Submissions for variant NM_002693.3(POLG):c.2862C>G (p.Ile954Met)

dbSNP: rs2152060967

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001563093	SCV001785973	likely pathogenic	not provided	2021-05-19	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32668698)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388026	SCV004099602	uncertain significance	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2862C>G (p.Ile954Met) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251216 control chromosomes. c.2862C>G has been reported in the literature in individuals affected with Alpers syndrome (Smigiel_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32668698). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003626675	SCV004375528	uncertain significance	Progressive sclerosing poliodystrophy	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 954 of the POLG protein (p.Ile954Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with respiratory failure and hypotonia (PMID: 32668698). ClinVar contains an entry for this variant (Variation ID: 1198809). 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 with a positive predictive value of 95%. 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.