Submissions for variant NM_000284.4(PDHA1):c.910C>T (p.Arg304Ter)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	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.
GeneDx	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, Hospices Civils de Lyon	RCV000760291	SCV000890132	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2015-10-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000196688	SCV005051189	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	PDHA1: PVS1, PS2, PM2, PS4:Moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760291	SCV005839356	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2024-09-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg304*) in the PDHA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDHA1 are known to be pathogenic (PMID: 10679936, 21914562). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pyruvate dehydrogenase complex deficiency (PMID: 33204598). This variant is also known as c.1024C>T (Arg342*). ClinVar contains an entry for this variant (Variation ID: 214935). For these reasons, this variant has been classified as Pathogenic.