rs863224146
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4PM6_SupportingPM2PVS1
This summary comes from the ClinGen Evidence Repository: The c.910C>T; p. R304X variant in the PDHA1 gene is a nonsense mutation resulting in truncation >50bp upstream of the last exon-exon junction in PDHA1 and is predicted to undergo nonsense mediated decay (PVS1). While this mutation occurs in a hotspot domain (aa position R304, phosphorylation loop region), it is predicted to undergo nonsense mediated decay so PM1 was not scored. This variant is absent from population databases (PM2). This variant has been reported once in the literature in an 8-day old patient with neonatal lactic acidosis, microcephaly, hypotonia and psychomotor delay (PMID:21914562). The variant was not seen in patient’s mother, but maternity was not confirmed (PM6_supporting). Blood pyruvate was significantly elevated at 0.84mM with a lactate/pyruvate ratio of 19, which the PDHA1 Curation Expert Panel agreed was supportive of pathogenicity (PP4). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PVS1, PM2, PM6_supporting, PP4). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 03/10/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA321113/MONDO:0019169/014
Frequency
Consequence
NM_000284.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHA1 | NM_000284.4 | c.910C>T | p.Arg304Ter | stop_gained | 10/11 | ENST00000422285.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHA1 | ENST00000422285.7 | c.910C>T | p.Arg304Ter | stop_gained | 10/11 | 1 | NM_000284.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1059100Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 332492
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30283815, 21914562, 33204598) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | PDHA1: PVS1, PS2, PM2, PS4:Moderate - |
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Oct 22, 2015 | - - |
Pyruvate dehydrogenase complex deficiency Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Apr 02, 2021 | The c.910C>T; p. R304X variant in the PDHA1 gene is a nonsense mutation resulting in truncation >50bp upstream of the last exon-exon junction in PDHA1 and is predicted to undergo nonsense mediated decay (PVS1). While this mutation occurs in a hotspot domain (aa position R304, phosphorylation loop region), it is predicted to undergo nonsense mediated decay so PM1 was not scored. This variant is absent from population databases (PM2). This variant has been reported once in the literature in an 8-day old patient with neonatal lactic acidosis, microcephaly, hypotonia and psychomotor delay (PMID: 21914562). The variant was not seen in patient’s mother, but maternity was not confirmed (PM6_supporting). Blood pyruvate was significantly elevated at 0.84mM with a lactate/pyruvate ratio of 19, which the PDHA1 Curation Expert Panel agreed was supportive of pathogenicity (PP4). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PVS1, PM2, PM6_supporting, PP4). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 03/10/2021. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at