ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.2978G>A (p.Arg993His)

gnomAD frequency: 0.00001  dbSNP: rs546883829
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188595 SCV000242218 uncertain significance not provided 2015-01-09 criteria provided, single submitter clinical testing p.Arg993His (CGC>CAC): c.2978 G>A in exon 18 of the POLG gene (NM_002693.2). The R993H missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R993H is a conservative amino acid substitution as both Arginine and Histidine are positively charged, polar residues. However, this variant occurs in the polymerase domain of the POLG gene at a position that is highly conserved across species, and multiple in silico algorithms predict that R993H is possibly damaging to the structure/function of the POLG protein. Therefore, based on the currently available information, it is unclear whether R993H is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY,MITONUC-MITOP panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV001314840 SCV001505390 uncertain significance Progressive sclerosing poliodystrophy 2023-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 993 of the POLG protein (p.Arg993His). This variant is present in population databases (rs546883829, gnomAD 0.01%). 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: 206541). 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 expected to disrupt 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.

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