Submissions for variant NM_000284.4(PDHA1):c.844A>C (p.Met282Leu)

gnomAD frequency: 0.00715  dbSNP: rs2229137

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001271289	SCV001736734	benign	Pyruvate dehydrogenase complex deficiency	2021-04-02	reviewed by expert panel	curation	The allele frequency of the c.844A>C (p.M282L) variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021.
GeneDx	RCV000127400	SCV000170963	benign	not specified	2013-12-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224670	SCV000280888	benign	not provided	2016-05-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000127400	SCV000701595	benign	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311510	SCV000846551	benign	Inborn genetic diseases	2015-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000011632	SCV001328768	benign	Pyruvate dehydrogenase E1-alpha deficiency	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Invitae	RCV000011632	SCV001728359	benign	Pyruvate dehydrogenase E1-alpha deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127400	SCV002051272	benign	not specified	2021-12-20	criteria provided, single submitter	clinical testing	Variant summary: PDHA1 c.844A>C (p.Met282Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.021 in 183510 control chromosomes, predominantly at a frequency of 0.26 within the East Asian subpopulation in the gnomAD database, including 329 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 831999.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in PDHA1 causing Pyruvate Dehydrogenase Deficiency phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, all but one classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
OMIM	RCV000011632	SCV000031864	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2017-08-15	no assertion criteria provided	literature only
Natera, Inc.	RCV001271289	SCV001452367	benign	Pyruvate dehydrogenase complex deficiency	2020-09-16	no assertion criteria provided	clinical testing