ClinVar Genomic variation as it relates to human health

The PDHA1 c.379C>T (p.Arg127Trp) missense variant results in the substitution of arginine at amino acid position 127 with tryptophan. This variant has been reported in five studies in a total of six affected probands, including in four affected females in a heterozygous state (Fujii et al. 1994, Lissens et al. 2000; Willemsen et al. 2006, Imbard et al. 2011; Dong et al. 2020). Of these, three cases were confirmed to have a pyruvate dehydrogenase complex deficiency and a phenotype consistent with disease (Fujii et al. 1994, Willemsen et al. 2006, Imbard et al. 2011). Segregation was reported in one family comprising of a mother with a milder phenotype of intellectual disability, truncal ataxia, and dysarthria and two sons with a severe metabolic acidosis, both of which died in infancy. Methylation studies demonstrated skewed X-inactivation in the mother's fibroblast cells (Fujii et al. 1994). Willemsen et al. also reported skewed inactivation of the maternal X allele of above 90% in a female proband with a severe phenotype including neonatal muscle hypotonia and psycho-motor delays from three months of age, and microcephaly and tetraspasticity with neurological signs of pyramidal tract involvement from the age of 12 months (Willemsen et al. 2006). This variant is reported in the Genome Aggregation Database in one allele in a female individual at a frequency of 0.000032 in the African/African American population (version 3.1.2). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.379C>T (p.Arg127Trp) variant is classified as likely pathogenic for primary pyruvate dehydrogenase complex deficiency.

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 8024267). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000214940) and a different missense change at the same codon (p.Arg127Gln / ClinVar ID: VCV000871395) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the PDHA1 protein (p.Arg127Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 8024267, 10679936, 21914562, 25356417, 32005694). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg98Trp. ClinVar contains an entry for this variant (Variation ID: 214940). 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) performed at Invitae indicates that this missense variant is expected to disrupt PDHA1 protein function. This variant disrupts the p.Arg127 amino acid residue in PDHA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21914562). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.