Submissions for variant NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser)

dbSNP: rs1555933963

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578359	SCV000680324	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2017-12-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091316	SCV001247271	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001091316	SCV001446424	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000578359	SCV001521299	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2020-05-05	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000578359	SCV002021650	likely pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2019-06-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824834	SCV002074233	pathogenic	Pyruvate dehydrogenase complex deficiency	2022-01-13	criteria provided, single submitter	clinical testing	Variant summary: PDHA1 c.491A>G (p.Asn164Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183518 control chromosomes (gnomAD). c.491A>G has been reported in the literature in multiple male individuals affected with Pyruvate Dehydrogenase Deficiency (e.g. Lissens_2000, DeBrosse_2012, Shin_2017). These data indicate that the variant is very likely to be associated with disease. These publications also reported enzymatic measurements from patient derived fibroblasts, and demonstrated low activities (Lissens_2000, Shin_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001091316	SCV002522033	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25978847, 32445240, 10679936)
MGZ Medical Genetics Center	RCV000578359	SCV002581684	likely pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2022-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV000578359	SCV004299491	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2023-05-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDHA1 protein function. ClinVar contains an entry for this variant (Variation ID: 488569). This missense change has been observed in individual(s) with Leigh syndrome and/or pyruvate dehydrogenase deficiency (PMID: 10679936, 32445240). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 164 of the PDHA1 protein (p.Asn164Ser).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000578359	SCV004807425	uncertain significance	Pyruvate dehydrogenase E1-alpha deficiency	2024-03-26	criteria provided, single submitter	clinical testing