Submissions for variant NM_000284.4(PDHA1):c.863G>A (p.Arg288His)

dbSNP: rs137853258

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000011637	SCV001443728	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2019-11-01	criteria provided, single submitter	clinical testing	This variant (also referred to as p.Arg288His) has been previously reported as a heterozygous change in a similarly affected female with pyruvate dehydrogenase deficiency and skewed X-inactivation within fibroblasts (PMID: 10486093). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.977G>A (p.Arg326His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function.Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.977G>A (p.Arg326His) variant is classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011637	SCV005087042	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pyruvate dehydrogenase E1-alpha deficiency (MIM#312170). (I) 0110 - This gene is associated with X-linked dominant disease. Males can also be affected; however, severe variants are presumed to be embryonically lethal (PMID: 22142326). Unaffected heterozygous females have also been reported (PMID: 23021068). (I) 0115 - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity, the severity of phenotypic presentation can vary. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated dehydrogenase E1 component domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Arg288Cys) has been classified as pathogenic by a clinical laboratory in ClinVar, and p.(Arg288Ser) has been reported in the literature as de novo in an eight month old with brain anomalies, seizures, and dysmorphic features (PMID: 31618753). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and observed as de novo by a clinical laboratory in ClinVar, and has been reported in the literature in an individual with pyruvate dehydrogenase complex deficiency (PMID: 10486093). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000011637	SCV000031869	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	1999-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748515	SCV005366761	pathogenic	PDHA1-related disorder	2024-07-13	no assertion criteria provided	clinical testing	The PDHA1 c.977G>A variant is predicted to result in the amino acid substitution p.Arg326His. This variant was reported in an individual with Pyruvate dehydrogenase deficiency (Lissens W et al 1999. PubMed ID: 10486093) and in an infant with multiple congenital abnormalities (Retterer et al. 2015. PubMed ID: 6633542). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.