ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2636A>G (p.Gln879Arg) (rs368587966)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188586 SCV000242208 pathogenic not provided 2014-03-05 criteria provided, single submitter clinical testing p.Gln879Arg (CAG>CGG): c.2636 A>G in exon 17 of the POLG gene (NM_002693.2). The Gln879Arg 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 5,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Gln879Arg mutation is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species in the polymerase domain of the protein and a different missense mutation at the same codon (Gln879His) was identified in a patient with hepatotoxicity and encephalopathy who had another disease-causing mutation on the other chromosome (Horvath et al., 2008; McFarland et al., 2008). Functional studies indicate that Gln879His moderately decreases the polymerase activity of the enzyme, confirming the functional importance of this position in the protein (Kasiviswanathan et al., 2009). The variant is found in INFANT-EPI,DEPLTN-MITOP,CHILD-EPI panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188586 SCV000858276 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758312 SCV000886970 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2636A>G (NP_002684.1:p.Gln879Arg) [GRCH38: NC_000015.10:g.89321223T>C] variant in POLG gene is interpretated to be a Pathogenic 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM2:This variant is absent in key population databases. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Invitae RCV000758312 SCV001386878 uncertain significance Progressive sclerosing poliodystrophy 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 879 of the POLG protein (p.Gln879Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs368587966, ExAC 0.01%). This variant has not been reported in the literature in individuals with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206532). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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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