Submissions for variant NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)

dbSNP: rs863224147

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001796726	SCV002037609	pathogenic	Pyruvate dehydrogenase complex deficiency	2021-10-25	reviewed by expert panel	curation	The c.1132C>T (p.R378C) variant in PDHA1 has been reported in multiples males and females with pyruvate dehydrogenase deficiency and is one of the more common pathogenic variants seen in this cohort (PMID: 22896851). It has been seen in at least three individuals with decreased pyruvate dehydrogenase activity (PP4; Patient 6 in PMID: 8962591; Subject M-7 in PMID: 20002461; Subject 35-2 in PMID: 10679936). This variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least 4 unrelated individuals with pyruvate dehydrogenase deficiency [PM6_Strong; utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID: 10679936, subject 35-2; PMID: 20002461, subject M-7; PMID: 21914562, subject AM8; PMID: 21914562, subject AF22]. Of note, to our knowledge, there are no reports of this variant being inherited from a healthy mother, however it is important to note that not all cases reported in the literature had mothers who were tested. This variant is absent from gnomAD v2.1.1 (PM2). Another missense variant at this position [c.1133G>A, p.R378H] has been reported in at least six other probands (PM5; PMIDs: 8032855 - 1 case, 7887409 - 2 cases, 9409363 - 3 cases) and is a known pathogenic variant. The computational predictor REVEL gives a score of 0.907, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM5, PM6_strong, PP3, PP4.
GeneDx	RCV000198575	SCV000252034	pathogenic	not provided	2023-09-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20002461, 10679936, 28639102, 27629047, 31665838, 8962591, 32005694, 33092611, 33914258, 32445240, 34052969, 35027292, 35094435, 36675121, 33588022)
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000497402	SCV000590879	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2017-06-07	criteria provided, single submitter	clinical testing	This missense variant in the PDHA1 gene was identified in a female patient with developmental delay and neurological disorder.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497402	SCV001393905	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2022-09-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 214936). This missense change has been observed in individual(s) with pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 8962591, 20002125, 20002461, 24718837, 28639102). 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 378 of the PDHA1 protein (p.Arg378Cys).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000497402	SCV001429428	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2018-12-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000497402	SCV002016567	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2021-01-29	criteria provided, single submitter	clinical testing
Robert's Program, Boston Children's Hospital	RCV001788065	SCV002030083	pathogenic	SUDDEN INFANT DEATH SYNDROME	2021-10-01	criteria provided, single submitter	research	We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PM2, PP1, PP2, PP5
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000497402	SCV005418353	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency		criteria provided, single submitter	clinical testing	PS3+PS4_Moderate+PM2_Supporting+PM6+PP3