ClinVar Genomic variation as it relates to human health

The NM_002693.2:c.3151G>A (NP_002684.1:p.Gly1051Arg) [GRCH38: NC_000015.10:g.89319053C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:14745080 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Likely Pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1051 of the POLG protein (p.Gly1051Arg). This variant is present in population databases (rs121918049, gnomAD 0.0008%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects POLG function (PMID: 17980715, 20185557). 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. ClinVar contains an entry for this variant (Variation ID: 566044). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 14745080, 28130605, 30818899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals.

The c.3151G>A (p.G1051R) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 3151, causing the glycine (G) at amino acid position 1051 to be replaced by an arginine (R). Based on the available evidence, this variant is classified as likely pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, the clinical significance for autosomal dominant POLG-related progressive external ophthalmoplegia is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/282698) total alleles studied. This variant has been confirmed in trans with a second POLG variant in a patient with Alpers syndrome (Li, 2021). It has also been observed in the homozygous state in an individual from a large autism cohort; however, no details were provided regarding whether the patient had clinical symptoms of a POLG-related disorder (Doan, 2019)._x000D_ _x000D_ A different nucleotide substitution resulting in the same missense change, c.3151G>C (p.G1051R), has been previously reported in the compound heterozygous state with other POLG variants in multiple individuals with autosomal recessive POLG-related disorders (Mancuso, 2004; Formichi, 2016; Da Pozzo, 2017). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, G1051R is highly destabilizing to the local structure (Ambry internal data). Functional studies using yeast models have shown that G1051R causes increased mtDNA instability and mutant frequency, indicative of defects in the mtDNA genome (Baruffini, 2007; Baruffini, 2010; Stumpf, 2010). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.