ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1721G>A (p.Arg574Gln) (rs764287987)

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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 RCV000758294 SCV000886948 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1721G>A (NP_002684.1:p.Arg574Gln) [GRCH38: NC_000015.10:g.89325678C>T] 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. PM2:This variant is absent in key population databases. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000791102 SCV000930375 likely pathogenic POLG-related disorders 2019-04-27 criteria provided, single submitter clinical testing
Invitae RCV000758294 SCV001560774 uncertain significance Progressive sclerosing poliodystrophy 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 574 of the POLG protein (p.Arg574Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs764287987, ExAC 0.005%). This variant has been observed in combination with another POLG variant in individual(s) with POLG-related conditions (PMID: 28815208). ClinVar contains an entry for this variant (Variation ID: 619321). 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: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg574 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20601675, 16621917). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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