rs137853250
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000284.4(PDHA1):c.1133G>A(p.Arg378His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378C) has been classified as Pathogenic.
Frequency
Consequence
NM_000284.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHA1 | NM_000284.4 | c.1133G>A | p.Arg378His | missense_variant | 11/11 | ENST00000422285.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHA1 | ENST00000422285.7 | c.1133G>A | p.Arg378His | missense_variant | 11/11 | 1 | NM_000284.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2022 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1991 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | 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 - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Aug 12, 2019 | ACMG classification criteria: PS4, PM2, PP2, PP3 - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at