Submissions for variant NM_002693.3(POLG):c.394G>A (p.Gly132Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002886619	SCV003254387	uncertain significance	Progressive sclerosing poliodystrophy	2021-12-18	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with autosomal dominant POLG-related disease (PMID: 33469851). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 132 of the POLG protein (p.Gly132Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230756	SCV003929295	uncertain significance	not specified	2023-04-25	criteria provided, single submitter	clinical testing	Variant summary: POLG c.394G>A (p.Gly132Arg) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of 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 181886 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.394G>C also resulting in (p.Gly132Arg) has been reported in the literature in a heterozygous individual in the context of POLG related conditions (Deepha_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: 33469851). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.