Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001753598 | SCV001994842 | pathogenic | Pyruvate dehydrogenase complex deficiency | 2021-04-02 | reviewed by expert panel | curation | 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. |
Gene |
RCV000196688 | SCV000252033 | pathogenic | not provided | 2022-06-24 | criteria provided, single submitter | clinical testing | 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) |
Génétique des Maladies du Développement, |
RCV000760291 | SCV000890132 | pathogenic | Pyruvate dehydrogenase E1-alpha deficiency | 2015-10-22 | criteria provided, single submitter | clinical testing |