Submissions for variant NM_000284.4(PDHA1):c.1133G>A (p.Arg378His)

dbSNP: rs137853250

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000011620	SCV000746768	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2017-12-18	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267918	SCV001446428	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251895	SCV002523221	likely pathogenic	See cases	2019-08-12	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM2, PP2, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011620	SCV004299496	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2022-10-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg378 amino acid residue in PDHA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8962591, 20002125, 20002461, 24718837, 28639102). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 10873). This missense change has been observed in individual(s) with pyruvate dehydrogenase E1-alpha deficiency (PMID: 1909401, 16713755). 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 histidine, which is basic and polar, at codon 378 of the PDHA1 protein (p.Arg378His).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011620	SCV005086000	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2024-09-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pyruvate dehydrogenase E1-alpha deficiency. (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity resulting from the PDHA1 variant, the severity of phenotypic presentation can vary. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple individuals with pyruvate dehydrogenase complex deficiency (PMID: 33092611, 1909401, 23021068). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001267918	SCV005201185	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	Expression studies found this variant to be associated with very low level of enzyme activity compared to wild-type (PMID: 33588022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1909401, 16713755, 8032855, 25356417, 10679936, 23021068, 33092611, 33726816, 33588022)
Ambry Genetics	RCV004955255	SCV005470632	pathogenic	Inborn genetic diseases	2024-08-13	criteria provided, single submitter	clinical testing	The c.1133G>A (p.R378H) alteration is located in exon 11 (coding exon 11) of the PDHA1 gene. This alteration results from a G to A substitution at nucleotide position 1133, causing the arginine (R) at amino acid position 378 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with Pyruvate dehydrogenase E1-alpha deficiency (DeBrosse, 2012; Wesó-Kucharska, 2022). Additionally, this variant has been determined to be the result of a de novo mutation in multiple affected individuals, both male and female (Imbard, 2011; Pavlu-Pereira, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000011620	SCV000031852	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	1991-01-01	no assertion criteria provided	literature only