ClinVar

Description

Variant summary: POLG c.1790G>A (p.Arg597Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Another missense variant altering this residue (p.Arg597Trp) is classified as pathogenic/likely pathgenic in ClinVar. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250900 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1790G>A has been reported in the literature in an individual affected with progressive external ophthalmoplegia who was reported as compound heterozygous with a likely pathogenic variant (Hou_2022). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.