rs137853252
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000284.4(PDHA1):c.904C>T(p.Arg302Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302H) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHA1 | NM_000284.4 | c.904C>T | p.Arg302Cys | missense_variant | 10/11 | ENST00000422285.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHA1 | ENST00000422285.7 | c.904C>T | p.Arg302Cys | missense_variant | 10/11 | 1 | NM_000284.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1040169Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 320259
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Sep 06, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDHA1 function (PMID: 9671272, 21846590). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 10879). This missense change has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 1293379, 9671272, 20002461, 21846590, 26865159). 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 cysteine, which is neutral and slightly polar, at codon 302 of the PDHA1 protein (p.Arg302Cys). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 22, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2022 | Published functional studies demonstrate that colonies harboring the R302C variant had no functional enzyme activity (Drakulic et al., 2018); 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: 27864847, 21846590, 25495354, 25525159, 26865159, 9671272, 1293379, 31658717, 31665995, 20002461, 29445841, 35261462) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
PDHA1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2023 | The PDHA1 c.1018C>T variant is predicted to result in the amino acid substitution p.Arg340Cys. This variant, also known as c.904C>T, p.Arg302Cys in the transcript NM_000284.4, has been reported to be causative for pyruvate dehydrogenase deficiency (Quintana et al. 2009. PubMed ID: 20002461; Glushakova et al. 2011. PubMed ID: 21846590; Parrini et al. 2017. PubMed ID: 27864847; Pirot et al. 2016. PubMed ID: 26865159; Stranneheim et al. 2014. PubMed ID: 25495354). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at