ClinVar

Description

A G278R variant that is likely pathogenic was identified in the PDHA1 gene. It has been reported previously as de novo in a male with ataxia, lactic acidosis, hypertonia and basal ganglia lesions (Asencion et al., 2016). The G278R variant was not observed in approximately 6500 ndividuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G278R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (M282V) has been reported in the Human Gene Mutation Database in association with pyruvate dehydrogenase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Several in-silico splice prediction models predict that G278R damages the natural acceptor site of intron 8 and leads to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.