ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1763G>A (p.Gly588Asp) (rs371334941)

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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 RCV000413337 SCV000705195 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000413337 SCV000491091 likely pathogenic not provided 2015-12-29 criteria provided, single submitter clinical testing The G588D variant in the POLG gene has been reported as a likely pathogenic variant in three unrelated individuals with clinical presentations suggestive of POLG deficiency who were each identified to harbor at least one known pathogenic POLG variant on the opposite allele (Tang et al., 2011). The G588D variant was not observed with any significant frequency in approximately 6,500 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 G588D variant 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 silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (P587L, P589L, L592F) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G588D variant is a strong candidate for a pathogenic variant.
Invitae RCV000557537 SCV000630112 uncertain significance Progressive sclerosing poliodystrophy 2017-04-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 588 of the POLG protein (p.Gly588Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals with clinical features consistent with POLG deficiency (PMID: 21880868). Both of these individuals were compound heterozygotes with a pathogenic variant on the other chromosome (in trans). ClinVar contains an entry for this variant (Variation ID: 372694). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000557537 SCV000887146 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1763G>A (NP_002684.1:p.Gly588Asp) [GRCH38: NC_000015.10:g.89325636C>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. 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. 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 Likely Pathogenic.

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