Submissions for variant NM_002693.3(POLG):c.1292G>T (p.Gly431Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058482	SCV003441698	uncertain significance	Progressive sclerosing poliodystrophy	2023-07-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 431 of the POLG protein (p.Gly431Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 12707443). ClinVar contains an entry for this variant (Variation ID: 2137741). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587415	SCV005077305	uncertain significance	not specified	2024-04-29	criteria provided, single submitter	clinical testing	Variant summary: POLG c.1292G>T (p.Gly431Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1292G>T has been reported in the literature in an individual affected with Progressive external ophthalmoplegia. These data do not allow any conclusion about variant significance. 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: 12707443). ClinVar contains an entry for this variant (Variation ID: 2137741). Based on the evidence outlined above, the variant was classified as uncertain significance.