ClinVar Genomic variation as it relates to human health

The NM_002693.2:c.3542G>A (NP_002684.1:p.Ser1181Asn) [GRCH38: NC_000015.10:g.89317477C>T] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. 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. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 35811315, 35101151)

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1181 of the POLG protein (p.Ser1181Asn). This variant is present in population databases (rs149921636, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal dominant POLG-related conditions (PMID: 35101151). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374526). 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 POLG protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: POLG c.3542G>A (p.Ser1181Asn) results in a conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251492 control chromosomes (gnomAD). c.3542G>A has been reported in the literature in four affected individuals and this variant co-segregated in a family with autosomal dominant axonal neuropathy, proximal muscle fatigability, ptosis, and ragged red fbers (Dohrn_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35101151, 35811324, 24508722). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.