Submissions for variant NM_002693.3(POLG):c.1543A>G (p.Ile515Val)

gnomAD frequency: 0.00001  dbSNP: rs748919988

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490068	SCV000577431	uncertain significance	not provided	2017-03-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the POLG gene. The I515V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I515V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I515V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. However, missense variants in nearby residues (S511N, K512M) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302676	SCV001491894	uncertain significance	Progressive sclerosing poliodystrophy	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 515 of the POLG protein (p.Ile515Val). This variant is present in population databases (rs748919988, 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: 426869). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000490068	SCV005411136	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV004732902	SCV005341742	uncertain significance	POLG-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The POLG c.1543A>G variant is predicted to result in the amino acid substitution p.Ile515Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0015% 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.