ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.862C>T (p.Arg288Cys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001204675 SCV001375891 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 288 of the PDHA1 protein (p.Arg288Cys). 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 individuals affected with pyruvate dehydrogenase E1-alpha (PDHE1α) deficiency (PMID: 28918066, Invitae). In at least one individual the variant was observed to be de novo. 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: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg288 amino acid residue in PDHA1. Other variant(s) that disrupt this residue have been observed in individuals with PDHA1-related conditions (PMID: 10486093, 26633542), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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