ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.506C>T (p.Ala169Val) (rs863224150)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel,ClinGen RCV001526400 SCV001736732 pathogenic Pyruvate dehydrogenase complex deficiency 2021-05-06 reviewed by expert panel curation The c.506C>T variant in the PDHA1 gene is a missense variant occurring in a hotspot domain (aa position A169, located in α β heterodimer interface (PM1). This variant is absent from population databases (PM2). This variant has been reported in three individuals in the literature with presentations consistent with PDHA1-related disease. These three cases include two assumed de novo cases (PMID: 20002461 and PMID: 21914562), and one maternity confirmed de novo case via exome sequencing in PMID: 31683770 (PS2). PMID: 20002461 Western Blot studies showed reduced E1a, and Imbard et al 2011 PDC studies indicate activity <3rd percentile in fibroblasts (PP4). In silico predictors suggest a deleterious effect (REVEL score – 0.946; PP3). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM1, PM2, PS2, PP3, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021.
GeneDx RCV000199416 SCV000252040 pathogenic not provided 2021-05-14 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 20002461, 29445841, 21914562, 31683770)
Invitae RCV000640506 SCV000762098 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 169 of the PDHA1 protein (p.Ala169Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with PDHA1-related disease, and found to be de novo in one of these cases (PMID: 20002461, 21914562, Invitae). ClinVar contains an entry for this variant (Variation ID: 214941). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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