ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.202C>T (p.Gln68Ter) (rs202039305)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000296330 SCV000329672 pathogenic not provided 2016-06-30 criteria provided, single submitter clinical testing The Q68X nonsense variant in the POLG gene has been reported previously in an individual with Alpers syndrome who had a second pathogenic POLG variant identified (Wong et al., 2008; Saneto et al., 2010). The Q68X variant was not observed 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. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, many other nonsense variants downstream of this position have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). Therefore, Q68X is considered a pathogenic variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758262 SCV000886908 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.202C>T (NP_002684.1:p.Gln68Ter) [GRCH38: NC_000015.10:g.89333553G>A] 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. PVS1:This variant is a predicted null variant in POLG where loss of function is a known mechanism of disease. 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. PM4:This variant causes alteration in the length of expressed protein. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

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