ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1369C>T (p.Arg457Trp)

gnomAD frequency: 0.00001  dbSNP: rs766242100
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188656 SCV000242279 uncertain significance not provided 2021-03-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on 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 RCV000758282 SCV000886934 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1369C>T (NP_002684.1:p.Arg457Trp) [GRCH38: NC_000015.10:g.89327231G>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. PM2:This variant is absent in key population databases. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001847835 SCV002105547 uncertain significance Hereditary spastic paraplegia 2020-05-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000758282 SCV002126274 uncertain significance Progressive sclerosing poliodystrophy 2022-09-03 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 457 of the POLG protein (p.Arg457Trp). This variant is present in population databases (rs766242100, gnomAD 0.009%). 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: 206594). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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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