The NM_002693.2:c.678G>C (NP_002684.1:p.Gln226His) [GRCH38: NC_000015.10:g.89330258C>G] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The c.678G>C (p.Q226H) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 678, causing the glutamine (Q) at amino acid position 226 to be replaced by a histidine (H). The p.Q226H alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18156159, 21880868, 33600046, 40004527, 39595984)

BP4, PM3

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster yielded discordant predictions regarding whether this amino acid change is damaging to the protein.

Variant summary: POLG c.678G>C (p.Gln226His) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00041 in 247722 control chromosomes, predominantly at a frequency of 0.00077 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for disease-causing variants in POLG, allowing no conclusion about variant significance. c.678G>C has been reported in the literature in individuals affected with POLG-Related Spectrum Disorders, including parkinsonism (Montaut_2018) and adult-onset chronic progressive external ophthalmoplegia (Heighton_2019) without strong evidence for causality, and as a compound heterozygous genotype together with a pathogenic variant in an individual diagnosed with sensory ataxic neuropathy with mtDNA deletions (Keller_2021). 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: 38871447, 31521625, 33600046, 29913018). ClinVar contains an entry for this variant (Variation ID: 206581). Based on the evidence outlined above, the variant was classified as uncertain significance.

POLG: PM2:Supporting, PM3:Supporting, BP4

The POLG c.678G>C variant is predicted to result in the amino acid substitution p.Gln226His. This variant has been reported in the compound heterozygous state in an individual with infantile muscular atrophy and weakness (Keller et al. 2021. PubMed ID: 33600046). Additionally, this variant was reported in the heterozygous state in one patient with clinical features suggestive of POLG deficiency, although a second plausible causative variant was not identified (Tang et al. 2011. PubMed ID: 21880868, Supplementary Table 3). This variant is reported in 0.076% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.