ClinVar Genomic variation as it relates to human health

The NM_002693.2:c.679C>T (NP_002684.1:p.Arg227Trp) [GRCH38: NC_000015.10:g.89330257G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 . 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. 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.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 227 of the POLG protein (p.Arg227Trp). This variant is present in population databases (rs121918056, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 12707443, 16621917, 16957900, 19307547, 22277967, 25281868). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13515). 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. For these reasons, this variant has been classified as Pathogenic.

The c.679C>T (p.R227W) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 679, causing the arginine (R) at amino acid position 227 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD) database, the POLG c.679C>T alteration was observed in 0.0004% (1/247,648) of total alleles studied, with a frequency of 0.003% (1/30,600) in the South Asian subpopulation. This alteration has been previously reported in multiple patients with autosomal recessive POLG-related mitochondrial disorders (Agostino 2003; Lamantea, 2004; de Vries, 2007; Horga, 2014; Hikmat, 2017). This amino acid position is highly conserved in available vertebrate species. The p.R227W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Variant summary: POLG c.679C>T (p.Arg227Trp) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) 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 4e-06 in 247648 control chromosomes (gnomAD). c.679C>T has been reported in the literature in multiple individuals affected with features of Mitochondrial DNA Depletion Syndrome - POLG Related (e.g. de Vries_2007, Hikmat_2017, Lindstrand_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28471437, 31694722, 16957900). ClinVar contains an entry for this variant (Variation ID: 13515). Based on the evidence outlined above, the variant was classified as pathogenic.

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; This variant is associated with the following publications: (PMID: 16957900, 24508722, 22277967, 31694722, 12707443, 15349879, 24091540, 31440721, 33726816, 18991720, 16545482, 15913923, 19307547, 25281868, 28471437)

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with POLG-related disorders, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.