ClinVar Miner

Submissions for variant NM_000284.4(PDHA1):c.1133G>A (p.Arg378His)

dbSNP: rs137853250
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000011620 SCV000746768 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2017-12-18 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001267918 SCV001446428 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251895 SCV002523221 likely pathogenic See cases 2019-08-12 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM2, PP2, PP3
Invitae RCV000011620 SCV004299496 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2022-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the PDHA1 protein (p.Arg378His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pyruvate dehydrogenase E1-alpha deficiency (PMID: 1909401, 16713755). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 10873). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDHA1 protein function. This variant disrupts the p.Arg378 amino acid residue in PDHA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8962591, 20002125, 20002461, 24718837, 28639102). 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.
OMIM RCV000011620 SCV000031852 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 1991-01-01 no assertion criteria provided literature only

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