ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.729C>A (p.Asp243Glu)

dbSNP: rs757917194
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523877 SCV000621308 uncertain significance not provided 2021-12-13 criteria provided, single submitter clinical testing Identified in an individual with a disorder in the metabolic clinical subgroup, however, additional clinical and segregation information was not provided (Coutelier et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29482223)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758485 SCV000887201 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.729C>A (NP_002684.1:p.Asp243Glu) [GRCH38: NC_000015.10:g.89330207G>T] variant in POLG gene is interpretated to be a Uncertain Significance 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. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV000763998 SCV000894949 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b 2022-01-11 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001121512 SCV001280137 uncertain significance POLG-Related Spectrum Disorders 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000758485 SCV001396786 uncertain significance Progressive sclerosing poliodystrophy 2022-02-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 243 of the POLG protein (p.Asp243Glu). This variant is present in population databases (rs757917194, gnomAD 0.0009%). This missense change has been observed in individual(s) with cerebellar ataxia (PMID: 29482223). ClinVar contains an entry for this variant (Variation ID: 452496). 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: "Possibly 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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