ClinVar

Description

Variant summary: POLG c.2584G>A (p.Ala862Thr) results in a non-conservative amino acid change located in the palm domain (IPR047580) 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 4e-06 in 251356 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2584G>A has been reported in the literature in multiple compound heterozygous individuals affected with POLG-Related Spectrum Disorders (e.g., Wong_2008, Stricker_2009, Ferreira_2011, Lax_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant was unable to complement a null MIP1 (the yeast ortholog of POLG) mutant or restore mitochondrial respiration in yeast (e.g., Stricker_2009). The following publications have been ascertained in the context of this evaluation (PMID: 21550804, 22189570, 19762913, 18546365). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.