ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3383G>A (p.Arg1128His) (rs1405268319)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000728455 SCV000856033 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758473 SCV000887186 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3383G>A (NP_002684.1:p.Arg1128His) [GRCH38: NC_000015.10:g.89318640C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.
Invitae RCV000758473 SCV001545289 uncertain significance Progressive sclerosing poliodystrophy 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1128 of the POLG protein (p.Arg1128His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365). ClinVar contains an entry for this variant (Variation ID: 593423). 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 disruptive, 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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