Submissions for variant NM_002693.3(POLG):c.154C>A (p.Gln52Lys)

gnomAD frequency: 0.00006  dbSNP: rs376683989

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000992680	SCV000242151	likely benign	not provided	2020-06-16	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758285	SCV000886939	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.154C>A (NP_002684.1:p.Gln52Lys) [GRCH38: NC_000015.10:g.89333601G>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. 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 Uncertain Significance.
Athena Diagnostics	RCV000992680	SCV001145143	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758285	SCV001230110	uncertain significance	Progressive sclerosing poliodystrophy	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 52 of the POLG protein (p.Gln52Lys). 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: 206485). 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) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000992680	SCV001747748	uncertain significance	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399700	SCV002705150	uncertain significance	Inborn genetic diseases	2017-06-14	criteria provided, single submitter	clinical testing	The p.Q52K variant (also known as c.154C>A), located in coding exon 1 of the POLG gene, results from a C to A substitution at nucleotide position 154. The glutamine at codon 52 is replaced by lysine, an amino acid with similar properties. This amino acid position is 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	RCV003985748	SCV004111657	uncertain significance	POLG-related disorder	2022-11-02	criteria provided, single submitter	clinical testing	The POLG c.154C>A variant is predicted to result in the amino acid substitution p.Gln52Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89876832-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.