality
Penetrance for gene: METTL5 were set to Complete
Review for gene: METTL5 was set to GREEN
Added comment: [1] - PMID: 29302074 :
In a WES/WGS study of 404 consanguineous families with two or more offspring affected by ID, Hu et al. identified two sibs homozygous for a METTL5 missense variant [NM_014168:c.182G>A / p.Gly61Asp]. These 2 subjects, born to first cousin parents from Iran, presented with early learning impairment, aggressive behaviour, severe microcephaly (-7SD and -8SD) and ID formally evaluated to be in the severe range. Sanger confirmation of variants and segregation studies were performed for all available and informative members in families participating in the study. In silico predictions were all in favour of a deleterious effect (PolyPhen2, MutationTaster, SIFT, CADD) and the variant was absent from ExAC. The effect of the specific variant was studied in ref. 2 (below).

[2] - DOI: 10.1016/j.ajhg.2019.09.007 :
Richard et al. (2019) reported on 5 additional individuals from 2 consanguineous families. Common phenotype consisted of speech delay, moderate/severe ID (4/4), microcephaly (4/4 - though milder than in the first report), behavioral problems (ADHD, aggressiveness, autistic feat.) and possibly some overlapping facial features (nose and ear abnormalities). 3 sibs from the 1st family, from Pakistan, were homozygous for a frameshift variant (NM_014167.2:c.344_345delGA / p.Arg115Asnfs*19) while sibs from the 2nd family, from Yemen, were homozygous for p.Lys191Valfs*1 (c.571_572delAA). Confirmation and segregation studies supported a role for the variants.

The authors performed additional studies for METTL5 and all 3 variants reported to date, notably:
- Based on RNA-seq data from the Allen Brain Atlas, METTL5 is expressed in the developing and adult human brain (incl. cerebellar cortex, hippocampus and striatum).
- Immunostaining in mouse brain demonstrated ubiquitous expression (postnatal day 30).
- In rat hippocampal neurons, enrichment of METTL5 was found in the soma, the nucleus and pre- and post- synaptic regions.
- Myc-/GFP-tagged METTL5 wt or mutants were transiently expressed in COS7 cells, and were found in the cytoplasm and nucleus. Levels of the 2 frameshift variants were significantly reduced compared with wt, although this was not the case for Gly61Asp.
- Upon transfection of rat hippocampal neurons, METTL5-GFP tagged wt and mt proteins showed similar localicalization in nucleus and dendrites.
- Western blot on HEK293T cells transfected with Myc-METTL5 wt or mt constructs demonstrated decreased amounts for the frameshift (but not the missense) variants while comparison after addition of a proteasome inhibitor or cyclohexamide suggested that this is not probably due to decreased mutant protein - rather than mRNA (NMD) - stability.
- In zebrafish, morpholino knockdown of mettl5 led to reduced head size and head/body ratio (reproducing the microcephaly phenotype) and curved tails. Forebrain and midbrain sizes were also significantly reduced.

Based on the ACMG criteria, Gly61Asp is classified as VUS (PM2, PP1, PP3) and the frameshift ones as pathogenic (PS3, PM2, PM4, PP1, PP3).

The authors comment that METTL5 is an uncharacterized member of the methyltransferase superfamily (of 33 METTL proteins). Variants in other methyltransferase-like genes (mainly METTL23) have been associated with ID, while various histone-/DNA-/tRNA-/rRNA- methyltransferases such as EHMT1, DNMT3A, NSUN2, FTSJ1, etc have been implicated in ID. Given the role of methyltransferases in neurodevelopment and neuroplasticity, homology comparisons suggesting presence of relevant domain in METTL5 and accumulation of the protein in the nucleus, a role as epigenetic regulator is proposed (see also ref. 3).

[3] - Conference abstract by Helmut et al. ["A novel m6A RNA methyltransferase in mammals - characterization of Mettl5 mutant mice in the German Mouse Clinic" - Oral presentation in the 33rd International Mammalian Genome Conference Sept. 2019 - available at : https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf ]
The group using an in vitro methyltransferase assay, identified METTL5 as a m6A RNA methyltransferase. Generation of Mettl5-knockout mice using the CRISPR/Cas technology, suggested that homozygous mice are subviable, with lower body mass and abnormal growth of nasal bones in half. Homozygous mice were hypoactive and hypoexploratory during an open field test at the age of 8 weeks, while further alterations were observed in neurological functions. Phenotypic deviations were absent or very mild in heterozygous animals. As a result, the mouse model appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation).

----
There is no associated entry in OMIM (neither for the gene nor for a related disorder). G2P does not list any phenotype for this gene, either.

METTL5 is included in the SysID database as a current primary ID gene (cited: 27457812, 28097321 / Given the shared co-authors with the study by Richard et al. as well as the overlapping variants, these articles probably report on the same individuals recently described in more detail).

The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
----

Overall, METTL5 could be considered for inclusion in the ID panel probably as green (3 families, 3 variants, segregation, suggested role of the gene, relevant expression patterns, some evidence at the variant-level, zebrafish and mouse models) or amber (underlying effect of Gly61Asp unknown and variant classified as VUS).
Sources: Literature
Intellectual disability v2.1047 CSDE1 Konstantinos Varvagiannis gene: CSDE1 was added
gene: CSDE1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CSDE1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSDE1 were set to http://doi.org/10.1126/sciadv.aax2166
Phenotypes for gene: CSDE1 were set to Autism; Global developmental delay; Intellectual disability
Penetrance for gene: CSDE1 were set to unknown
Review for gene: CSDE1 was set to GREEN
Added comment: Guo et al. (2019 - DOI: 10.1126/sciadv.aax2166) report on 18 individuals from 18 unrelated families, with heterozygous likely gene disrupting (stopgain/frameshift/spice-site) CSDE1 variants.

Initial sequencing with MIPs found in 3 individuals from an autism cohort (4045 probands), while subsequent targeted sequencing of a larger cohort (autism spectrum/ID network) led to identification of 5 additional relevant individuals and Genematcher/collaborations a further 10 (the latter by WES).

Consistent phenotypes included ASD (10 of 15 formally evaluated), DD (motor: 15/17 - speech: 17/17) and ID (mild to severe in 14 of 16 assessed, in further 2 in the below-average range). Recurrent seizures or epilepsy were reported for 7 of 16 patients. Other variable features were anxiety or ADHD, increased OFC, ocular, hand and MRI anomalies.

The study was mainly focused on LGD variants with p.R123* (NM_001242891.1:c.367C>T) being a reccurrent one, found in 3 families.

8 of these variants were de novo, 8 further inherited (often from a less severely affected parent, although parental neuropsychiatric status was not available for individuals from all 3 groups). In 2 cases inheritance was unknown (only 1 parental sample available).

3 individuals with de novo missense variants were also identified. Features in those individuals also included ASD and/or DD and ID (2/3) [Table S1].

Arguments to support involvement of the CSDE1 variants included the:
- role of the gene encoding an RNA binding protein implicated in neuronal migration/differentiation (cited : 24012837, 29129916),
- statistically significant burden of the variants in the cohorts examined,
- relevant CSDE1 intolerance scores (pLI of 1 and %RVIS of 6.18),
- relevant human (mRNA) / mouse (protein) spatial and temporal expression patterns,
- exclusion of apparent alternative diagnoses to the extent possible in many subjects with CNVs/SNVs/ROH of uncertain significance in very few,
- cosegregation with rather similar neuropsychiatric phenotypes in case of carrier parents,
- enrichment of ASD-related genes (and FMRP targets) among CSDE1-binding targets,
- suppression of Ctnnb1 expression (at the protein level) affecting Wnt/β-catenin signalling,
- effect of knockdown and/or mutants in mouse (shRNA) and Drosophila (mt and siRNA) models affecting synapse formation and synaptic transmission,
- rescue of many of the previous phenotypes by expression of human CSDE1 (mice), expression of stabilized β-Catenin (mice) or RNAi-stable-dUNR (Drosophila) [also supporting LoF as the underlying effect of variants].

CSDE1 is not commonly included in gene panels for ID offered by diagnostic laboratories. There is no associated phenotype in OMIM/G2P.

Overall, this gene could be considered for inclusion in the ID panel probably as green (or amber).
Sources: Literature
Laterality disorders and isomerism v0.51 RSPH4A Louise Daugherty Classified gene: RSPH4A as Red List (low evidence)
Laterality disorders and isomerism v0.51 RSPH4A Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.51 RSPH4A Louise Daugherty Gene: rsph4a has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.50 RSPH9 Louise Daugherty Classified gene: RSPH9 as Red List (low evidence)
Laterality disorders and isomerism v0.50 RSPH9 Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.50 RSPH9 Louise Daugherty Gene: rsph9 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.49 RSPH3 Louise Daugherty Classified gene: RSPH3 as Red List (low evidence)
Laterality disorders and isomerism v0.49 RSPH3 Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.49 RSPH3 Louise Daugherty Gene: rsph3 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.48 RSPH1 Louise Daugherty Classified gene: RSPH1 as Red List (low evidence)
Laterality disorders and isomerism v0.48 RSPH1 Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.48 RSPH1 Louise Daugherty Gene: rsph1 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.47 GAS8 Louise Daugherty Classified gene: GAS8 as Red List (low evidence)
Laterality disorders and isomerism v0.47 GAS8 Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.47 GAS8 Louise Daugherty Gene: gas8 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.46 DRC1 Louise Daugherty Classified gene: DRC1 as Red List (low evidence)
Laterality disorders and isomerism v0.46 DRC1 Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.46 DRC1 Louise Daugherty Gene: drc1 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.45 CCNO Louise Daugherty Classified gene: CCNO as Red List (low evidence)
Laterality disorders and isomerism v0.45 CCNO Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.45 CCNO Louise Daugherty Gene: ccno has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.44 HYDIN Louise Daugherty Classified gene: HYDIN as Red List (low evidence)
Laterality disorders and isomerism v0.44 HYDIN Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.44 HYDIN Louise Daugherty Gene: hydin has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v0.43 DNAJB13 Louise Daugherty Classified gene: DNAJB13 as Red List (low evidence)
Laterality disorders and isomerism v0.43 DNAJB13 Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Red. Respiratory Specialist Test Group commented that this gene is NOT associated with laterality disorders.
Laterality disorders and isomerism v0.43 DNAJB13 Louise Daugherty Gene: dnajb13 has been classified as Red List (Low Evidence).
Pneumothorax - familial v1.18 COL3A1 Louise Daugherty Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos Syndrome, type IV to Ehlers-Danlos Syndrome, type IV; Ehlers-Danlos syndrome, vascular type, 130050
Respiratory ciliopathies including non-CF bronchiectasis v0.156 RAG2 Louise Daugherty Phenotypes for gene: RAG2 were changed from Combined immunodeficiency (CID); Combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A) to Combined immunodeficiency (CID); Combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A); early onset and progressive lung disease
Respiratory ciliopathies including non-CF bronchiectasis v0.155 RAG1 Louise Daugherty Phenotypes for gene: RAG1 were changed from Combined immunodeficiency (CID); Combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A) to Combined immunodeficiency (CID); Combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A); early onset and progressive lung disease
Inborn errors of metabolism v1.313 PDK3 Sarah Leigh Classified gene: PDK3 as Amber List (moderate evidence)
Inborn errors of metabolism v1.313 PDK3 Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least three unrelated cases, together with functional studies.
Inborn errors of metabolism v1.313 PDK3 Sarah Leigh Gene: pdk3 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.344 PDK3 Sarah Leigh Classified gene: PDK3 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.344 PDK3 Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least three unrelated cases, together with functional studies.
Undiagnosed metabolic disorders v1.344 PDK3 Sarah Leigh Gene: pdk3 has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.312 PDK3 Sarah Leigh Added comment: Comment on mode of pathogenicity: A gain of function mechanism has been reported for the p.R158H variant, resulting in a more activity than the wild-type kinase (PMID: 23297365).
Inborn errors of metabolism v1.312 PDK3 Sarah Leigh Mode of pathogenicity for gene: PDK3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Undiagnosed metabolic disorders v1.343 PDK3 Sarah Leigh Added comment: Comment on mode of pathogenicity: A gain of function mechanism has been reported for the p.R158H variant, resulting in a more activity than the wild-type kinase (PMID: 23297365).
Undiagnosed metabolic disorders v1.343 PDK3 Sarah Leigh Mode of pathogenicity for gene: PDK3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Undiagnosed metabolic disorders v1.342 PDK1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.
Inborn errors of metabolism v1.311 PDK1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.
Undiagnosed metabolic disorders v1.342 NDUFA12 Sarah Leigh changed review comment from: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Inborn errors of metabolism v1.311 NDUFA12 Sarah Leigh changed review comment from: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Inborn errors of metabolism v1.311 MRPS16 Sarah Leigh changed review comment from: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.
Undiagnosed metabolic disorders v1.342 MRPS16 Sarah Leigh changed review comment from: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.
Inborn errors of metabolism v1.311 COX4I2 Sarah Leigh changed review comment from: Comment on list classification: This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).
Undiagnosed metabolic disorders v1.342 COX4I2 Sarah Leigh changed review comment from: Comment on list classification: This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).
Inborn errors of metabolism v1.311 COA5 Sarah Leigh changed review comment from: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. No additional variants have been reported to date.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Associated with phenotype in OMIM and as a possible G2P. At least 1 variant reported.
Undiagnosed metabolic disorders v1.342 COA5 Sarah Leigh changed review comment from: Associated with phenotype in OMIM and as a possible G2P. At least 1 variant reported.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Associated with phenotype in OMIM and as a possible G2P. At least 1 variant reported.
Inborn errors of metabolism v1.311 COA5 Sarah Leigh changed review comment from: Comment on list classification: No additional variants have been reported to date.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. No additional variants have been reported to date.
Undiagnosed metabolic disorders v1.342 ATP5E Sarah Leigh changed review comment from: Comment on list classification: Updated information and Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Updated information and Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.
Inborn errors of metabolism v1.311 ATP5E Sarah Leigh changed review comment from: Comment on list classification: Based on Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Based on Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.
Undiagnosed metabolic disorders v1.342 ATP5A1 Sarah Leigh changed review comment from: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys in this publication have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys in this publication have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Inborn errors of metabolism v1.311 ATP5A1 Sarah Leigh changed review comment from: Comment on list classification: The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys mentioned in this article have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Primary immunodeficiency v1.132 STAT4 Louise Daugherty changed review comment from: New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID so was rated as Red by the group.; to: Potential risk allele for SLE. New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID so was rated as Red by the group.
Primary immunodeficiency v1.132 STAT4 Louise Daugherty reviewed gene: STAT4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 SAMD3 Louise Daugherty reviewed gene: SAMD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 PTPN22 Louise Daugherty reviewed gene: PTPN22: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 POMP Louise Daugherty reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 IL31RA Louise Daugherty changed review comment from: Not clearly a primary immunodeficiency. New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID.; to: Not clearly a primary immunodeficiency. New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID so was rated as Red by the group.
Primary immunodeficiency v1.132 LYZ Louise Daugherty reviewed gene: LYZ: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v1.132 IL31RA Louise Daugherty changed review comment from: New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID.; to: Not clearly a primary immunodeficiency. New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID.
Inborn errors of metabolism v1.311 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308; 26801680; 28902413
Undiagnosed metabolic disorders v1.342 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308; 26801680; 28902413
Inborn errors of metabolism v1.310 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308
Primary immunodeficiency v1.132 IL31RA Louise Daugherty changed review comment from: New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID.; to: New gene added after review of potential new genes for PID by the Immunology Test Group. This gene was noted as being only theoretical for PID.
Undiagnosed metabolic disorders v1.341 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308; 23297365
Primary immunodeficiency v1.132 IL31RA Louise Daugherty commented on gene: IL31RA
Undiagnosed metabolic disorders v1.340 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308
Undiagnosed metabolic disorders v1.339 PDK3 Sarah Leigh Added comment: Comment on phenotypes: Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism)
Undiagnosed metabolic disorders v1.339 PDK3 Sarah Leigh Phenotypes for gene: PDK3 were changed from Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism); ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905 to ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905
Inborn errors of metabolism v1.309 PDK3 Sarah Leigh Added comment: Comment on phenotypes: Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism)
Inborn errors of metabolism v1.309 PDK3 Sarah Leigh Phenotypes for gene: PDK3 were changed from ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905; ?Charcot-Marie-Tooth disease, X-linked dominant, 6, 300905; Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism) to ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905
Primary immunodeficiency v1.132 STAT4 Louise Daugherty Source London North GLH was added to STAT4.
Source Expert Review Red was added to STAT4.
Source NHS GMS was added to STAT4.
Rating Changed from No List (delete) to Red List (low evidence)
Primary immunodeficiency v1.132 SAMD3 Louise Daugherty Source London North GLH was added to SAMD3.
Source Expert Review Red was added to SAMD3.
Source NHS GMS was added to SAMD3.
Rating Changed from No List (delete) to Red List (low evidence)
Primary immunodeficiency v1.132 PTPN22 Louise Daugherty Source London North GLH was added to PTPN22.
Source Expert Review Red was added to PTPN22.
Source NHS GMS was added to PTPN22.
Source North West GLH was added to PTPN22.
Rating Changed from No List (delete) to Red List (low evidence)
Primary immunodeficiency v1.132 POMP Louise Daugherty Source London North GLH was added to POMP.
Source NHS GMS was added to POMP.
Source North West GLH was added to POMP.
Source Expert Review Green was added to POMP.
Rating Changed from No List (delete) to Green List (high evidence)
Primary immunodeficiency v1.132 LYZ Louise Daugherty Source London North GLH was added to LYZ.
Source Expert Review Red was added to LYZ.
Source NHS GMS was added to LYZ.
Rating Changed from No List (delete) to Red List (low evidence)
Primary immunodeficiency v1.132 IL31RA Louise Daugherty Source London North GLH was added to IL31RA.
Source Expert Review Red was added to IL31RA.
Source NHS GMS was added to IL31RA.
Rating Changed from No List (delete) to Red List (low evidence)
Primary immunodeficiency v1.131 STAT4 Louise Daugherty gene: STAT4 was added
gene: STAT4 was added to Primary immunodeficiency. Sources:
Mode of inheritance for gene: STAT4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: STAT4 were set to {Systemic lupus erythematosus, susceptibility to, 11}, 612253
Primary immunodeficiency v1.131 SAMD3 Louise Daugherty gene: SAMD3 was added
gene: SAMD3 was added to Primary immunodeficiency. Sources:
Mode of inheritance for gene: SAMD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SAMD3 were set to HLH, abnormal GRA
Primary immunodeficiency v1.131 PTPN22 Louise Daugherty gene: PTPN22 was added
gene: PTPN22 was added to Primary immunodeficiency. Sources:
Mode of inheritance for gene: PTPN22 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PTPN22 were set to {Systemic lupus erythematosus susceptibility to}; Lupus susceptibility
Primary immunodeficiency v1.131 POMP Louise Daugherty gene: POMP was added
gene: POMP was added to Primary immunodeficiency. Sources:
Mode of inheritance for gene: POMP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POMP were set to 26524591
Phenotypes for gene: POMP were set to CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Proteasome-associated autoinflammatory syndrome 2, 618048
Primary immunodeficiency v1.131 LYZ Louise Daugherty gene: LYZ was added
gene: LYZ was added to Primary immunodeficiency. Sources:
Mode of inheritance for gene: LYZ was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: LYZ were set to Amyloidosis, renal, 105200
Primary immunodeficiency v1.131 IL31RA Louise Daugherty gene: IL31RA was added
gene: IL31RA was added to Primary immunodeficiency. Sources:
Mode of inheritance for gene: IL31RA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: IL31RA were set to ?Amyloidosis, primary localized cutaneous 2, 613955
Inborn errors of metabolism v1.308 PDK1 Sarah Leigh Classified gene: PDK1 as Red List (low evidence)
Inborn errors of metabolism v1.308 PDK1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.
Inborn errors of metabolism v1.308 PDK1 Sarah Leigh Gene: pdk1 has been classified as Red List (Low Evidence).
Undiagnosed metabolic disorders v1.338 PDK1 Sarah Leigh Classified gene: PDK1 as Red List (low evidence)
Undiagnosed metabolic disorders v1.338 PDK1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.
Undiagnosed metabolic disorders v1.338 PDK1 Sarah Leigh Gene: pdk1 has been classified as Red List (Low Evidence).
Catecholaminergic polymorphic VT v1.21 TECRL James Eden reviewed gene: TECRL: Rating: AMBER; Mode of pathogenicity: None; Publications: 27861123; Phenotypes: Ventricular tachycardia, catecholaminergic polymorphic, 3 614021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v1.20 SLC22A5 James Eden reviewed gene: SLC22A5: Rating: RED; Mode of pathogenicity: None; Publications: 26190315; Phenotypes: Carnitine deficiency, systemic primary 212140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.307 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 27604308
Undiagnosed metabolic disorders v1.337 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 27604308
Inborn errors of metabolism v1.306 NDUFA12 Sarah Leigh Added comment: Comment on phenotypes: Complex I (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Inborn errors of metabolism v1.306 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency, 256000; Complex I (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Leigh syndrome due to mitochondrial complex 1 deficiency,256000; Isolated complex I deficiency to ?Mitochondrial complex I deficiency, nuclear type 23 618244
Undiagnosed metabolic disorders v1.336 NDUFA12 Sarah Leigh Added comment: Comment on phenotypes: Complex I (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Undiagnosed metabolic disorders v1.336 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from Complex I (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Leigh syndrome due to mitochondrial complex 1 deficiency,256000 to ?Mitochondrial complex I deficiency, nuclear type 23 618244
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Deleted their comment
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Inborn errors of metabolism v1.305 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.335 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.335 NDUFA12 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Undiagnosed metabolic disorders v1.335 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Brugada syndrome v1.45 SCN5A Ivone Leong commented on gene: SCN5A
Undiagnosed metabolic disorders v1.334 MRPS16 Sarah Leigh Publications for gene: MRPS16 were set to 27604308; 28749478; 15505824
Undiagnosed metabolic disorders v1.333 MRPS16 Sarah Leigh Classified gene: MRPS16 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.333 MRPS16 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.
Undiagnosed metabolic disorders v1.333 MRPS16 Sarah Leigh Gene: mrps16 has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.304 MRPS16 Sarah Leigh Classified gene: MRPS16 as Amber List (moderate evidence)
Inborn errors of metabolism v1.304 MRPS16 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.
Inborn errors of metabolism v1.304 MRPS16 Sarah Leigh Gene: mrps16 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.332 MRPS16 Sarah Leigh Added comment: Comment on phenotypes: Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); CORPUS CALLOSUM, AGENESIS OF, WITH DYSMORPHISM AND FATAL LACTIC ACIDOSIS
Undiagnosed metabolic disorders v1.332 MRPS16 Sarah Leigh Phenotypes for gene: MRPS16 were changed from Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Combined oxidative phosphorylation deficiency 2, 610498; CORPUS CALLOSUM, AGENESIS OF, WITH DYSMORPHISM AND FATAL LACTIC ACIDOSIS to Combined oxidative phosphorylation deficiency 2 610498
Inborn errors of metabolism v1.303 MRPS16 Sarah Leigh Added comment: Comment on phenotypes: Multiple respiratory chain complex deficiencies (disorders of protein synthesis);Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only));CORPUS CALLOSUM, AGENESIS OF, WITH DYSMORPHISM AND FATAL LACTIC ACIDOSIS
Inborn errors of metabolism v1.303 MRPS16 Sarah Leigh Phenotypes for gene: MRPS16 were changed from Combined oxidative phosphorylation deficiency 2, 610498; Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); CORPUS CALLOSUM, AGENESIS OF, WITH DYSMORPHISM AND FATAL LACTIC ACIDOSIS to Combined oxidative phosphorylation deficiency 2 610498
Undiagnosed metabolic disorders v1.331 MRPS16 Sarah Leigh Publications for gene: MRPS16 were set to 27604308
Inborn errors of metabolism v1.302 MRPS16 Sarah Leigh Publications for gene: MRPS16 were set to 27604308
Hypertrophic cardiomyopathy - teen and adult v1.74 CACNA1C James Eden reviewed gene: CACNA1C: Rating: AMBER; Mode of pathogenicity: None; Publications: 26253506; Phenotypes: Brugada syndrome 3 611875, Long QT syndrome 8 618447, Timothy syndrome 601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hypertrophic cardiomyopathy - teen and adult v1.74 ACTN2 James Eden reviewed gene: ACTN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 20022194, 27287556; Phenotypes: Cardiomyopathy, dilated, 1AA, with or without LVNC 612158, Cardiomyopathy, hypertrophic, 23, with or without LVNC 612158; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated cardiomyopathy - adult and teen v0.46 NEXN James Eden edited their review of gene: NEXN: Changed rating: AMBER
Dilated cardiomyopathy - adult and teen v0.46 MYBPC3 James Eden Deleted their comment
Dilated cardiomyopathy - adult and teen v0.46 MYBPC3 James Eden edited their review of gene: MYBPC3: Added comment: Gene currently tested on Manchester DCM panel. Currently no stated association with DCM on ClinGen Knowledge Base. Cardiodb.org/ACGV: excess of MYBPC3 in cases vs controls = 0.53% (p=0.2002).; Changed rating: RED
Inborn errors of metabolism v1.301 COX4I2 Sarah Leigh Added comment: Comment on phenotypes: Mitochondrial Diseases;Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Inborn errors of metabolism v1.301 COX4I2 Sarah Leigh Phenotypes for gene: COX4I2 were changed from Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis, 612714; Mitochondrial Diseases; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis 612714 to Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis 612714
Undiagnosed metabolic disorders v1.330 COX4I2 Sarah Leigh Added comment: Comment on phenotypes: Mitochondrial Diseases;Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Undiagnosed metabolic disorders v1.330 COX4I2 Sarah Leigh Phenotypes for gene: COX4I2 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis 612714 to Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis 612714
Inborn errors of metabolism v1.300 COX4I2 Sarah Leigh Publications for gene: COX4I2 were set to 27604308; 19268275; 22592081
Undiagnosed metabolic disorders v1.329 COX4I2 Sarah Leigh Publications for gene: COX4I2 were set to 27604308
Inborn errors of metabolism v1.299 COX4I2 Sarah Leigh Classified gene: COX4I2 as Amber List (moderate evidence)
Inborn errors of metabolism v1.299 COX4I2 Sarah Leigh Added comment: Comment on list classification: This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).
Inborn errors of metabolism v1.299 COX4I2 Sarah Leigh Gene: cox4i2 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.328 COX4I2 Sarah Leigh Classified gene: COX4I2 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.328 COX4I2 Sarah Leigh Added comment: Comment on list classification: This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).
Undiagnosed metabolic disorders v1.328 COX4I2 Sarah Leigh Gene: cox4i2 has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.298 COX4I2 Sarah Leigh Publications for gene: COX4I2 were set to 27604308
Dilated cardiomyopathy - adult and teen v0.46 RYR2 James Eden Deleted their comment
Dilated cardiomyopathy - adult and teen v0.46 RYR2 James Eden edited their review of gene: RYR2: Added comment: RYR2 is not currently tested in Manchester for DCM. RYR2 (whole gene) is associated with ARVD and CPVT on OMIM. Limited association of RYR2 variants with DCM. The RYR2 exon 3 deletion was reported in one article in 2 families with CPVT combined with additional features of dilated cardiomyopathy (https://www.ncbi.nlm.nih.gov/pubmed/17875969). This deletion is more commonly associated with LVNC cardiomyopathy in the literature (https://www.ncbi.nlm.nih.gov/pubmed/24394973, https://www.ncbi.nlm.nih.gov/pubmed/26018045).; Changed rating: AMBER; Changed publications: 17875969
Dilated cardiomyopathy - adult and teen v0.46 RYR2 James Eden reviewed gene: RYR2: Rating: RED; Mode of pathogenicity: None; Publications: 24394973, 26018045, 22374134, 16828071; Phenotypes: Arrhythmogenic right ventricular dysplasia 2 600996, Ventricular tachycardia, catecholaminergic polymorphic, 1 604772; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inborn errors of metabolism v1.297 COA5 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.327 COA5 Sarah Leigh Publications for gene: COA5 were set to 27604308
Inborn errors of metabolism v1.297 COA5 Sarah Leigh Phenotypes for gene: COA5 were changed from ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors) to ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500
Undiagnosed metabolic disorders v1.326 COA5 Sarah Leigh Phenotypes for gene: COA5 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 to ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500
Inborn errors of metabolism v1.296 COA5 Sarah Leigh Phenotypes for gene: COA5 were changed from ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors) to ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors)
Inborn errors of metabolism v1.296 COA5 Sarah Leigh Added comment: Comment on phenotypes: ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500
Inborn errors of metabolism v1.296 COA5 Sarah Leigh Phenotypes for gene: COA5 were changed from ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors) to ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors)
Inborn errors of metabolism v1.295 COA5 Sarah Leigh Publications for gene: COA5 were set to 27604308
Undiagnosed metabolic disorders v1.325 ATP5E Sarah Leigh Classified gene: ATP5E as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.325 ATP5E Sarah Leigh Gene: atp5e has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.294 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 27626380; 25954304
Undiagnosed metabolic disorders v1.324 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 27626380; 25954304
Undiagnosed metabolic disorders v1.323 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 27626380; 25954304
Undiagnosed metabolic disorders v1.322 ATP5E Sarah Leigh Added comment: Comment on phenotypes: Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Undiagnosed metabolic disorders v1.322 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits) to ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053
Inborn errors of metabolism v1.293 ATP5E Sarah Leigh Added comment: Comment on phenotypes: Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Inborn errors of metabolism v1.293 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 to ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053
Inborn errors of metabolism v1.292 ATP5E Sarah Leigh Added comment: Comment on publications: pmid 27626380: knockout of the mouse homolog of human ATP5E is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Inborn errors of metabolism v1.292 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 27626380; 25954304
Undiagnosed metabolic disorders v1.321 ATP5E Sarah Leigh Added comment: Comment on publications: pmid 27626380: knockout of the mouse homolog of human ATP5E is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Undiagnosed metabolic disorders v1.321 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 27626380; 25954304
Undiagnosed metabolic disorders v1.320 ATP5E Sarah Leigh Classified gene: ATP5E as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.320 ATP5E Sarah Leigh Added comment: Comment on list classification: Updated information and Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.
Undiagnosed metabolic disorders v1.320 ATP5E Sarah Leigh Gene: atp5e has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v1.291 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710; 27626380; 25954304
Undiagnosed metabolic disorders v1.319 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 27604308; 20566710
Inborn errors of metabolism v1.290 ATP5E Sarah Leigh Mode of inheritance for gene: ATP5E was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.318 ATP5E Sarah Leigh Mode of inheritance for gene: ATP5E was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v1.290 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710
Inborn errors of metabolism v1.289 ATP5E Sarah Leigh Classified gene: ATP5E as Amber List (moderate evidence)
Inborn errors of metabolism v1.289 ATP5E Sarah Leigh Added comment: Comment on list classification: Based on Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.
Inborn errors of metabolism v1.289 ATP5E Sarah Leigh Gene: atp5e has been classified as Amber List (Moderate Evidence).
Progressive cardiac conduction disease v0.28 TNNI3K Rebecca Whittington changed review comment from: OMIM: cardiac conduction with/without DCM. A number of families reported one patient at 3.5years. HGMD: Four variants missense and one splice. Conduction defects appear to be presenting feature.; to: OMIM: cardiac conduction with/without DCM. A number of families reported one patient at 3.5years. HGMD: Four variants missense and one splice. Four literature reports, with reasonable segregation suggested: Fan 2018 (PMID 29355681); Podliesna 2019; Xi 2015 (PMID 25791106); Theis 2014 (PMID: 24925317). Conduction defects appear to be presenting feature.
Progressive cardiac conduction disease v0.28 TNNI3K Rebecca Whittington reviewed gene: TNNI3K: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiac conduction disease with or without dilated cardiomyopathy 616117; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Undiagnosed metabolic disorders v1.317 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 27604308
Inborn errors of metabolism v1.288 ATP5E Sarah Leigh Publications for gene: ATP5E were set to PMID: 20566710
Undiagnosed metabolic disorders v1.316 ATP5A1 Sarah Leigh changed review comment from: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.; to: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys in this publication have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Arrhythmogenic cardiomyopathy v1.36 PLN James Eden reviewed gene: PLN: Rating: GREEN; Mode of pathogenicity: None; Publications: 23595706, 23568436, 24909667, 25700660, 30763825; Phenotypes: Cardiomyopathy, dilated, 1P 609909, Cardiomyopathy, hypertrophic, 18 613874; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic cardiomyopathy v1.36 RYR2 James Eden reviewed gene: RYR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 25041964, 27761164; Phenotypes: Arrhythmogenic right ventricular dysplasia 2 600996, Ventricular tachycardia, catecholaminergic polymorphic, 1 604772; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Brugada syndrome v1.45 SCN5A Sarah Leigh Publications for gene: SCN5A were set to 20031634; 27761167
Arrhythmogenic cardiomyopathy v1.36 SCN5A James Eden reviewed gene: SCN5A: Rating: RED; Mode of pathogenicity: None; Publications: 26916278, 24317018, 28069705; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic cardiomyopathy v1.36 RBM20 James Eden reviewed gene: RBM20: Rating: RED; Mode of pathogenicity: None; Publications: 29650543, 22466703, 22561820; Phenotypes: Cardiomyopathy, dilated, 1DD 613172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Brugada syndrome v1.44 SCN5A Ivone Leong Mode of inheritance for gene: SCN5A was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic cardiomyopathy v1.36 DES James Eden reviewed gene: DES: Rating: AMBER; Mode of pathogenicity: None; Publications: 23168288, 30370089, 20829228, 25921558, 29212896; Phenotypes: Cardiomyopathy, dilated, 1I 604765, Myopathy, myofibrillar, 1 601419, Scapuloperoneal syndrome, neurogenic, Kaeser type 181400; Mode of inheritance: Unknown
Intellectual disability v2.1047 MED25 Rebecca Foulger Publications for gene: MED25 were set to 25792360; 25527630
Intellectual disability v2.1046 MED25 Rebecca Foulger changed review comment from: 10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.; to: DOI:10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.
Intellectual disability v2.1046 MED25 Rebecca Foulger commented on gene: MED25: 10.1159/000501114 (Nair et al., 2019b) report an additional Lebanese family with 2 affected siblings with delayed psychomotor and language development, with craniofacial anomalies. A homozyogus p.Ile173Thr change in MED25 was found, which may be a Founder variant.
Intellectual disability v2.1046 MED25 Rebecca Foulger commented on gene: MED25
Genetic epilepsy syndromes v1.342 KATNB1 Rebecca Foulger Tag watchlist tag was added to gene: KATNB1.
Genetic epilepsy syndromes v1.342 PMPCB Konstantinos Varvagiannis changed review comment from: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature; to: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen; to: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1046 INTS6 Konstantinos Varvagiannis reviewed gene: INTS6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.342 POLG2 Rebecca Foulger Publications for gene: POLG2 were set to 31286721; 27592148; 30157269
Genetic epilepsy syndromes v1.341 SPATA5 Rebecca Foulger Classified gene: SPATA5 as Green List (high evidence)
Genetic epilepsy syndromes v1.341 SPATA5 Rebecca Foulger Added comment: Comment on list classification: The Green review by Helen Lord (September 23rd 2019) supports the existing Green rating of SPATA5.
Genetic epilepsy syndromes v1.341 SPATA5 Rebecca Foulger Gene: spata5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.340 KATNB1 Rebecca Foulger Classified gene: KATNB1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.340 KATNB1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber, and added watchlist tag: KATNB1 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype. Linked to lissencephaly with microcephaly in OMIM. There are sufficient cases from from the literature to support inclusion on the epilepsy panel (PMIDs:25521378, 25521379, 26640080) but epilepsy is not a feature in all cases and a Red recent review was left by Helen Lord. Therefore rated Amber as other panels may be more appropriate.
Genetic epilepsy syndromes v1.340 KATNB1 Rebecca Foulger Gene: katnb1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.339 GABRA5 Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence)
Genetic epilepsy syndromes v1.339 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA5 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-70 in OMIM, and there are three cases from 2 publications (PMIDs 29961870 and 31056671) of GABRA5 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord.
Genetic epilepsy syndromes v1.339 GABRA5 Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.338 GABRA2 Rebecca Foulger Classified gene: GABRA2 as Green List (high evidence)
Genetic epilepsy syndromes v1.338 GABRA2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA2 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-78 in OMIM, and there are sufficient cases from from the literature (PMIDs:29422393, 29961870, 31032849, https://doi.org/10.1101/678219) of GABRA2 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord.
Genetic epilepsy syndromes v1.338 GABRA2 Rebecca Foulger Gene: gabra2 has been classified as Green List (High Evidence).
Primary immunodeficiency v1.130 WDR1 Louise Daugherty commented on gene: WDR1: Autoinflammatory periodic fever, immunodeficiency and thrombocytopaenia - sibling pair and mouse model - ?sufficient for green
Primary immunodeficiency v1.130 USP18 Louise Daugherty commented on gene: USP18: Pseudo TORCH syndrome: Aicardi-Goutiere like - severe intracranial haemorrhage, thrombocytopaenia, seizures, liver failure caused by interferon activation - probable green association, is it a relevant phenotype?
2 families (one homozygous, one compound het where one variant was the same as the first family with possible common ancestor) - borderline, with lack of USP18 expression - abnormal activation of the immune system (interferon) - is this a likely presentation in immunology clinic?
Primary immunodeficiency v1.130 TNFRSF11A Louise Daugherty commented on gene: TNFRSF11A: Osteopetrosis (AR) - green association, reported to have hypogammaglobulinaemia - presume a feasible presentation in immunology?
Primary immunodeficiency v1.130 SH3BP2 Louise Daugherty commented on gene: SH3BP2: Cherubism - green association, but is there an immunological phenotype?
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Marked gene: PAK1 as ready
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Primary immunodeficiency v1.130 SAMD9L Louise Daugherty commented on gene: SAMD9L: Ataxia pancytopaenia syndrome - 2 unrelated families, no functional work - amber association, is there an immunological phenotype?
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Classified gene: PAK1 as Green List (high evidence)
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Added comment: Comment on list classification: Updated PAK1 from Amber to Green: Subsequent to the 8th August Webex, Konstantinos Varvagiannis left a Green review of PAK1 on the Epilepsy panel based on an additional 2019 paper (Horn et al, PMID:31504246). Green rating is supported by a new review by Helen Lord.
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Primary immunodeficiency v1.130 RET Louise Daugherty commented on gene: RET: MEN2 / MTC - ?relevant phenotype / Hirschsprung in LOF
Primary immunodeficiency v1.130 RANBP2 Louise Daugherty commented on gene: RANBP2: Encephalopathy acute, infection induced susceptibility to, 3: 10 families, variable susceptibility to encephalopathy with infections - discuss penetrance and although there is an absence of primary immune dysfunction, whether this is a phenocopy like presentation? - Would a result be clinically useful?
Primary immunodeficiency v1.130 PTEN Louise Daugherty commented on gene: PTEN: Cowden (macrocephaly, variable GDD, skin features, malignancy risk) - some patients reported to have primary immunodef / hypogammaglob. / lymphopaenia / T&B cell abn. / susceptibility to infections). Green association - relevant phenotype?
Primary immunodeficiency v1.130 PSMB9 Louise Daugherty commented on gene: PSMB9: ?Proteasome-associated autoinflammatory syndrome 3, digenic. One patient, one similar patient het for this and another gene (PSMB4) hence ?digenic - amber on association
Primary immunodeficiency v1.130 PSMB4 Louise Daugherty commented on gene: PSMB4: ?Proteasome-associated autoinflammatory syndrome 3, digenic. One patient het for this and another gene (PSMB9) hence ?digenic - amber on association
Primary immunodeficiency v1.130 PSMA3 Louise Daugherty commented on gene: PSMA3: ?Proteasome-associated autoinflammatory syndrome 1, digenic. Two unrelated children het
for this and another gene (PSMB8) hence ?digenic - amber on association
Primary immunodeficiency v1.130 NRAS Louise Daugherty commented on gene: NRAS: Noonan (plus malignancies in somatic variants): ?relevant phenotype
Primary immunodeficiency v1.130 NLRP1 Louise Daugherty commented on gene: NLRP1: Autoinflammation - two cases, ?AD / AR – unclear
Primary immunodeficiency v1.130 MBL2 Louise Daugherty commented on gene: MBL2: Chronic infections due to MBL deficiency: 5% Europeans, 10% sub-saharan Africans, mostly unaffected. Increased risk of infections - is it useful clinically or if undergoing immunosuppression? Is it tested for clinically at present
Primary immunodeficiency v1.130 MASP2 Louise Daugherty changed review comment from: Chronic infections due to MBL deficiency: 5% Europeans, 10% sub-saharan Africans, mostly unaffected. Increased risk of infections - is it useful clinically or if undergoing immunosuppression? Is it tested for clinically at present?; to: MASP2 deficiency: 4% caucasians, up to 18% of African populations - mostly asymptomatic. Is this a risk factor - is it useful in clinical practice? I don't know if this is a recurrent variant - may be too common?
Primary immunodeficiency v1.130 MASP2 Louise Daugherty commented on gene: MASP2: Chronic infections due to MBL deficiency: 5% Europeans, 10% sub-saharan Africans, mostly unaffected. Increased risk of infections - is it useful clinically or if undergoing immunosuppression? Is it tested for clinically at present?
Primary immunodeficiency v1.130 HPS4 Louise Daugherty commented on gene: HPS4: Hermansky-Pudlak - OCA, bleeding, lysosomal ceroid storage: green association, phenotype
Primary immunodeficiency v1.130 HPS6 Louise Daugherty commented on gene: HPS6: Hermansky-Pudlak - OCA, bleeding, lysosomal ceroid storage: green association, phenotype
Genetic epilepsy syndromes v1.336 GABRA2 Rebecca Foulger changed review comment from: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girls with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.; to: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girl with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.
Primary immunodeficiency v1.130 HPS1 Louise Daugherty commented on gene: HPS1: Hermansky-Pudlak - OCA, bleeding, lysosomal ceroid storage: green association, phenotype
Primary immunodeficiency v1.130 GUCY2C Louise Daugherty commented on gene: GUCY2C: AD: diarrhoea 6, relatively mild with potential IBD association one family ?GOF, vs AR: meconium ileus, one family. ?Phenotypic relevance and also amber on association
Primary immunodeficiency v1.130 GTF2H5 Louise Daugherty commented on gene: GTF2H5: Trichothiodystrophy: green association (3 unrelated cases), ?phenotype relevant: recurrent infective exacerbations of asthma
Genetic epilepsy syndromes v1.336 KATNB1 Rebecca Foulger changed review comment from: KATNB1 was added to the panel and rated Grey by Konstantinos Varvagiannis. Summary of evidence is as follows (see Konstantinos Varvagiannis' review for details): 3 publications reporting patients with biallelic KATNB1 variants. The phenotype includes seizures in some, but not all cases:

PMID:25521378. Mishra-Gorur et al. 2014 report 5 families with malformations of cortical development and homozygous KATNB1 variants. In many families homozygous variants in additional genes were also reported. Epilepsy was reported in 3/7 individuals (from 2 families): Supplementary Table S1).

PMID:25521379. Hu et al., 2014 report 3 Middle Eastern families with microcephaly, Global DD and seizures, and 3 different homozygous variants in KATNB1.

PMID:26640080. Yigit el al. 2016 report a homozygous acceptor splice-site intronic KATNB1 variant in a 5 year old Turkish girl born to consanguineous cousins, who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, dental abnormalities and developmental delay. She developed seizures age 6 months.; to: KATNB1 was added to the panel and rated Green by Konstantinos Varvagiannis. Summary of evidence is as follows (see Konstantinos Varvagiannis' review for details): 3 publications reporting patients with biallelic KATNB1 variants. The phenotype includes seizures in some, but not all cases:

PMID:25521378. Mishra-Gorur et al. 2014 report 5 families with malformations of cortical development and homozygous KATNB1 variants. In many families homozygous variants in additional genes were also reported. Epilepsy was reported in 3/7 individuals (from 2 families): Supplementary Table S1).

PMID:25521379. Hu et al., 2014 report 3 Middle Eastern families with microcephaly, Global DD and seizures, and 3 different homozygous variants in KATNB1.

PMID:26640080. Yigit el al. 2016 report a homozygous acceptor splice-site intronic KATNB1 variant in a 5 year old Turkish girl born to consanguineous cousins, who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, dental abnormalities and developmental delay. She developed seizures age 6 months.
Primary immunodeficiency v1.130 ERCC3 Louise Daugherty commented on gene: ERCC3: Trichothiodystrophy / XP: DNA repair - short, microcephaly, delay, ectodermal features with photosensitivity. Omim 2 sibs in a consang family Jan 17 - amber association, relevant phenotype?)
Primary immunodeficiency v1.130 ERCC2 Louise Daugherty commented on gene: ERCC2: Trichothiodystrophy / XP: DNA repair - short, microcephaly, delay, ectodermal features and recurrent infections - green association, probably a relevant phenotype?)
Primary immunodeficiency v1.130 DNASE1L3 Louise Daugherty commented on gene: DNASE1L3: SLE in Arab families (6 but consistent with founder effect)
Primary immunodeficiency v1.130 CTC1 Louise Daugherty commented on gene: CTC1: Cerebroretinal microangiopathy with calcifications and cysts: spasticity / dystonia / ataxia / seizures / cognitive decline (green association but ?phenotype)
Primary immunodeficiency v1.130 CFHR5 Louise Daugherty commented on gene: CFHR5: Glomerulonephritis with C3 deposits (green re association - ?phenotype)
Primary immunodeficiency v1.130 CFB Louise Daugherty commented on gene: CFB: ?Complement factor B deficiency: one family, relevant phenotype - ?amber
Primary immunodeficiency v1.130 CARD14 Louise Daugherty commented on gene: CARD14: Psoriasis ?relevant phenotype (also some evidence of presence in controls - is it useful clinically?
Primary immunodeficiency v1.130 BLOC1S6 Louise Daugherty commented on gene: BLOC1S6: ?Hermansky-Pudlak: one patient - amber, relevant phenotype
Primary immunodeficiency v1.130 AP1S3 Louise Daugherty commented on gene: AP1S3: Pustular psoriasis susceptibility: variant seen in cases > controls. Is this a relevant phenotype / is this clinically useful?
Primary immunodeficiency v1.130 ADAM17 Louise Daugherty commented on gene: ADAM17: Inflammatory skin and bowel disease neonatal: one family, moderately elevated IgE, no evidence of immunodeficiency although nail, ear, eye infections - a phenocopy? Phenotypic opinion? Amber on association
Primary immunodeficiency v1.130 ERCC2 Louise Daugherty Source North West GLH was added to ERCC2.
Source NHS GMS was added to ERCC2.
Source London North GLH was added to ERCC2.
Primary immunodeficiency v1.130 BLOC1S6 Louise Daugherty Source Expert Review Red was added to BLOC1S6.
Source GRID V2.0North West GLH was added to BLOC1S6.
Source GRID V2.0 was added to BLOC1S6.
Source NHS GMS was added to BLOC1S6.
Source Victorian Clinical Genetics Services, London North GLH was added to BLOC1S6.
Rating Changed from No List (delete) to Red List (low evidence)
Primary immunodeficiency v1.129 BLOC1S6 Louise Daugherty All sources for gene: BLOC1S6 were removed
Primary immunodeficiency v1.128 ERCC3 Louise Daugherty Source Expert Review Red was added to ERCC3.
Source Victorian Clinical Genetics Services was added to ERCC3.
Primary immunodeficiency v1.128 ERCC2 Louise Daugherty Source Expert Review Red was added to ERCC2.
Source Victorian Clinical Genetics Services was added to ERCC2.
Primary immunodeficiency v1.128 BLOC1S6 Louise Daugherty Source GRID V2.0 was added to BLOC1S6.
Source Expert Review Red was added to BLOC1S6.
Source Victorian Clinical Genetics Services, London North GLH, NHS GMS was added to BLOC1S6.
Primary immunodeficiency v1.127 SH3BP2 Louise Daugherty commented on gene: SH3BP2: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red


Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 SH3BP2 Louise Daugherty commented on gene: SH3BP2: Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 RET Louise Daugherty commented on gene: RET: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 RET Louise Daugherty commented on gene: RET: Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 RANBP2 Louise Daugherty commented on gene: RANBP2: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 RANBP2 Louise Daugherty commented on gene: RANBP2: Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 MBL2 Louise Daugherty commented on gene: MBL2: relevant to 5-10% of the population and that there are three specific missense variants described. Rated Amber.
Primary immunodeficiency v1.127 MBL2 Louise Daugherty Tag curated-variant-list tag was added to gene: MBL2.
Primary immunodeficiency v1.127 MASP2 Louise Daugherty commented on gene: MASP2: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 MASP2 Louise Daugherty commented on gene: MASP2: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 MASP2 Louise Daugherty commented on gene: MASP2: Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 GTF2H5 Louise Daugherty commented on gene: GTF2H5: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 GTF2H5 Louise Daugherty commented on gene: GTF2H5: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 GTF2H5 Louise Daugherty commented on gene: GTF2H5: Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 ERCC3 Louise Daugherty commented on gene: ERCC3: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 ERCC3 Louise Daugherty commented on gene: ERCC3: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 ERCC3 Louise Daugherty commented on gene: ERCC3: Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 ERCC2 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red


Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 BLOC1S6 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red


Genes with discrepant ratings (PID 100K vs sumbmitted LNGLH submitted Immunology lists)--agreed rating in webex call 28 March 2019
Primary immunodeficiency v1.127 ERCC2 Louise Daugherty commented on gene: ERCC2: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 ERCC2 Louise Daugherty commented on gene: ERCC2: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 BLOC1S6 Louise Daugherty commented on gene: BLOC1S6: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Primary immunodeficiency v1.127 BLOC1S6 Louise Daugherty commented on gene: BLOC1S6: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Red
Amyloidosis v0.18 APOC2 Eleanor Williams commented on gene: APOC2: Added the missense tag
Amyloidosis v0.18 APOC2 Eleanor Williams Tag missense tag was added to gene: APOC2.
Periodic fever syndromes v1.12 APOC2 Eleanor Williams commented on gene: APOC2: Added missense tag.
Periodic fever syndromes v1.12 APOC2 Eleanor Williams Tag missense tag was added to gene: APOC2.
Periodic fever syndromes v1.12 APOC2 Eleanor Williams Classified gene: APOC2 as Green List (high evidence)
Periodic fever syndromes v1.12 APOC2 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England rare disease clinical team, upgrading this gene from Amber to Green. 2 cases with variants detected are reported, plus 4 other patients in which APOC2 p.Lys41Thr mutant protein was found by mass spectrometry.
Periodic fever syndromes v1.12 APOC2 Eleanor Williams Gene: apoc2 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.287 STAT2 Sarah Leigh Classified gene: STAT2 as Amber List (moderate evidence)
Inborn errors of metabolism v1.287 STAT2 Sarah Leigh Added comment: Comment on list classification: Based on recommendation of Helen Britain (Clinical Fellow, Genomics England), that the majority of cases will be presenting in the context of overwhelming infection. The raised lactate and encephalomyopathy are potentially relevant phenotypes for this panel, however more evidence is needed on how common this presentation is, and whether it is always clearly associated with a proven infection.
Inborn errors of metabolism v1.287 STAT2 Sarah Leigh Gene: stat2 has been classified as Amber List (Moderate Evidence).
Rare multisystem ciliopathy disorders v1.121 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Rare multisystem ciliopathy disorders v1.121 FAM149B1 Eleanor Williams Added comment: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Rare multisystem ciliopathy disorders v1.121 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.127 USP18 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMA3 should be Green; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that USP18 should be Green
Primary immunodeficiency v1.127 USP18 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMA3 should be Green
Primary immunodeficiency v1.127 USP18 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group; to: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group, but flagged for further follow up with the Immunology Test Group due to the subsequent conflicting review. Evidence /opinion needs consensus before upgrading to Green
Primary immunodeficiency v1.127 PSMB9 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group; to: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group, but flagged for further follow up with the Immunology Test Group due to the subsequent conflicting review. Evidence /opinion needs consensus before upgrading to Green
Primary immunodeficiency v1.127 PSMB9 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMA3 should be Green; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMB9 should be Green
Primary immunodeficiency v1.127 PSMB9 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMA3 should be Green
Primary immunodeficiency v1.127 PSMB4 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMB4 should be Green
Rare multisystem ciliopathy disorders v1.120 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Rare multisystem ciliopathy disorders. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Primary immunodeficiency v1.127 PSMB4 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group; to: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group, but flagged for further follow up with the Immunology Test Group due to the subsequent conflicting review. Evidence /opinion needs consensus before upgrading to Green
Primary immunodeficiency v1.127 PSMA3 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group; to: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group, but flagged for further follow up with the Immunology Test Group due to the subsequent conflicting review. Evidence /opinion needs consensus before upgrading to Green
Cardiomyopathies - including childhood onset v0.13 ALMS1 Rebecca Whittington gene: ALMS1 was added
gene: ALMS1 was added to Cardiomyopathies - including childhood onset. Sources: Expert Review
Mode of inheritance for gene: ALMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALMS1 were set to PMID: 15689433
Phenotypes for gene: ALMS1 were set to OMIM 203800
Penetrance for gene: ALMS1 were set to Complete
Review for gene: ALMS1 was set to GREEN
Added comment: Presentation with congestive cardiac failure within the first 3 months of life is common patients with Alstrom Syndrome.
Sources: Expert Review
Primary immunodeficiency v1.127 USP18 Tracy Briggs edited their review of gene: USP18: Added comment: I think USP18 should be green: five PTS patients from two unrelated families; Changed rating: GREEN
Primary immunodeficiency v1.127 PSMB9 Tracy Briggs edited their review of gene: PSMB9: Added comment: I think CANDLE should be green; Changed rating: GREEN
Primary immunodeficiency v1.127 PSMB4 Tracy Briggs edited their review of gene: PSMB4: Added comment: I think CANDLE should be green these should be covered in the testing; Changed rating: GREEN
Primary immunodeficiency v1.127 PSMA3 Tracy Briggs edited their review of gene: PSMA3: Added comment: I think CANDLE should be green; Changed rating: GREEN
Mitochondrial disorders v2.0 Sarah Leigh promoted panel to version 2.0
Mitochondrial disorders v1.487 Sarah Leigh Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Mitochondrial disorders v1.486 CYCS Sarah Leigh Publications for gene: CYCS were set to PMID: 18345000; 24326104
Primary immunodeficiency v1.126 PSMA3 Louise Daugherty changed review comment from: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.; to: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. Although discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 to rate Amber in the confirmed follow up email on 20th June North West GLH reasserted that PSMA3 should be Green
Disorders of sex development v2.0 MYRF Martina Owens gene: MYRF was added
gene: MYRF was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYRF were set to 30985895; 29446546; 31069960; 30070761; 30532227
Phenotypes for gene: MYRF were set to Cardiac-urogenital syndrome; gonadal hypoplasia; Müllerian duct hypoplasia
Penetrance for gene: MYRF were set to unknown
Review for gene: MYRF was set to AMBER
Added comment: Hamanaka et al 2019 (PMID:30985895): enrichment study plus an independent cohort. Identified 3 de novo MYRF truncating variants in 4 DSD cases (3 families - 2 cases were monozygotic twins) and a de novo missense variant in 1 DSD case. Pinz et al 2018 (PMID: 29446546) reported de novo truncating MYRF variants in 2 male cases with genitourinary anomalies with congenital heart defects. Chitayat et al 2018 (PMID: 30070761) reported truncating variant in a patient with ambiguous genitalia and hypoplastic left heart syndrome. Qi et al 2018 (PMID: 30532227) reported 7 de novo patients with DSD, congenital heart defects and congenital diaphragmatic hernia. Rossetti et al 2019 (PMID: 31069960) reported above patients and 2 further patients with genitourinary anomalies and congenital diaphragmatic hernia.
Sources: Literature
Primary immunodeficiency v1.126 WDR1 Louise Daugherty Classified gene: WDR1 as Amber List (moderate evidence)
Primary immunodeficiency v1.126 WDR1 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.126 WDR1 Louise Daugherty Gene: wdr1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.125 USP18 Louise Daugherty Classified gene: USP18 as Amber List (moderate evidence)
Primary immunodeficiency v1.125 USP18 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.125 USP18 Louise Daugherty Gene: usp18 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.124 TNFRSF11A Louise Daugherty Classified gene: TNFRSF11A as Amber List (moderate evidence)
Primary immunodeficiency v1.124 TNFRSF11A Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.124 TNFRSF11A Louise Daugherty Gene: tnfrsf11a has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.123 SAMD9L Louise Daugherty Classified gene: SAMD9L as Amber List (moderate evidence)
Primary immunodeficiency v1.123 SAMD9L Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.123 SAMD9L Louise Daugherty Gene: samd9l has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.122 PSMB9 Louise Daugherty Classified gene: PSMB9 as Amber List (moderate evidence)
Primary immunodeficiency v1.122 PSMB9 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.122 PSMB9 Louise Daugherty Gene: psmb9 has been classified as Amber List (Moderate Evidence).
Dilated cardiomyopathy - adult and teen v0.46 DMD Ivone Leong Phenotypes for gene: DMD were changed from OMIM: 300376 Becker muscular dystrophy; 302045 Cardiomyopathy, dilated, 3B; 310200 Duchenne muscular dystrophy to Becker muscular dystrophy, 300376; Cardiomyopathy, dilated, 3B, 302045; Duchenne muscular dystrophy, 310200
Dilated cardiomyopathy - adult and teen v0.45 BAG3 Ivone Leong Phenotypes for gene: BAG3 were changed from OMIM 613881: Cardiomyopathy, dilated, 1HH; 612954 Myopathy, myofibrillar, 6 to Cardiomyopathy, dilated, 1HH, 613881; Myopathy, myofibrillar, 6, 612954
Primary immunodeficiency v1.121 PSMB4 Louise Daugherty Classified gene: PSMB4 as Amber List (moderate evidence)
Primary immunodeficiency v1.121 PSMB4 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.121 PSMB4 Louise Daugherty Gene: psmb4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.120 SH3BP2 Louise Daugherty commented on gene: SH3BP2: OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): SH3BP2 .PanelApp HGNC gene symbol check: SH3BP2 . IUIS Disease: Cherubism . IUIS Inheritance: AD .T cells: Variable, .B cells: N/A, .IUIS Other affected cells: Stroma cells, bone cells. IUIS Associated features: Bone degeneration in jaws. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Non-Inflammasome Related Conditions
Primary immunodeficiency v1.120 SH3BP2 Louise Daugherty commented on gene: SH3BP2: Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: SH3BP2 GRID_Gene_Symbol: SH3BP2 GRID_Transcript_ENS_Community submitted: ENST00000503393 GRID_Transcript_RefSeq: NM_001122681.1 GRID_Transcript_ENS_used_on_Production: ENST00000503393
Primary immunodeficiency v1.120 MBL2 Louise Daugherty commented on gene: MBL2: Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: MBL2 GRID_Gene_Symbol: MBL2 GRID_Transcript_ENS_Community submitted: ENST00000373968 GRID_Transcript_RefSeq: NM_000242.2 GRID_Transcript_ENS_used_on_Production: ENST00000373968
Undiagnosed metabolic disorders v1.316 SPTLC1 Catherine Snow Publications for gene: SPTLC1 were set to 27604308
Undiagnosed metabolic disorders v1.315 SPTLC1 Catherine Snow Classified gene: SPTLC1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.315 SPTLC1 Catherine Snow Gene: sptlc1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.314 SPTLC1 Catherine Snow reviewed gene: SPTLC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20097765, 21618344, 20097765, 30420926; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IA, 162400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inborn errors of metabolism v1.286 SPTLC1 Catherine Snow changed review comment from: Promoted from Amber to Green. This gene is associated with a relevant disease in OMIM and there is enough evidence to support a gene-disease association.

SPTLC1, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID 20097765 reports that mutations in SPTLC1 cause a gain of function mechanism, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.

Confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/) and in sufficient publications.; to: Promoted from Amber to Green. This gene is associated with a relevant disease in OMIM and there is enough evidence to support a gene-disease association.

SPTLC1, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID 20097765 reports that mutations in SPTLC1 cause a gain of function mechanism, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.

Confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/) and in sufficient publications.

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Inborn errors of metabolism v1.286 SPTLC1 Catherine Snow Classified gene: SPTLC1 as Green List (high evidence)
Inborn errors of metabolism v1.286 SPTLC1 Catherine Snow Gene: sptlc1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v1.285 SPTLC1 Catherine Snow Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Inborn errors of metabolism v1.285 SPTLC1 Catherine Snow Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Inborn errors of metabolism v1.284 SPTLC1 Catherine Snow Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Inborn errors of metabolism v1.284 SPTLC1 Catherine Snow Publications for gene: SPTLC1 were set to 27604308
Inborn errors of metabolism v1.283 SPTLC1 Catherine Snow reviewed gene: SPTLC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20097765, 21618344, 20097765, 30420926; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IA, 162400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inborn errors of metabolism v1.283 SPTLC2 Catherine Snow Classified gene: SPTLC2 as Green List (high evidence)
Inborn errors of metabolism v1.283 SPTLC2 Catherine Snow Gene: sptlc2 has been classified as Green List (High Evidence).
Primary immunodeficiency v1.120 SH3BP2 Louise Daugherty commented on gene: SH3BP2
Undiagnosed metabolic disorders v1.314 SPTLC2 Catherine Snow Publications for gene: SPTLC2 were set to 27604308
Primary immunodeficiency v1.120 MBL2 Louise Daugherty edited their review of gene: MBL2: Changed rating: AMBER
Undiagnosed metabolic disorders v1.313 SPTLC2 Catherine Snow Classified gene: SPTLC2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.313 SPTLC2 Catherine Snow Gene: sptlc2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.312 SPTLC2 Catherine Snow reviewed gene: SPTLC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 20920666; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IC, 613640; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency v1.120 MBL2 Louise Daugherty commented on gene: MBL2: Original metadata downloaded from ESID Registry. ESID_Gene_original: MBL, PanelApp HGNC gene symbol check: MBL2, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Complement deficiencies / Mannose-binding lectin (MBL) / Mannose-binding lectin deficiency (MBL)
Inborn errors of metabolism v1.282 SPTLC2 Catherine Snow Publications for gene: SPTLC2 were set to 27604308; 20920666
Inborn errors of metabolism v1.282 SPTLC2 Catherine Snow Publications for gene: SPTLC2 were set to 27604308
Inborn errors of metabolism v1.281 SPTLC2 Catherine Snow changed review comment from: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.
SPTLC2, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID: 20920666 reports on three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families and also confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/).
This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.

SPTLC2, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID: 20920666 reports on three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families and also confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/).

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Inborn errors of metabolism v1.281 SPTLC2 Catherine Snow reviewed gene: SPTLC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20920666; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IC, 613640; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis edited their review of gene: PMPCB: Changed publications: 29576218
Genetic epilepsy syndromes v1.336 PMPCB Konstantinos Varvagiannis gene: PMPCB was added
gene: PMPCB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCB were set to 29576218
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954
Penetrance for gene: PMPCB were set to Complete
Review for gene: PMPCB was set to GREEN
Added comment: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature
Intellectual disability v2.1046 PMPCB Konstantinos Varvagiannis gene: PMPCB was added
gene: PMPCB was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954
Penetrance for gene: PMPCB were set to Complete
Review for gene: PMPCB was set to GREEN
gene: PMPCB was marked as current diagnostic
Added comment: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Primary immunodeficiency v1.120 PSMA3 Louise Daugherty Classified gene: PSMA3 as Amber List (moderate evidence)
Primary immunodeficiency v1.120 PSMA3 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.120 PSMA3 Louise Daugherty Gene: psma3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.119 GUCY2C Louise Daugherty Classified gene: GUCY2C as Amber List (moderate evidence)
Primary immunodeficiency v1.119 GUCY2C Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.119 GUCY2C Louise Daugherty Gene: gucy2c has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v1.118 GUCY2C Louise Daugherty Phenotypes for gene: GUCY2C were changed from Diarrhea 6, 614616; meconium ileus to Diarrhea 6, 614616; meconium ileus, 614665
Primary immunodeficiency v1.117 CTC1 Louise Daugherty Classified gene: CTC1 as Amber List (moderate evidence)
Primary immunodeficiency v1.117 CTC1 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Amber to reflect the agreed rating agreed by the GMS Immunology Specialist Test Group
Primary immunodeficiency v1.117 CTC1 Louise Daugherty Gene: ctc1 has been classified as Amber List (Moderate Evidence).
Progressive cardiac conduction disease v0.28 TBX5 James Eden reviewed gene: TBX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 29755943; Phenotypes: Holt-Oram syndrome 142900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency v1.116 WDR1 Louise Daugherty commented on gene: WDR1: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 USP18 Louise Daugherty commented on gene: USP18: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 TNFRSF11A Louise Daugherty commented on gene: TNFRSF11A: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 SAMD9L Louise Daugherty commented on gene: SAMD9L: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 PTEN Louise Daugherty commented on gene: PTEN: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 PSMB9 Louise Daugherty commented on gene: PSMB9: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 PSMB4 Louise Daugherty commented on gene: PSMB4: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 PSMA3 Louise Daugherty commented on gene: PSMA3: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 GUCY2C Louise Daugherty commented on gene: GUCY2C: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 DNASE1L3 Louise Daugherty commented on gene: DNASE1L3: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 CTC1 Louise Daugherty commented on gene: CTC1: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 CFHR5 Louise Daugherty commented on gene: CFHR5: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 AP1S3 Louise Daugherty commented on gene: AP1S3: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 ADAM17 Louise Daugherty commented on gene: ADAM17: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber.
Primary immunodeficiency v1.116 WDR1 Louise Daugherty edited their review of gene: WDR1: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 USP18 Louise Daugherty edited their review of gene: USP18: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 TNFRSF11A Louise Daugherty edited their review of gene: TNFRSF11A: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 SAMD9L Louise Daugherty edited their review of gene: SAMD9L: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 PTEN Louise Daugherty edited their review of gene: PTEN: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 PSMB9 Louise Daugherty edited their review of gene: PSMB9: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 PSMB4 Louise Daugherty edited their review of gene: PSMB4: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 PSMA3 Louise Daugherty edited their review of gene: PSMA3: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 GUCY2C Louise Daugherty edited their review of gene: GUCY2C: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 DNASE1L3 Louise Daugherty edited their review of gene: DNASE1L3: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 CTC1 Louise Daugherty edited their review of gene: CTC1: Added comment: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber; Changed rating: AMBER
Primary immunodeficiency v1.116 CFHR5 Louise Daugherty commented on gene: CFHR5: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber
Primary immunodeficiency v1.116 AP1S3 Louise Daugherty commented on gene: AP1S3: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber
Primary immunodeficiency v1.116 ADAM17 Louise Daugherty commented on gene: ADAM17: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is only enough evidence to rate this gene Amber
Progressive cardiac conduction disease v0.28 SCN1B James Eden reviewed gene: SCN1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 18464934; Phenotypes: Cardiac conduction defect, nonspecific 612838; Mode of inheritance: Unknown
Progressive cardiac conduction disease v0.28 NKX2-5 James Eden reviewed gene: NKX2-5: Rating: AMBER; Mode of pathogenicity: None; Publications: 28259982, 15109497; Phenotypes: Atrial septal defect 7, with or without AV conduction defects 108900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 EMD James Eden reviewed gene: EMD: Rating: AMBER; Mode of pathogenicity: None; Publications: 29349559; Phenotypes: Emery-Dreifuss muscular dystrophy 1, X-linked 310300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Progressive cardiac conduction disease v0.28 DES James Eden changed review comment from: No association with conduction disease on OMIM but three missense variants have been associated with cardiomyopathy with atrioventricular block in the literature: c.46C>T p.(Arg16Cys), c.1237G>A p.(Glu413Lys), c.1358C>T p.(Thr453Ile).; to: No association with conduction disease on OMIM but three missense variants have been associated with cardiomyopathy with atrioventricular block in HGMD: c.46C>T p.(Arg16Cys), c.1237G>A p.(Glu413Lys), c.1358C>T p.(Thr453Ile).
Progressive cardiac conduction disease v0.28 DES James Eden reviewed gene: DES: Rating: AMBER; Mode of pathogenicity: None; Publications: 16376610, 16890305; Phenotypes: Cardiomyopathy, dilated, 1I 604765; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 TRPM4 James Eden reviewed gene: TRPM4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29568272, 29748318, 30021168, 20562447; Phenotypes: Progressive familial heart block, type IB 604559; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 SCN5A James Eden reviewed gene: SCN5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11804990, 16643399, 15466643, 15372490; Phenotypes: Heart block, nonprogressive 113900, Sick sinus syndrome 1 608567; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 LMNA James Eden reviewed gene: LMNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 29095976, 23582089; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 HCN4 James Eden reviewed gene: HCN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19796353, 16407510, 12750403, 17646576; Phenotypes: Brugada syndrome 8 613123, Sick sinus syndrome 2 163800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency v1.115 WDR1 Kimberly Gilmour reviewed gene: WDR1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 USP18 Kimberly Gilmour reviewed gene: USP18: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 TNFRSF11A Kimberly Gilmour reviewed gene: TNFRSF11A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 SAMD9L Kimberly Gilmour reviewed gene: SAMD9L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 PTEN Kimberly Gilmour reviewed gene: PTEN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 PSMB9 Kimberly Gilmour reviewed gene: PSMB9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 PSMB4 Kimberly Gilmour reviewed gene: PSMB4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 PSMA3 Kimberly Gilmour reviewed gene: PSMA3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 GUCY2C Kimberly Gilmour reviewed gene: GUCY2C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 DNASE1L3 Kimberly Gilmour reviewed gene: DNASE1L3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 CTC1 Kimberly Gilmour reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 CFHR5 Kimberly Gilmour reviewed gene: CFHR5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 AP1S3 Kimberly Gilmour reviewed gene: AP1S3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.115 ADAM17 Kimberly Gilmour reviewed gene: ADAM17: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Dilated cardiomyopathy - adult and teen v0.44 MYBPC3 James Eden reviewed gene: MYBPC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 20186049, 27532257; Phenotypes: Cardiomyopathy, dilated, 1MM (615396), Cardiomyopathy, hypertrophic, 4 (115197), Left ventricular noncompaction 10 (615396); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Dilated cardiomyopathy - adult and teen v0.44 MYBPC3 James Eden Deleted their review
Primary immunodeficiency v1.114 WDR1 Tracy Briggs reviewed gene: WDR1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 USP18 Tracy Briggs reviewed gene: USP18: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 TNFRSF11A Tracy Briggs reviewed gene: TNFRSF11A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 SAMD9L Tracy Briggs reviewed gene: SAMD9L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 PTEN Tracy Briggs reviewed gene: PTEN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 PSMB9 Tracy Briggs reviewed gene: PSMB9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 PSMB4 Tracy Briggs reviewed gene: PSMB4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 PSMA3 Tracy Briggs reviewed gene: PSMA3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 GUCY2C Tracy Briggs reviewed gene: GUCY2C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 DNASE1L3 Tracy Briggs reviewed gene: DNASE1L3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 CTC1 Tracy Briggs reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 CFHR5 Tracy Briggs reviewed gene: CFHR5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 AP1S3 Tracy Briggs reviewed gene: AP1S3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency v1.114 ADAM17 Tracy Briggs reviewed gene: ADAM17: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.43 SEC63 Eleanor Williams changed review comment from: Check of rating - currently red on all renal panels, green on Polycystic liver disease panel.; to: Check of rating - currently red on all renal panels, green on Polycystic liver disease panel. So keep red.
Unexplained paediatric onset end-stage renal disease v0.43 SIX1 Eleanor Williams commented on gene: SIX1: Checking rating - currently red on all renal panels so keep red.
Undiagnosed metabolic disorders v1.312 SPR Catherine Snow changed review comment from: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association. Sepiapterin reductase (SR) deficiency leads to altered tetrahydrobiopterin (BH4) biosynthesis and abnormal biogenic amine metabolism. Most individuals improve with L-dopa administration, therefore treatable tag has been added.; to: Promoted from Amber to Green. This gene is associated with a relevant disease in OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association. Sepiapterin reductase (SR) deficiency leads to altered tetrahydrobiopterin (BH4) biosynthesis and abnormal biogenic amine metabolism. Most individuals improve with L-dopa administration, therefore treatable tag has been added.
Undiagnosed metabolic disorders v1.312 SPR Catherine Snow Publications for gene: SPR were set to 27604308
Undiagnosed metabolic disorders v1.311 SPR Catherine Snow Classified gene: SPR as Green List (high evidence)
Undiagnosed metabolic disorders v1.311 SPR Catherine Snow Gene: spr has been classified as Green List (High Evidence).
Unexplained paediatric onset end-stage renal disease v0.43 SEC63 Eleanor Williams commented on gene: SEC63: Check of rating - currently red on all renal panels, green on Polycystic liver disease panel.
Undiagnosed metabolic disorders v1.310 SPR Catherine Snow reviewed gene: SPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22018912, 22522443, 22018912, 24588500, 28189489, 21431957, 16650784; Phenotypes: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained paediatric onset end-stage renal disease v0.43 PRKCSH Eleanor Williams commented on gene: PRKCSH: Check of rating - currently red on all renal panels, green on Polycystic liver disease panel.
Inborn errors of metabolism v1.281 SPR Catherine Snow Tag treatable tag was added to gene: SPR.
Inborn errors of metabolism v1.281 SPR Catherine Snow Publications for gene: SPR were set to 27604308; 22018912; 22522443; 22018912; 24588500; 28189489; 21431957; 16650784
Short QT syndrome v1.20 CACNA2D1 James Eden changed review comment from: See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome.; to: See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome. Only one patient with Short QT syndrome tested to date in Manchester.
Inborn errors of metabolism v1.281 SPR Catherine Snow Publications for gene: SPR were set to 27604308; 22018912; 22522443; 22018912; 24588500; 28189489; 21431957; 16650784
Short QT syndrome v1.20 CACNB2 James Eden changed review comment from: See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome.; to: See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome. Only one patient with Short QT syndrome tested to date in Manchester.
Short QT syndrome v1.20 SCN5A James Eden reviewed gene: SCN5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 19862833, 30420954, 16301704; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inborn errors of metabolism v1.281 SPR Catherine Snow Publications for gene: SPR were set to 27604308; 22018912; 22522443; 22018912; 24588500; 28189489; 21431957; 16650784
Inborn errors of metabolism v1.280 SPR Catherine Snow Publications for gene: SPR were set to 27604308
Inborn errors of metabolism v1.280 SPR Catherine Snow Classified gene: SPR as Green List (high evidence)
Inborn errors of metabolism v1.280 SPR Catherine Snow Gene: spr has been classified as Green List (High Evidence).
Short QT syndrome v1.20 SCN5A James Eden Deleted their review
Inborn errors of metabolism v1.279 SPR Catherine Snow reviewed gene: SPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22018912, 22522443, 22018912, 24588500, 28189489, 21431957, 16650784; Phenotypes: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v1.20 CACNB2 James Eden changed review comment from: See figure 3 of Campuzano 2018, gene associated with Short QT syndrome.; to: See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome.
Short QT syndrome v1.20 CACNA2D1 James Eden changed review comment from: See figure 3 of Campuzano 2018, gene associated with Short QT syndrome.; to: See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome.
Short QT syndrome v1.20 SLC4A3 James Eden reviewed gene: SLC4A3: Rating: AMBER; Mode of pathogenicity: None; Publications: 18382206, 19862833, 30420954; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.20 SCN5A James Eden reviewed gene: SCN5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 19862833, 30420954, 16301704; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained paediatric onset end-stage renal disease v0.43 ACTA2 Eleanor Williams commented on gene: ACTA2: Is currently red on all renal panels.
Short QT syndrome v1.20 SCN5A James Eden Deleted their review
Short QT syndrome v1.20 CACNB2 James Eden reviewed gene: CACNB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19862833, 30420954, 16301704; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.20 CACNB2 James Eden Deleted their review
Short QT syndrome v1.20 CACNA2D1 James Eden reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 18382206, 19862833, 30420954; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.20 CACNA2D1 James Eden Deleted their review
Brugada syndrome v1.43 KCNH2 James Eden reviewed gene: KCNH2: Rating: RED; Mode of pathogenicity: None; Publications: 24400717, 23874304, 16043162; Phenotypes: Long QT syndrome 2 613688, Short QT syndrome 1 609620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained paediatric onset end-stage renal disease v0.43 CEP290 Eleanor Williams Added comment: Comment on mode of inheritance: Setting MOI to biallelic as per the Renal ciliopathies panel
Unexplained paediatric onset end-stage renal disease v0.43 CEP290 Eleanor Williams Mode of inheritance for gene: CEP290 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained paediatric onset end-stage renal disease v0.42 ICK Eleanor Williams commented on gene: ICK: Added new-gene-name tag, new approved HGNC gene symbol for ICK is CILK1
Unexplained paediatric onset end-stage renal disease v0.42 ICK Eleanor Williams Tag new-gene-name tag was added to gene: ICK.
Unexplained paediatric onset end-stage renal disease v0.42 XDH Moin Saleem reviewed gene: XDH: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 WDR73 Moin Saleem reviewed gene: WDR73: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 WDR60 Moin Saleem reviewed gene: WDR60: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 WDR35 Moin Saleem reviewed gene: WDR35: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TXNDC15 Moin Saleem reviewed gene: TXNDC15: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TRAF3IP1 Moin Saleem reviewed gene: TRAF3IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TP53RK Moin Saleem reviewed gene: TP53RK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TNS2 Moin Saleem reviewed gene: TNS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TMEM107 Moin Saleem reviewed gene: TMEM107: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TCTN2 Moin Saleem reviewed gene: TCTN2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 TBC1D8B Moin Saleem reviewed gene: TBC1D8B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 SLC2A9 Moin Saleem reviewed gene: SLC2A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 SLC22A12 Moin Saleem reviewed gene: SLC22A12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 PODXL Moin Saleem reviewed gene: PODXL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 OSGEP Moin Saleem reviewed gene: OSGEP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 NUP85 Moin Saleem reviewed gene: NUP85: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 NUP133 Moin Saleem reviewed gene: NUP133: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 MT-TF Moin Saleem reviewed gene: MT-TF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 MMACHC Moin Saleem reviewed gene: MMACHC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 MKKS Moin Saleem reviewed gene: MKKS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 MAGI2 Moin Saleem reviewed gene: MAGI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 LZTFL1 Moin Saleem reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 LAGE3 Moin Saleem reviewed gene: LAGE3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 KIAA0753 Moin Saleem reviewed gene: KIAA0753: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 KIAA0586 Moin Saleem reviewed gene: KIAA0586: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 ITSN1 Moin Saleem reviewed gene: ITSN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 IFT43 Moin Saleem reviewed gene: IFT43: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 IFT122 Moin Saleem reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 ICK Moin Saleem reviewed gene: ICK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 HYLS1 Moin Saleem reviewed gene: HYLS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 HOGA1 Moin Saleem reviewed gene: HOGA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 GRHPR Moin Saleem reviewed gene: GRHPR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 GATM Moin Saleem reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 FAT1 Moin Saleem reviewed gene: FAT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 EMP2 Moin Saleem reviewed gene: EMP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 DYNC2H1 Moin Saleem reviewed gene: DYNC2H1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 DLC1 Moin Saleem reviewed gene: DLC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 DHCR7 Moin Saleem reviewed gene: DHCR7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 DDX59 Moin Saleem reviewed gene: DDX59: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 CSPP1 Moin Saleem reviewed gene: CSPP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 CFHR3 Moin Saleem reviewed gene: CFHR3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 CFHR1 Moin Saleem reviewed gene: CFHR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 CEP104 Moin Saleem reviewed gene: CEP104: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 CENPF Moin Saleem reviewed gene: CENPF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 BBS7 Moin Saleem reviewed gene: BBS7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 B9D2 Moin Saleem reviewed gene: B9D2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 ARMC9 Moin Saleem reviewed gene: ARMC9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.42 AGXT Moin Saleem reviewed gene: AGXT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.41 XDH Eleanor Williams reviewed gene: XDH: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.41 WDR73 Eleanor Williams reviewed gene: WDR73: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.41 WDR60 Eleanor Williams reviewed gene: WDR60: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Unexplained paediatric onset end-stage renal disease v0.41 WDR35 Eleanor Williams reviewed gene: WDR35: Rating: