Submissions for variant NM_002693.3(POLG):c.2177A>G (p.Lys726Arg)

gnomAD frequency: 0.00001  dbSNP: rs774599342

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188565	SCV000242185	uncertain significance	not specified	2016-11-18	criteria provided, single submitter	clinical testing	p.Lys726Arg (AAG>AGG): c.2177 A>G in exon 13 of the POLG gene (NM_002693.2). A variant of uncertain significance has been identified in the POLG gene. The c.2177 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.2177 A>G may create a cryptic splice acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. If c.2177 A>G does not alter splicing, it will result in the K726R missense change, which is a conservative amino acid substitution that is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. However, a missense variant in a nearby residue (R722H) has been reported in the Human Gene Mutation Database in association with a POLG-related disorder (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000729876	SCV000857569	uncertain significance	not provided	2017-10-16	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758300	SCV000886955	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2177A>G (NP_002684.1:p.Lys726Arg) [GRCH38: NC_000015.10:g.89323492T>C] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. PM2:This variant is absent in key population databases. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758300	SCV001223373	uncertain significance	Progressive sclerosing poliodystrophy	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 726 of the POLG protein (p.Lys726Arg). This variant is present in population databases (rs774599342, gnomAD 0.009%). 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: 206514). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.