Submissions for variant NM_002693.3(POLG):c.2165G>T (p.Arg722Leu)

dbSNP: rs185645212

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188564	SCV000242184	uncertain significance	not provided	2024-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758299	SCV000886954	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2165G>T (NP_002684.1:p.Arg722Leu) [GRCH38: NC_000015.10:g.89323504C>A] 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. PS1:This variation causes same amino-acid change as an established pathogenic variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758299	SCV001399597	uncertain significance	Progressive sclerosing poliodystrophy	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 722 of the POLG protein (p.Arg722Leu). This variant is present in population databases (rs185645212, gnomAD 0.006%). 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: 206513). 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.
Ambry Genetics	RCV002426911	SCV002727374	uncertain significance	Inborn genetic diseases	2019-06-10	criteria provided, single submitter	clinical testing	The p.R722L variant (also known as c.2165G>T), located in coding exon 12 of the POLG gene, results from a G to T substitution at nucleotide position 2165. The arginine at codon 722 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. 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.