Submissions for variant NM_002693.3(POLG):c.131A>G (p.Gln44Arg)

gnomAD frequency: 0.00036  dbSNP: rs757120802

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724683	SCV000227269	uncertain significance	not provided	2017-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000724683	SCV000581756	likely benign	not provided	2021-03-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551143	SCV000630091	uncertain significance	Progressive sclerosing poliodystrophy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 44 of the POLG protein (p.Gln44Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 195177). 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 not expected to disrupt POLG protein function with a negative 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000551143	SCV000887093	likely benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.131A>G (NP_002684.1:p.Gln44Arg) [GRCH38: NC_000015.10:g.89333624T>C] 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. BP3:This variant results in inframe indel in repeats without known function. 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.
Baylor Genetics	RCV000551143	SCV001529892	uncertain significance	Progressive sclerosing poliodystrophy	2018-03-22	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002381572	SCV002694782	uncertain significance	Inborn genetic diseases	2018-02-08	criteria provided, single submitter	clinical testing	The p.Q44R variant (also known as c.131A>G), located in coding exon 1 of the POLG gene, results from an A to G substitution at nucleotide position 131. The glutamine at codon 44 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003985738	SCV004113161	uncertain significance	POLG-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The POLG c.131A>G variant is predicted to result in the amino acid substitution p.Gln44Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.