ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.905G>A (p.Arg302His) (rs1064794149)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481593 SCV000567981 pathogenic not provided 2015-09-09 criteria provided, single submitter clinical testing The R302H missense variant in the PDHA1 gene was been reported previously in association withpyruvate dehydrogenase complex (PDHc) deficiency (Otero et al., 1998; Soares-Fernanades et al.,2008). The R302H substitution occurs at a position that is conserved across species. In silico analysispredicts this variant is probably damaging to the protein structure/function. Missense variants at thesame position (R302C and R302L) and in nearby residues (H292L, D296E, G298E) have also beenreported in the Human Gene Mutation Database in association with PDHc (Stenson et al., 2014),supporting the functional importance of this region of the protein. Males with a pathogenic variant inthe PDHA1 gene typically present with severe neonatal lactic acidosis while the presentation infemales is more variable and is dependent upon the pattern of X-inactivation. Given the available evidence, we interpret R302H as a pathogenic variant.
Invitae RCV001216859 SCV001388676 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 302 of the PDHA1 protein (p.Arg302His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of PDH complex deficiency (PMID: 9671272, 18197404, 21914562, Invitae). ClinVar contains an entry for this variant (Variation ID: 419850). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg302 amino acid residue in PDHA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20002461, 1293379, 26865159, 21846590, 9671272, ). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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