ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.904C>T (p.Arg302Cys) (rs137853252)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199671 SCV000252032 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The R302C variant in the PDHA1 gene has been reported previously in several unrelated female individuals in association with pyruvate dehydrogenase complex (PDHc) deficiency (Quintana et al., 2010; Glushakova et al., 2011; Dahl et al. 1992). This variant has also been reported in a male with PDHc deficiency who was a somatic mosaic for the R302C variant (Quintana et al., 2010). Functional studies in yeast demonstrated that colonies harboring the R302C variant had no functional enzyme activity (Drakulic et al., 2018). The R302C variant is not observed in large population cohorts (Lek et al., 2016). The R302C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense variants in the same residue (R302H, R302L) have been reported in individuals with decreased PDH activity/PDHc deficiency (Soares-Fernandes et al., 2008; Otero et al., 1998; Lissense et al., 2000). Therefore, we interpret R302C as a pathogenic variant
Ambry Genetics RCV000622696 SCV000742265 pathogenic Inborn genetic diseases 2017-04-07 criteria provided, single submitter clinical testing
Invitae RCV000011626 SCV000832378 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 302 of the PDHA1 protein (p.Arg302Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals affected with pyruvate dehydrogenase deficiency (PMID: 20002461, 1293379, 26865159, 21846590, 9671272). ClinVar contains an entry for this variant (Variation ID: 10879). Experimental studies have shown that this missense change disrupts protein function (PMID: 21846590, 9671272). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Lab, University of California San Francisco RCV000011626 SCV001167627 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2018-09-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000199671 SCV001249123 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000011626 SCV001521302 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2020-09-22 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000011626 SCV000031858 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 1998-01-01 no assertion criteria provided literature only

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