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Undiagnosed metabolic disorders v1.613 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Undiagnosed metabolic disorders v1.613 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 27604308
Undiagnosed metabolic disorders v1.607 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Undiagnosed metabolic disorders v1.606 PIGM Sarah Leigh Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906
Undiagnosed metabolic disorders v1.603 SEC23B Arina Puzriakova Added comment: Comment on mode of inheritance: There is limited evidence linking this gene with Cowden syndrome (monoallelic variants). Only one family has been reported to date (PMID:26522472). This gene:disease association is provisional in OMIM, 'limited' disease confidence category in G2P and is not listed in ClinGen (whereas CDAII is). Biallelic phenotype remains relevant to this panel (PMID: 35163229).

On this basis, updating the MOI from 'Both mono- and biallelic' to 'Biallelic' only.
Undiagnosed metabolic disorders v1.602 SEC23B Arina Puzriakova Publications for gene: SEC23B were set to 27604308
Undiagnosed metabolic disorders v1.600 SLC6A20 Sarah Leigh edited their review of gene: SLC6A20: Added comment: The gene disease associations of SLC6A20 with Hyperglycinuria (OMIM:138500) and Iminoglycinuria, digenic (OMIM:242600) have been refuted in OMIM. The single SLC6A20 variant rs17279437 has been reclassified as a polymorphism, because it is present in 19,986 of 278,932 alleles and in 856 homozygotes in the gnomAD database (v2.1.1), for an allele frequency of 0.07165 (Personal Communication to OMIM from Hamosh, A. Baltimore, Md. 3rd April 2023).; Changed rating: RED; Changed phenotypes to: Hyperglycinuria 138500, Iminoglycinuria, digenic 242600
Undiagnosed metabolic disorders v1.597 SLC12A3 Sarah Leigh Publications for gene: SLC12A3 were set to 27604308
Undiagnosed metabolic disorders v1.593 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.591 ETFB Sarah Leigh Publications for gene: ETFB were set to 27604308
Undiagnosed metabolic disorders v1.588 ETFA Sarah Leigh Publications for gene: ETFA were set to 27604308
Undiagnosed metabolic disorders v1.586 OGDH Sarah Leigh reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.584 OGDH Sarah Leigh Publications for gene: OGDH were set to 27604308
Undiagnosed metabolic disorders v1.575 SPG7 Sarah Leigh Publications for gene: SPG7 were set to 27604308
Undiagnosed metabolic disorders v1.572 GABRG2 Achchuthan Shanmugasundram Publications for gene: GABRG2 were set to 16510738; 15342642; 23708187
Undiagnosed metabolic disorders v1.568 GPHN Arina Puzriakova Publications for gene: GPHN were set to 27604308
Undiagnosed metabolic disorders v1.564 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Undiagnosed metabolic disorders v1.560 SDHA Arina Puzriakova Publications for gene: SDHA were set to 27604308
Undiagnosed metabolic disorders v1.557 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Undiagnosed metabolic disorders v1.555 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Undiagnosed metabolic disorders v1.552 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Added comment: Comment on mode of inheritance: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the MOI should be updated from 'biallelic' only to 'both mono- and biallelic' on Mitochondrial GMS panels (R354 and R63). As there was sufficient supporting evidence for the change, the MOI has also been updated to 'both' on this panel to ensure all panels reflect correct knowledge. Heterozygous variants can be associated with abnormal mitochondrial accumulation and therefore also within the scope of the panel.
Undiagnosed metabolic disorders v1.548 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 27604308
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Added comment: Comment on list classification: Gene was recently upgraded from Amber to Green on GMS panels and therefore also updating the rating here to ensure all panels display correct knowledge.
Undiagnosed metabolic disorders v1.546 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to support this gene-disease association and therefore ATP5A1 has been promoted to Green.
Undiagnosed metabolic disorders v1.544 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 27604308; 23599390; 23596069
Undiagnosed metabolic disorders v1.536 ACO2 Sarah Leigh Publications for gene: ACO2 were set to
Undiagnosed metabolic disorders v1.534 PRODH Sarah Leigh Added comment: Comment on list classification: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).
Undiagnosed metabolic disorders v1.523 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27604308
Undiagnosed metabolic disorders v1.519 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308
Undiagnosed metabolic disorders v1.517 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.515 SPTLC1 Sarah Leigh Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Undiagnosed metabolic disorders v1.507 CPT2 Arina Puzriakova Publications for gene: CPT2 were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.501 HIBADH Zornitza Stark gene: HIBADH was added
gene: HIBADH was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HIBADH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIBADH were set to 34176136
Phenotypes for gene: HIBADH were set to organic aciduria
Review for gene: HIBADH was set to RED
Added comment: Single family reported with two siblings presenting with 3-Hydroxyisobutyric aciduria. Male sib with neurodevelopmental symptoms, female sibling asymptomatic. No functional studies
Sources: Literature
Undiagnosed metabolic disorders v1.501 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS2; Inherited white matter disorders; Intellectual disability; Intracerebral calcification disorders to Aicardi-Goutieres syndrome 2, OMIM:610181
Undiagnosed metabolic disorders v1.496 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25595726; 25597510; 25597511; 25650066
Undiagnosed metabolic disorders v1.495 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Undiagnosed metabolic disorders v1.477 APOA5 Sarah Leigh Publications for gene: APOA5 were set to 27604308; 12417525; 27678447; 16200213
Undiagnosed metabolic disorders v1.475 APOA5 Sarah Leigh Publications for gene: APOA5 were set to 27604308; 27678447; 16200213
Undiagnosed metabolic disorders v1.474 APOA5 Sarah Leigh Publications for gene: APOA5 were set to 27604308
Undiagnosed metabolic disorders v1.472 APOA1 Sarah Leigh Publications for gene: APOA1 were set to 27604308
Undiagnosed metabolic disorders v1.467 ATAD3A Arina Puzriakova Publications for gene: ATAD3A were set to 27640307
Undiagnosed metabolic disorders v1.463 ALDH18A1 Sarah Leigh Publications for gene: ALDH18A1 were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.462 ALDH18A1 Sarah Leigh reviewed gene: ALDH18A1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.456 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.455 OCRL Eleanor Williams Publications for gene: OCRL were set to 27604308; 8504307; 9632163; 9632163; 15627218; 27625797
Undiagnosed metabolic disorders v1.454 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.445 NDUFC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Undiagnosed metabolic disorders v1.444 NDUFC2 Sarah Leigh Publications for gene: NDUFC2 were set to
Undiagnosed metabolic disorders v1.441 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Sterol-C4-methyl oxidase deficiency (Disorders of sterol biosynthesis); Microcephaly, congenital cataract, and psoriasiform dermatitis, 616834; (SC4MOL DEFICIENCY) to Sterol-C4-methyl oxidase deficiency (Disorders of sterol biosynthesis); Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Undiagnosed metabolic disorders v1.440 GLS Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) must first be validated within the Genomics England pipeline.

When excluding cases with the STR, the remaining evidence is not sufficient for inclusion as diagnostic-grade and therefore keeping Amber until the STR is validated or additional cases arise.
Undiagnosed metabolic disorders v1.439 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Glucosidase 1 deficiency (Disorders of protein N-glycosylation) to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Undiagnosed metabolic disorders v1.438 GLS Arina Puzriakova Publications for gene: GLS were set to 27604308
Undiagnosed metabolic disorders v1.436 GLS Arina Puzriakova reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30970188, 30575854, 30239721; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733, Developmental and epileptic encephalopathy 71, OMIM:618328, Developmental and epileptic encephalopathy, 71, MONDO:0032678, ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339, Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.436 MPI Arina Puzriakova Publications for gene: MPI were set to 27604308
Undiagnosed metabolic disorders v1.433 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism.

There is enough evidence to support a gene-disease association, so this gene has been rated Green.
Sources: Literature
Undiagnosed metabolic disorders v1.431 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.431 DDC Arina Puzriakova Publications for gene: DDC were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.429 COX6B1 Arina Puzriakova Publications for gene: COX6B1 were set to 27604308
Undiagnosed metabolic disorders v1.427 SCO1 Arina Puzriakova Publications for gene: SCO1 were set to 27604308
Undiagnosed metabolic disorders v1.424 AHCY Arina Puzriakova Added comment: Comment on list classification: Promoted from Red to Green - multiple unrelated families with this neurometabolic disorder caused by biallelic variants in AHCY.
Undiagnosed metabolic disorders v1.421 AHCY Arina Puzriakova Publications for gene: AHCY were set to 27604308
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.419 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Undiagnosed metabolic disorders v1.418 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.418 ALG14 Sarah Leigh Publications for gene: ALG14 were set to 27604308
Undiagnosed metabolic disorders v1.417 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Undiagnosed metabolic disorders v1.414 TANGO2 Sarah Leigh Publications for gene: TANGO2 were set to
Undiagnosed metabolic disorders v1.413 DDC Lothar Schlueter reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28100251, 30952622; Phenotypes: Aromatic L-amino acid decarboxylase deficiency 608643, floppy child, dystonia, hypotonia, developmental delay, oculogyric crisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.412 FMO3 Rebecca Foulger Publications for gene: FMO3 were set to 27604308
Undiagnosed metabolic disorders v1.410 SETX Catherine Snow reviewed gene: SETX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyotrophic lateral sclerosis 4, juvenile, 602433, Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, 606002; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.409 SKIV2L Catherine Snow reviewed gene: SKIV2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 22444670, 30397475; Phenotypes: Trichohepatoenteric syndrome 2, 614602; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.408 SLC12A3 Catherine Snow reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22009145; Phenotypes: Gitelman syndrome, 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.407 SLC18A2 Catherine Snow reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31240161, 23363473, 26497564, 28716265; Phenotypes: ?Parkinsonism-dystonia, infantile, 2, 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.406 SLC35A2 Catherine Snow reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30746764; Phenotypes: Congenital disorder of glycosylation, type IIm, 300896; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Undiagnosed metabolic disorders v1.405 SLC3A1 Catherine Snow reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.404 SLC6A3 Catherine Snow Publications for gene: SLC6A3 were set to 27604308
Undiagnosed metabolic disorders v1.403 SLC6A3 Catherine Snow Added comment: Comment on list classification: ted from Amber to Green. SLC6A3 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.402 RBP4 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. RBP4 is associated with retinoid metabolism on OMIM, but not on Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.400 SLC6A8 Catherine Snow reviewed gene: SLC6A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21660517; Phenotypes: Cerebral creatine deficiency syndrome 1, 300352; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Undiagnosed metabolic disorders v1.399 SLC7A9 Catherine Snow reviewed gene: SLC7A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
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
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
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
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
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
Undiagnosed metabolic disorders v1.391 TTC37 Catherine Snow Publications for gene: TTC37 were set to 27604308
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
Undiagnosed metabolic disorders v1.389 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308
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
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
Undiagnosed metabolic disorders v1.387 WFS1 Catherine Snow Publications for gene: WFS1 were set to 27604308
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 v1.385 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 v1.384 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
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
Undiagnosed metabolic disorders v1.383 VPS33B Catherine Snow Publications for gene: VPS33B were set to 27604308
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
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
Undiagnosed metabolic disorders v1.380 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308
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
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
Undiagnosed metabolic disorders v1.377 TTPA Catherine Snow Publications for gene: TTPA were set to 27604308
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
Undiagnosed metabolic disorders v1.375 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308
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
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 v1.371 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
Undiagnosed metabolic disorders v1.371 TAT Catherine Snow Publications for gene: TAT were set to 27604308
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
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 v1.366 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
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
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 v1.363 DNM2 Sarah Leigh Publications for gene: DNM2 were set to
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 v1.358 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
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 v1.356 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
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
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 v1.348 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
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 v1.345 TMEM126A Sarah Leigh Publications for gene: TMEM126A were set to 27604308
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 v1.342 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.
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.
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.
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).
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.
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.
Undiagnosed metabolic disorders v1.342 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308; 26801680; 28902413
Undiagnosed metabolic disorders v1.341 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308; 23297365
Undiagnosed metabolic disorders v1.340 PDK3 Sarah Leigh Publications for gene: PDK3 were set to 27604308
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 v1.337 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 27604308
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 v1.334 MRPS16 Sarah Leigh Publications for gene: MRPS16 were set to 27604308; 28749478; 15505824
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 v1.331 MRPS16 Sarah Leigh Publications for gene: MRPS16 were set to 27604308
Undiagnosed metabolic disorders v1.329 COX4I2 Sarah Leigh Publications for gene: COX4I2 were set to 27604308
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 v1.327 COA5 Sarah Leigh Publications for gene: COA5 were set to 27604308
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 v1.321 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 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 v1.319 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 27604308; 20566710
Undiagnosed metabolic disorders v1.317 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 27604308
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.
Undiagnosed metabolic disorders v1.316 SPTLC1 Catherine Snow Publications for gene: SPTLC1 were set to 27604308
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
Undiagnosed metabolic disorders v1.314 SPTLC2 Catherine Snow Publications for gene: SPTLC2 were set to 27604308
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
Undiagnosed metabolic disorders v1.312 SPR Catherine Snow Publications for gene: SPR were set to 27604308
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
Undiagnosed metabolic disorders v1.310 SLC25A12 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 biallelic variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.308 SLC25A12 Ivone Leong Publications for gene: SLC25A12 were set to 27604308
Undiagnosed metabolic disorders v1.307 SDHC Ivone Leong reviewed gene: SDHC: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.307 SDHAF2 Ivone Leong reviewed gene: SDHAF2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.307 SC5D Ivone Leong Added comment: Comment on publications: There are >3 unrelated cases and an animal model.
Undiagnosed metabolic disorders v1.307 SC5D Ivone Leong Publications for gene: SC5D were set to 27604308
Undiagnosed metabolic disorders v1.306 SC5D Ivone Leong Added comment: 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 v1.305 RNASEH2B Ivone Leong changed review comment from: Comment on list classification: Demoted from Amber to Red. RNASEH2B is associated with Aicardi-Goutieres syndrome 2 on OMIM and Gene2Phenotype. There are 2 unrelated cases on OMIM supporting the gene-disease link between RNASEH2B with Aicardi-Goutieres syndrome; however, RNASEH2B does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.; to: Comment on list classification: Demoted from Amber to Red. RNASEH2B is associated with Aicardi-Goutieres syndrome 2 on OMIM and Gene2Phenotype. There are 2 unrelated cases on OMIM about RNASEH2B causing Aicardi-Goutieres syndrome; however, RNASEH2B does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.305 RNASEH2C Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red. RNASEH2C is associated with Aicardi-Goutieres syndrome 3 on OMIM and Gene2Phenotype. There are 2 unrelated cases from the same geographical region on OMIM about RNASEH2C causing Aicardi-Goutieres syndrome; however, RNASEH2C does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.304 RNASEH2B Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red. RNASEH2B is associated with Aicardi-Goutieres syndrome 2 on OMIM and Gene2Phenotype. There are 2 unrelated cases on OMIM supporting the gene-disease link between RNASEH2B with Aicardi-Goutieres syndrome; however, RNASEH2B does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.301 HARS2 Sarah Leigh Added comment: Comment on publications: PMID: 21464306: One family reported, with five affected siblings who were compound heterozygous for variants L200V and V368L. Functional evidence in c.elegans was provided. PMID: 27650058: patients with sporadic Perrault syndrome IV-1 and VI-I were homozygous for the c.1010A>G (p.Tyr337Cys) variant. The patients were claimed not to be related, but originated from the same region in Morocco and the variant was characterised as being in the same haplotype, suggesting a founder effect. Found at a frequency of 1/121332 in Exac.
Undiagnosed metabolic disorders v1.301 HARS2 Sarah Leigh Publications for gene: HARS2 were set to 27604308
Undiagnosed metabolic disorders v1.300 HARS2 Sarah Leigh Added comment: Comment on list classification: This gene was discussed on the NHSE GMS Mitochondrial Specialist Group Meeting call on 25th February 2019. It was confirmed that Perrault syndrome was relevant for this panel, and that there was enough evidence for the gene to be Green.
Undiagnosed metabolic disorders v1.298 FECH Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 16 variants identified in unrelated cases.
Undiagnosed metabolic disorders v1.296 DHODH Sarah Leigh Publications for gene: DHODH were set to 27604308
Undiagnosed metabolic disorders v1.295 DHODH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 11 variants reported in 6 families (PMID 19915526), together with a knockout mouse model (PMID 27626380).
Undiagnosed metabolic disorders v1.293 DHCR24 Sarah Leigh Publications for gene: DHCR24 were set to 27604308
Undiagnosed metabolic disorders v1.292 DHCR24 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in at least cases, two of the variants were in cis in a case which was compound heterozygous with another variant (PMID 11519011). Supportive functional studies were also presented.
Undiagnosed metabolic disorders v1.290 DCXR Sarah Leigh Publications for gene: DCXR were set to 27604308
Undiagnosed metabolic disorders v1.289 DCXR Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified within Ashkenazi Jewish population, that functional studies have shown to be loss of function variants that result in lack of the normal DCXR protein.
Undiagnosed metabolic disorders v1.287 CYP7B1 Sarah Leigh Publications for gene: CYP7B1 were set to 27604308; 9802883; 18252231; 19187859
Undiagnosed metabolic disorders v1.286 CYP7B1 Sarah Leigh Added comment: Comment on list classification: At least 10 variants identified in unrelated cases of Spastic paraplegia 5A, autosomal recessive 270800 and one of these variants was also found in 3 unrelated cases of Bile acid synthesis defect, congenital, 3 613812, which is a more relevant phenotype for metabolic panels.
Undiagnosed metabolic disorders v1.284 PTS Ivone Leong Added comment: 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.
Undiagnosed metabolic disorders v1.283 CYP7B1 Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 10 variants identified in unrelated cases of Spastic paraplegia 5A, autosomal recessive 270800 and one of these variants was also found in a case of Bile acid synthesis defect, congenital, 3 613812.
Undiagnosed metabolic disorders v1.282 CYP7B1 Sarah Leigh Publications for gene: CYP7B1 were set to 27604308 9802883 18252231 19187859
Undiagnosed metabolic disorders v1.281 CYP7B1 Sarah Leigh Publications for gene: CYP7B1 were set to 9802883; 27604308
Undiagnosed metabolic disorders v1.280 CTSC Sarah Leigh Added comment: Comment on phenotypes: Other lysosomal disorders, Cathepsin-related disorders;Unexplained skeletal dysplasia
Undiagnosed metabolic disorders v1.280 CTSC Sarah Leigh Phenotypes for gene: CTSC were changed from Papillon-Lef vre syndrome (Other lysosomal disorders, Cathepsin-related disorders); Unexplained skeletal dysplasia to Haim-Munk syndrome 245010; Papillon-Lefevre syndrome 245000; Periodontitis 1, juvenile 170650
Undiagnosed metabolic disorders v1.279 CTSC Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 13 variants identified in unrelated cases of Papillon-Lefevre syndrome 245000.
Undiagnosed metabolic disorders v1.278 CLDN19 Sarah Leigh Added comment: Comment on phenotypes: Disorder of magnesium metabolism; Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Undiagnosed metabolic disorders v1.278 CLDN19 Sarah Leigh Phenotypes for gene: CLDN19 were changed from Hypomagnesaemia type 5, renal with ocular involvement (Disorder of magnesium metabolism); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Hypomagnesemia 5, renal, with ocular involvement 248190
Undiagnosed metabolic disorders v1.277 CLDN19 Sarah Leigh Publications for gene: CLDN19 were set to 27604308
Undiagnosed metabolic disorders v1.276 CLDN19 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 6 unrelated cases.
Undiagnosed metabolic disorders v1.275 CLDN16 Sarah Leigh Added comment: Comment on phenotypes: Disorder of magnesium metabolism; Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Undiagnosed metabolic disorders v1.275 CLDN16 Sarah Leigh Phenotypes for gene: CLDN16 were changed from Hypomagnesaemia type 3, renal (Disorder of magnesium metabolism); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Hypomagnesemia 3, renal 248250
Undiagnosed metabolic disorders v1.274 CLDN16 Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 19 variants identified in unrelated cases.
Undiagnosed metabolic disorders v1.272 CISD2 Sarah Leigh Publications for gene: CISD2 were set to 27604308
Undiagnosed metabolic disorders v1.271 CISD2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as both RD and IF Gen2Phen gene. At least 3 variants reported in unrelated cases, together with segration and functional studies.
Undiagnosed metabolic disorders v1.269 APOB Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 5 variants associated with Hypobetalipoproteinemia 615558 without other variants in other genes and 2 variants associated with Hypercholesterolemia, familial, 2 144010 in numberous cases.
Undiagnosed metabolic disorders v1.267 ALPL Sarah Leigh Publications for gene: ALPL were set to 27604308
Undiagnosed metabolic disorders v1.266 ALPL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 16 variants reported in hypophosphatasia, infantile 241500, some of these variants and others were found in childhood and adult Hypophosphatasia and two addtional variants were reported in a case of perinatal lethal hypophosphatasia (PMID 11745997).
Undiagnosed metabolic disorders v1.264 IER3IP1 Helen Brittain reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, 614231; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.256 ALDH3A2 Sarah Leigh edited their review of gene: ALDH3A2: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported.; Changed rating: GREEN; Changed publications: 27604308, 10792573, 10577908; Changed phenotypes: Sjogren-Larsson syndrome 270200
Undiagnosed metabolic disorders v1.256 ALAS2 Sarah Leigh edited their review of gene: ALAS2: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 18 variants identified in Anemia, sideroblastic, 1 300751 and two variants in Protoporphyria, erythropoietic, X-linked 300752 in six unrelated families, together with functional studies.; Changed rating: GREEN; Changed publications: 27604308, 1570328, 7560104, 12663458, 18760763; Changed phenotypes: Anemia, sideroblastic, 1 300751, Protoporphyria, erythropoietic, X-linked 300752
Undiagnosed metabolic disorders v1.256 ADSL Sarah Leigh edited their review of gene: ADSL: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported associated with adenylosuccinase deficiency in at least 10 unrelated cases.; Changed rating: GREEN; Changed publications: 27604308, 18830228, 12016589, 10090474; Changed phenotypes: Adenylosuccinase deficiency 103050, Intellectual disability, Epileptic encephalopathy
Undiagnosed metabolic disorders v1.256 ADA Sarah Leigh edited their review of gene: ADA: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 30 variants reported associated with Adenosine deaminase deficiency.; Changed rating: GREEN; Changed publications: 27604308, 3684597, 2783588, 1680289; Changed phenotypes: Adenosine deaminase deficiency, partial 102700, Severe combined immunodeficiency due to ADA deficiency 102700, Combined B and T cell defect, SCID, Infantile enterocolitis & monogenic inflammatory bowel disease
Undiagnosed metabolic disorders v1.256 ACY1 Sarah Leigh edited their review of gene: ACY1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in at least 9 unrelated cases.; Changed rating: GREEN; Changed publications: 27604308, 24117009, 17562838, 16465618; Changed phenotypes: Aminoacylase 1 deficiency 609924, Intellectual disability
Undiagnosed metabolic disorders v1.256 ABHD12 Sarah Leigh edited their review of gene: ABHD12: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 7 variants identified in at least 6 unrelated cases; Changed rating: GREEN; Changed publications: 27604308, 20797687, 24697911 ; Changed phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract 612674, Hereditary ataxia, Posterior segment abnormalities, Congenital hearing impairment (profound/severe), PHARC syndrome (Disorders of complex lipid synthesis)
Undiagnosed metabolic disorders v1.256 ABCG8 Sarah Leigh edited their review of gene: ABCG8: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 9 variants identified in numberous unrelated cases; Changed rating: GREEN; Changed publications: 27604308, 11452359, 15996216, 11099417, 22981120; Changed phenotypes: Sitosterolemia 210250, Familial hypercholesterolaemia
Undiagnosed metabolic disorders v1.256 ABCG5 Sarah Leigh edited their review of gene: ABCG5: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 8 variants identified in unrelated cases; Changed rating: GREEN; Changed publications: 27604308, 11099417, 11138003, 20719861, 17976197; Changed phenotypes: Sitosterolemia 210250, Familial hypercholesterolaemia
Undiagnosed metabolic disorders v1.254 PSAT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for ?Phosphoserine aminotransferase deficiency 610992; Neu-Laxova syndrome 2 616038. At least 5 variants reported in 6 cases of Neu-Laxova syndrome 2 616038 and 2 variants in a case of ?Phosphoserine aminotransferase deficiency 610992.
Undiagnosed metabolic disorders v1.253 PSAT1 Sarah Leigh Publications for gene: PSAT1 were set to 27604308
Undiagnosed metabolic disorders v1.251 PRPS1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Arts syndrome 301835, Charcot-Marie-Tooth disease, X-linked recessive, 5 311070, Deafness, X-linked 1 304500 and Phosphoribosylpyrophosphate synthetase superactivity 300661. At least 22 variants have been reported across the phenotypes.
Undiagnosed metabolic disorders v1.248 ATP5A1 Sarah Leigh Publications for gene: ATP5A1 were set to 27604308
Undiagnosed metabolic disorders v1.247 ATP5A1 Sarah Leigh Added comment: 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.
Undiagnosed metabolic disorders v1.246 POR Sarah Leigh Publications for gene: POR were set to 27604308
Undiagnosed metabolic disorders v1.245 POR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 10 variants associated with Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750 and 6 variants associated with Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571.
Undiagnosed metabolic disorders v1.243 PNP Sarah Leigh Publications for gene: PNP were set to 27604308
Undiagnosed metabolic disorders v1.242 PNP Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 10 variants reported.
Undiagnosed metabolic disorders v1.240 PINK1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 12 variants were reported.
Undiagnosed metabolic disorders v1.239 PINK1 Sarah Leigh Added comment: Comment on publications: Many more publications
Undiagnosed metabolic disorders v1.239 PINK1 Sarah Leigh Publications for gene: PINK1 were set to 27604308
Undiagnosed metabolic disorders v1.237 PIGM Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 1 variant was reported in 2 unrelated families (PMID 16767100), together with supportive functional studies (PMID 17442906 & 25293775).
Undiagnosed metabolic disorders v1.236 PIGM Sarah Leigh Publications for gene: PIGM were set to 27604308; 25293775; 16767100
Undiagnosed metabolic disorders v1.234 PHGDH Sarah Leigh Publications for gene: PHGDH were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.233 PHGDH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for both phenotypes. At least 6 variants reported in 6 unrelated cases of Phosphoglycerate dehydrogenase deficiency 601815 and 4 variants reported in 4 unrelated cases of Neu-Laxova syndrome 1 256520.
Undiagnosed metabolic disorders v1.231 PEPD Sarah Leigh Publications for gene: PEPD were set to 27604308
Undiagnosed metabolic disorders v1.230 PEPD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 11 variants reported.
Undiagnosed metabolic disorders v1.228 PDPR Sarah Leigh Added comment: Comment on list classification: Not associated with a phenotype in OMIM or in Gen2Phen. At least 1 variant reported in a case of global developmental delay, typical Joubert syndrome, according to PMID 25558065.
Undiagnosed metabolic disorders v1.226 PCSK9 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 gain of function variants reported in unrelated cases of Hypercholesterolemia, familial, 3 603776 and at least 5 loss of function variants have been reported in unrelated cases of {Low density lipoprotein cholesterol level QTL 1} 603776.
Undiagnosed metabolic disorders v1.225 PCSK9 Sarah Leigh Publications for gene: PCSK9 were set to 27604308
Undiagnosed metabolic disorders v1.223 PCK1 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 unrelated cases.
Undiagnosed metabolic disorders v1.222 PCK1 Sarah Leigh Publications for gene: PCK1 were set to 27604308
Undiagnosed metabolic disorders v1.220 PANK2 Sarah Leigh Publications for gene: PANK2 were set to 27604308
Undiagnosed metabolic disorders v1.218 PANK2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 13 variants reported for Neurodegeneration with brain iron accumulation 234200 and 3 variants in 2 unrelated cases of HARP syndrome 607236.
Undiagnosed metabolic disorders v1.216 OPLAH 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 have been reported. It is not clear whether the mode of inheritance is biallelic or monoallelic as homozygous and heterozygote cases have been seen. The PMID 21651516 reports two sibs who are homozygous for a terminating variant, the younger brother is 5-oxoprolinase deficiency, however, his clinically unaffected sister just has increased 5-oxoproline excretion.
Undiagnosed metabolic disorders v1.215 OPLAH Sarah Leigh Publications for gene: OPLAH were set to 27604308
Undiagnosed metabolic disorders v1.213 OCRL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for both Dent disease 2 300555 and Lowe syndrome 309000. At least 5variants reported in Dent disease 2 300555 and 4 variants in Lowe syndrome 309000.
Undiagnosed metabolic disorders v1.212 OCRL Sarah Leigh Added comment: Comment on phenotypes: Lowe syndrome (Disorders of amino acid transport);Cataracts;Intellectual disability;Intellectual_disability;Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Undiagnosed metabolic disorders v1.212 OCRL Sarah Leigh Phenotypes for gene: OCRL were changed from Lowe syndrome (Disorders of amino acid transport); Cataracts; Intellectual disability; Intellectual_disability; Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Dent disease 2 300555; Lowe syndrome 309000
Undiagnosed metabolic disorders v1.211 OCRL Sarah Leigh Publications for gene: OCRL were set to 27604308
Undiagnosed metabolic disorders v1.210 NDUFB9 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, together with supportive functional studies.
Undiagnosed metabolic disorders v1.209 NDUFB9 Sarah Leigh Added comment: Comment on publications: PMID: 22200994 Reports one probound heterozygous for a variant (c.140G>T, p.Arg47Leu) within NDUFB9 with parents not available for genetic testing, and in vitro complement studies in patient fibroblasts showed wildtype NDUFB9 did not rescue complex I activity, therefore was deemed not pathogenic. Reports two brothers homozygous for a variant in the gene, with parents who are heterozygous carriers (c.191T>C, p.Leu64Pro). In vitro, fibroblasts from the proband showed low complex I activity, and wildtype NDUFB9 rescued complex I activity.
Undiagnosed metabolic disorders v1.209 NDUFB9 Sarah Leigh Publications for gene: NDUFB9 were set to 27604308
Undiagnosed metabolic disorders v1.206 MVK 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 8 variants reported in Hyper-IgD syndrome 260920, 9 variants reported in Mevalonic aciduria 610377 and 8 variants reported in Porokeratosis 3, multiple types 175900.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants reported for each phenotype.
Undiagnosed metabolic disorders v1.206 MVK Sarah Leigh Publications for gene: MVK were set to 27604308
Undiagnosed metabolic disorders v1.205 MVK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 8 variants reported in Hyper-IgD syndrome 260920, 9 variants reported in Mevalonic aciduria 610377 and 8 variants reported in Porokeratosis 3, multiple types 175900.
Undiagnosed metabolic disorders v1.202 MTPAP Sarah Leigh Publications for gene: MTPAP were set to 27604308
Undiagnosed metabolic disorders v1.201 MTPAP Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified in unrelated cases, and supportive functional studies.
Undiagnosed metabolic disorders v1.200 MTFMT Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 8 variants reported.
Undiagnosed metabolic disorders v1.199 MTFMT Sarah Leigh Publications for gene: MTFMT were set to 27604308
Undiagnosed metabolic disorders v1.197 MRPL3 Sarah Leigh Added comment: Comment on list classification: This gene was rated 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: 2 unrelated families (4 sibs + 1 unrelated case) and functional studies. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Undiagnosed metabolic disorders v1.196 MRPL3 Sarah Leigh Publications for gene: MRPL3 were set to 27604308
Undiagnosed metabolic disorders v1.194 MOCS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in at least 8 unrelated cases, together with supportive functional studies.
Undiagnosed metabolic disorders v1.193 MOCS2 Sarah Leigh Publications for gene: MOCS2 were set to 27604308
Undiagnosed metabolic disorders v1.191 MOCS1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported unrelated cases.
Undiagnosed metabolic disorders v1.190 MOCS1 Sarah Leigh Publications for gene: MOCS1 were set to 27604308
Undiagnosed metabolic disorders v1.188 MAOA Sarah Leigh Publications for gene: MAOA were set to 27604308
Undiagnosed metabolic disorders v1.187 MAOA Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 4 variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.186 MAGT1 Sarah Leigh Publications for gene: MAGT1 were set to 27604308
Undiagnosed metabolic disorders v1.185 MAGT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in unrelated cases, together with mouse knock-out model (PMID 29581357).
Undiagnosed metabolic disorders v1.183 LIPC 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 families with Hepatic lipase deficiency, 614025.
Undiagnosed metabolic disorders v1.182 LIPC 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 3 variants reported in two unrelated families with Hepatic lipase deficiency, 614025.
Undiagnosed metabolic disorders v1.181 LIPC Sarah Leigh Publications for gene: LIPC were set to 27604308; 1671786; 12777476; 22464213; 23219720
Undiagnosed metabolic disorders v1.179 LIPC Sarah Leigh Publications for gene: LIPC were set to 27604308
Undiagnosed metabolic disorders v1.177 LDLRAP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported.
Undiagnosed metabolic disorders v1.176 LDLRAP1 Sarah Leigh Publications for gene: LDLRAP1 were set to 27604308
Undiagnosed metabolic disorders v1.174 LDLR Sarah Leigh Publications for gene: LDLR were set to 27604308; 27821657
Undiagnosed metabolic disorders v1.173 LDLR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Over 2000 variants reported.
Undiagnosed metabolic disorders v1.172 LDLR Sarah Leigh Publications for gene: LDLR were set to 27604308
Undiagnosed metabolic disorders v1.170 LBR Sarah Leigh Publications for gene: LBR were set to 27604308
Undiagnosed metabolic disorders v1.169 LBR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Greenberg skeletal dysplasia 215140. At least 15 variants have been reported, in 5 unrelated cases of Pelger-Huet anomaly 169400, 3 unrelated cases of Pelger-Huet anomaly with mild skeletal anomalies 618019, 5 unrelated cases of Greenberg skeletal dysplasia 215140 and in a single case of ?Reynolds syndrome 613471.
Undiagnosed metabolic disorders v1.167 ISCU Sarah Leigh Added comment: Comment on list classification: Sufficient published reported biallelic cases, with supportive functional studies. The most frequent reported variant c.343+382G>C g.108567650G>C is deep in intron five of the gene and strengthens a weak splicing acceptor site, with consequent retention of a 100-bp intronic sequence upstream of the known terminal exon, introduction of a stop codon and decreased levels of ISCU mRNA and protein (PMID 18304497). This may be missed by standard sequencing.
Undiagnosed metabolic disorders v1.166 ISCU Sarah Leigh Publications for gene: ISCU were set to 27604308
Undiagnosed metabolic disorders v1.165 HSD17B10 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for mental retardation syndromic X-linked type 10 . At least 8 variants reported.
Undiagnosed metabolic disorders v1.164 HSD17B10 Sarah Leigh Publications for gene: HSD17B10 were set to 27604308
Undiagnosed metabolic disorders v1.162 HPS1 Sarah Leigh Publications for gene: HPS1 were set to 27604308
Undiagnosed metabolic disorders v1.161 HPS1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in at least 5 unrelated cases.
Undiagnosed metabolic disorders v1.159 HPD Sarah Leigh Publications for gene: HPD were set to 27604308; 10942115; 11073718; 26226126:30984715; 17560158
Undiagnosed metabolic disorders v1.158 HPD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for both phenotypes. At least 4 variants reported in unrelated cases of Tyrosinemia, type III 276710 and 4 variants in 6 unrelated cases of Hawkinsinuria 140350 (at least 2 of these cases were compound heterozygotes).
Undiagnosed metabolic disorders v1.157 HPD Sarah Leigh Publications for gene: HPD were set to 27604308
Undiagnosed metabolic disorders v1.155 HADH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Numerous variants reported in unrelated cases of Hyperinsulinemic hypoglycemia, familial, 4 609975.
Undiagnosed metabolic disorders v1.154 HADH Sarah Leigh Publications for gene: HADH were set to 27604308
Undiagnosed metabolic disorders v1.152 GNMT 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 2 unrelated cases, with supportive functional data.
Undiagnosed metabolic disorders v1.151 GNMT Sarah Leigh Publications for gene: GNMT were set to 27604308; 17660255
Undiagnosed metabolic disorders v1.150 GLUL 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 and as confirmed Gen2Phen gene. At least 3 variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.149 GLUL Sarah Leigh Publications for gene: GLUL were set to 27604308
Undiagnosed metabolic disorders v1.147 GK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported.
Undiagnosed metabolic disorders v1.146 GK Sarah Leigh Publications for gene: GK were set to 27604308
Undiagnosed metabolic disorders v1.145 GK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported.
Undiagnosed metabolic disorders v1.141 GAMT Sarah Leigh Publications for gene: GAMT were set to 27604308
Undiagnosed metabolic disorders v1.140 GAMT Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 4 unrelated cases.
Undiagnosed metabolic disorders v1.139 FTCD Sarah Leigh Publications for gene: FTCD were set to 27604308
Undiagnosed metabolic disorders v1.138 FTCD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 15 variants reported.
Undiagnosed metabolic disorders v1.136 FGFR2 Sarah Leigh Added comment: Comment on list classification: Associated with 14 phenotypes in OMIM and as confirmed Gen2Phen gene for acrocephalosyndactyly type V, Antley-Bixler syndrome, Apert syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, familial scaphocephaly syndrome, Jackson-Weiss syndrome, lacrimo-auriculo-dento-digital syndrome. At least 44 variants reported.
Undiagnosed metabolic disorders v1.133 DPM3 Sarah Leigh Publications for gene: DPM3 were set to 27604308
Undiagnosed metabolic disorders v1.132 DPM3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported as homozygotes in two unrelated cases, together with segregation and supportive functional studies.
Undiagnosed metabolic disorders v1.131 TANGO2 Sarah Leigh Added comment: Comment on list classification: Based on recommendations of Helen Britain (Clinical Fellow, Genomics England) as cases will have of periods of decompensation that are associated with hypoglycaemia and hyperammonaemia.
Undiagnosed metabolic disorders v1.129 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.
Undiagnosed metabolic disorders v1.127 IER3IP1 Sarah Leigh Added comment: Comment on list classification: Based on recommendation of Helen Britain (Clinical Fellow, Genomics England), that patients will present with features of microcephaly / neonatal diabetes / developmental delay, rather than metabolic disorder.
Undiagnosed metabolic disorders v1.126 IER3IP1 Sarah Leigh gene: IER3IP1 was added
gene: IER3IP1 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: IER3IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IER3IP1 were set to 21835305; 22991235; 24138066
Phenotypes for gene: IER3IP1 were set to Microcephaly, epilepsy, and diabetes syndrome 614231
Review for gene: IER3IP1 was set to AMBER
Added comment: Sources: Other
Undiagnosed metabolic disorders v1.125 POLG2 Sarah Leigh Publications for gene: POLG2 were set to 27604308
Undiagnosed metabolic disorders v1.122 FXN Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 9 variants identified in unrelated cases.
FXN is rated Red on the mitochondrial panels on the recommendation of the GMS mitochondrial specialist test group, including by Carl Fratter (Oxford University Hospitals NHS Trust). As it is associated with Friedreich’s ataxia, which is technically a mitochondrial disorder, but the phenotype is different to other mitochondrial conditions.
Undiagnosed metabolic disorders v1.121 RANBP2 Sarah Leigh Added comment: Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information (e.g. on penetrance) is required for a clear gene:disease association.
Undiagnosed metabolic disorders v1.120 PGAM2 Sarah Leigh changed review comment from: Comment on list classification: Additional case with biallelic variant and rhabdomyolysis; to: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants identified in 3 unrelated cases.
Undiagnosed metabolic disorders v1.120 DHCR7 Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and as confirmed Gen2Phen gene. At least 21 variants reported.
Undiagnosed metabolic disorders v1.117 FUT8 Louise Daugherty gene: FUT8 was added
gene: FUT8 was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: FUT8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT8 were set to 29304374
Phenotypes for gene: FUT8 were set to Congenital disorder of glycosylation with defective fucosylation, 618005
Review for gene: FUT8 was set to GREEN
Added comment: Adding to Undiagnosed metabolic disorders panel after reviewing panels for GMS, as recommended by the Genomics England clinical team, to benefit the 100K participants. Enough evidence to support gene-disease association and relevance to this panel to rate this gene Green.
Sources: Expert Review
Undiagnosed metabolic disorders v1.115 HYAL1 Sarah Leigh Publications for gene: HYAL1 were set to 27604308
Undiagnosed metabolic disorders v1.113 ARSG Sarah Leigh Publications for gene: ARSG were set to 20679209; 25452429; 26975023; 29300381
Undiagnosed metabolic disorders v1.108 UQCRQ Sarah Leigh Publications for gene: UQCRQ were set to 27604308; 18439546
Undiagnosed metabolic disorders v1.107 UQCRQ Sarah Leigh Publications for gene: UQCRQ were set to 27604308
Undiagnosed metabolic disorders v1.106 UQCRQ 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 variant reported in a consanguineous Israeli Bedouin kindred with Mitochondrial complex III deficiency, nuclear type 4 (615159)(PMID: 18439546).
Undiagnosed metabolic disorders v1.105 UQCRB Rebecca Foulger Publications for gene: UQCRB were set to 27604308
Undiagnosed metabolic disorders v1.104 UQCRB Sarah Leigh reviewed gene: UQCRB: Rating: ; Mode of pathogenicity: None; Publications: 28604960, 18439546; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3 615158; Mode of inheritance: None
Undiagnosed metabolic disorders v1.104 MANBA Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in 6 unrelated cases.
Undiagnosed metabolic disorders v1.102 ASAH1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in 6 cases of Farber lipogranulomatosis 228000 and 5 variants in 3 cases of Spinal muscular atrophy with progressive myoclonic epilepsy 159950.
Undiagnosed metabolic disorders v1.101 ASAH1 Sarah Leigh Publications for gene: ASAH1 were set to 27604308
Undiagnosed metabolic disorders v1.100 ARSG Sarah Leigh Publications for gene: ARSG were set to 20679209; 25452429; 26975023
Undiagnosed metabolic disorders v1.99 PGAM2 Sarah Leigh Publications for gene: PGAM2 were set to 27604308
Undiagnosed metabolic disorders v1.98 PGAM2 Sarah Leigh Added comment: Comment on list classification: Additional case with biallelic variant and rhabdomyolysis
Undiagnosed metabolic disorders v1.96 ATP13A2 Sarah Leigh Publications for gene: ATP13A2 were set to 27604308; 16964263; 27217339
Undiagnosed metabolic disorders v1.95 ATAD3A Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team and the clinical team: Sufficient evidence has been provided by the external expert review for this gene to be rated green.
Other aspects of the phenotype may warrant for this gene to be included on alternative specific panels (i.e. intellectual disability); however, not enough evidence is available at the moment. Therefore, this gene has also been added to the "watchlist" so that more cases can be collected.
Undiagnosed metabolic disorders v1.92 SLC35A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green as agreed with Helen Brittain following review of 2018 paper (PMID:30115659) and promotion to Green on the 'Congenital disorders of glycosylation' panel. In addition to the 'leaky' polymorphism reported in PMID:15576474, there are 3 cases (PMIDs 23873973, 28856833, 30115659) to support causation of glycosylation disorder.
Undiagnosed metabolic disorders v1.91 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 27604308
Undiagnosed metabolic disorders v1.90 ATAD3A Julia Baptista gene: ATAD3A was added
gene: ATAD3A was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307
Phenotypes for gene: ATAD3A were set to Lactic acidosis; Methylglutaconic aciduria; Neurological abnormalities; Cerebellar hypoplasia; Optic atrophy; Hypertrophic cardiomyopathy; Scoliosis; Spinal muscular atrophy
Review for gene: ATAD3A was set to GREEN
gene: ATAD3A was marked as current diagnostic
Added comment: A raised plasma lactate was reported in 4/7 families and methylglutaconic aciduria in 3/7 families (PMID: 27640307). Multiple patients with a diagnosis are described as having "severe metabolic disease".
Sources: Literature
Undiagnosed metabolic disorders v1.82 GLS Saikat Santra reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29468182; Phenotypes: Intellectual disability, Ataxia, Optic Atrophy; Mode of inheritance: None
Undiagnosed metabolic disorders v1.82 UPB1 Saikat Santra reviewed gene: UPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24526388, 25638458, 22525402; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 BCAT2 Saikat Santra reviewed gene: BCAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25653144; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 GAMT Saikat Santra reviewed gene: GAMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Creatine deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 DHCR7 Saikat Santra reviewed gene: DHCR7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dysmorphism, Cataract; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 RPIA Sarah Leigh commented on gene: RPIA: Review by Konstantinos Varvagiannis for the Genetic Epilepsy syndromes panel. 9 Dec 2018, 1:44 a.m.
Panel version: 0.1488
Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611. PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T or p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG or p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548]. PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis. PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis. 2 of the 3 patients described in the literature presented seizures. As a result this gene can be considered for inclusion in this panel as amber. [This gene is also present in the Undiagnosed metabolic disorders gene panel as red. Please consider upgrade based on these further publications.]. Sources: Literature
Undiagnosed metabolic disorders v1.82 RPIA Sarah Leigh Publications for gene: RPIA were set to 27604308
Undiagnosed metabolic disorders v1.81 RPIA Sarah Leigh Added comment: Comment on list classification: Based on additional variants reported in PMIDs 28801340; 30088433.
Undiagnosed metabolic disorders v1.79 ATXN7_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Undiagnosed metabolic disorders v1.78 ISCA-37440-Loss Louise Daugherty Region: ISCA-37440-Loss was added
Region: ISCA-37440-Loss was added to Undiagnosed metabolic disorders. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37440-Loss was set to BIALLELIC, autosomal or pseudoautosomal
Publications for Region: ISCA-37440-Loss were set to 11524703; 18234729; 16385448
Phenotypes for Region: ISCA-37440-Loss were set to mild/moderate mental retardation; facial dysmorphism; Hypotonia-cystinuria syndrome (HCS); 2p21 deletion syndrome; rapid weight gain in late childhood; failure to thrive; growth hormone deficiency; 606407; lactic acidemia; respiratory chain complex IV deficiency; hyperphagia; minor facial dysmorphism; severe somatic and developmental delay; nephrolithiasis; cystinuria; neonatal seizures; hypotonia
Undiagnosed metabolic disorders LCAT Rebecca Foulger reviewed LCAT
Undiagnosed metabolic disorders BCAT2 Sarah Leigh reviewed BCAT2
Undiagnosed metabolic disorders BCAT1 Sarah Leigh reviewed BCAT1