Submissions for variant NM_002693.3(POLG):c.3101G>A (p.Arg1034Lys)

gnomAD frequency: 0.00001  dbSNP: rs201014720

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493683	SCV000582143	uncertain significance	not provided	2024-02-22	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
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758321	SCV000886982	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3101G>A (NP_002684.1:p.Arg1034Lys) [GRCH38: NC_000015.10:g.89319231C>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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758321	SCV001564290	uncertain significance	Progressive sclerosing poliodystrophy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1034 of the POLG protein (p.Arg1034Lys). This variant is present in population databases (rs201014720, 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: 429545). 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 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.
Ambry Genetics	RCV002323854	SCV002607796	uncertain significance	Inborn genetic diseases	2019-11-28	criteria provided, single submitter	clinical testing	The p.R1034K variant (also known as c.3101G>A), located in coding exon 18 of the POLG gene, results from a G to A substitution at nucleotide position 3101. The arginine at codon 1034 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is not well 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.
CeGaT Center for Human Genetics Tuebingen	RCV000493683	SCV004041948	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	POLG: PM2
PreventionGenetics, part of Exact Sciences	RCV004732903	SCV005357495	uncertain significance	POLG-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The POLG c.3101G>A variant is predicted to result in the amino acid substitution p.Arg1034Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% 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.