ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1849C>T (p.Arg617Cys)

gnomAD frequency: 0.00002  dbSNP: rs144374017
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758409 SCV000887101 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1849C>T (NP_002684.1:p.Arg617Cys) [GRCH38: NC_000015.10:g.89325550G>A] 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. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000758409 SCV003294692 uncertain significance Progressive sclerosing poliodystrophy 2023-02-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 617 of the POLG protein (p.Arg617Cys). This variant is present in population databases (rs144374017, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365). ClinVar contains an entry for this variant (Variation ID: 619390). 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. 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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