Submissions for variant NM_002693.3(POLG):c.2998G>A (p.Glu1000Lys)

gnomAD frequency: 0.00002  dbSNP: rs1412887168

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758465	SCV000887177	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2998G>A (NP_002684.1:p.Glu1000Lys) [GRCH38: NC_000015.10:g.89319334C>T] 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. PM2:This variant is absent in key population databases. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758465	SCV002317414	uncertain significance	Progressive sclerosing poliodystrophy	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1000 of the POLG protein (p.Glu1000Lys). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 619429). 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) has been performed at Invitae 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	RCV002533817	SCV003532542	uncertain significance	Inborn genetic diseases	2021-01-05	criteria provided, single submitter	clinical testing	The c.2998G>A (p.E1000K) alteration is located in exon 19 (coding exon 18) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 2998, causing the glutamic acid (E) at amino acid position 1000 to be replaced by a lysine (K). The in silico prediction for the p.E1000K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003128692	SCV003805490	uncertain significance	not provided	2023-02-23	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
Mayo Clinic Laboratories, Mayo Clinic	RCV003128692	SCV004227454	uncertain significance	not provided	2021-12-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV003128692	SCV004229891	uncertain significance	not provided	2022-11-17	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
PreventionGenetics, part of Exact Sciences	RCV004733040	SCV005357482	uncertain significance	POLG-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The POLG c.2998G>A variant is predicted to result in the amino acid substitution p.Glu1000Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.