ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1684C>T (p.Arg562Trp)

gnomAD frequency: 0.00005  dbSNP: rs756952607
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Total submissions: 3
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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 RCV000758407 SCV000887098 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1684C>T (NP_002684.1:p.Arg562Trp) [GRCH38: NC_000015.10:g.89326640G>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. PS1:This variation causes same amino-acid change as an established pathogenic variant. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Athena Diagnostics RCV000992683 SCV001145148 uncertain significance not provided 2020-07-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000758407 SCV001515538 uncertain significance Progressive sclerosing poliodystrophy 2024-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 562 of the POLG protein (p.Arg562Trp). This variant is present in population databases (rs756952607, gnomAD 0.008%). This missense change has been observed in individual(s) with POLG-associated conditions (PMID: 35641312). ClinVar contains an entry for this variant (Variation ID: 619389). 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 with a positive 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.

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