Submissions for variant NM_002693.3(POLG):c.1991G>A (p.Gly664Glu)

dbSNP: rs773073959

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597218	SCV000702422	uncertain significance	not provided	2017-12-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706577	SCV000835636	uncertain significance	Progressive sclerosing poliodystrophy	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 664 of the POLG protein (p.Gly664Glu). This variant is present in population databases (rs773073959, gnomAD 0.04%). 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: 497733). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. 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	RCV002315887	SCV000848112	uncertain significance	Inborn genetic diseases	2016-10-31	criteria provided, single submitter	clinical testing	The p.G664E variant (also known as c.1991G>A), located in coding exon 10 of the POLG gene, results from a G to A substitution at nucleotide position 1991. The glycine at codon 664 is replaced by glutamic acid, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000597218	SCV001824614	uncertain significance	not provided	2022-11-29	criteria provided, single submitter	clinical testing	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
PreventionGenetics, part of Exact Sciences	RCV004732950	SCV005356590	uncertain significance	POLG-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The POLG c.1991G>A variant is predicted to result in the amino acid substitution p.Gly664Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.038% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.