ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 597 of the POLG protein (p.Arg597Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with progressive external ophthalmoplegia (PMID: 35289132). ClinVar contains an entry for this variant (Variation ID: 576551). 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 POLG protein function. This variant disrupts the p.Arg597 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19251978, 20138553, 21880868, 27538604). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The NM_002693.2:c.1790G>A (NP_002684.1:p.Arg597Gln) [GRCH38: NC_000015.10:g.89325609C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function

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.

PM2, PM3_supporting, PM5