ClinVar Genomic variation as it relates to human health

The NM_002693.2:c.3383G>A (NP_002684.1:p.Arg1128His) [GRCH38: NC_000015.10:g.89318640C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.

Reported previously in a one year old male with developmental delay, liver disease, and microcephaly who had another missense variant on the opposite allele (Wong et al., 2008; Kasiviswanathan et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32347949, 18546365, 21856450)

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1128 of the POLG protein (p.Arg1128His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365). ClinVar contains an entry for this variant (Variation ID: 593423). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

Variant summary: POLG c.3383G>A (p.Arg1128His) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase Family A palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251448 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3383G>A has been reported in an individual affected with features of Mitochondrial DNA Depletion Syndrome - POLG Related without strong evidence for causality (Wong_2008). This report does not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18546365). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: n=3; Likely pathogenic: n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

POLG: PP3