ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1850G>A (p.Arg617His) (rs779961986)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725018 SCV000333265 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000374839 SCV000569945 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The R617H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R617H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R617H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the R617H variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758555 SCV000887290 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1850G>A (NP_002684.1:p.Arg617His) [GRCH38: NC_000015.10:g.89325549C>T] variant in POLG gene is interpretated to be a Benign 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). Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Invitae RCV000758555 SCV001490491 uncertain significance Progressive sclerosing poliodystrophy 2020-03-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 617 of the POLG protein (p.Arg617His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs779961986, 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: 282075). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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