ClinVar Miner

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

dbSNP: 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 2018-01-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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"). 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). This variant is not present in population databases (ExAC no frequency). 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.

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