ClinVar Miner

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

dbSNP: rs137853250
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Total submissions: 8
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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
Labcorp Genetics (formerly Invitae), Labcorp RCV000011620 SCV004299496 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2022-10-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 10873). 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. This variant is not present in population databases (gnomAD no frequency). 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).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000011620 SCV005086000 pathogenic Pyruvate dehydrogenase E1-alpha deficiency 2024-09-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pyruvate dehydrogenase E1-alpha deficiency. (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity resulting from the PDHA1 variant, the severity of phenotypic presentation can vary. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple individuals with pyruvate dehydrogenase complex deficiency (PMID: 33092611, 1909401, 23021068). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx RCV001267918 SCV005201185 pathogenic not provided 2024-01-24 criteria provided, single submitter clinical testing Expression studies found this variant to be associated with very low level of enzyme activity compared to wild-type (PMID: 33588022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1909401, 16713755, 8032855, 25356417, 10679936, 23021068, 33092611, 33726816, 33588022)
Ambry Genetics RCV004955255 SCV005470632 pathogenic Inborn genetic diseases 2024-08-13 criteria provided, single submitter clinical testing The c.1133G>A (p.R378H) alteration is located in exon 11 (coding exon 11) of the PDHA1 gene. This alteration results from a G to A substitution at nucleotide position 1133, causing the arginine (R) at amino acid position 378 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with Pyruvate dehydrogenase E1-alpha deficiency (DeBrosse, 2012; Wesó-Kucharska, 2022). Additionally, this variant has been determined to be the result of a de novo mutation in multiple affected individuals, both male and female (Imbard, 2011; Pavlu-Pereira, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is 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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