ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2125C>T (p.Arg709Ter) (rs867038717)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431312 SCV000520838 pathogenic not provided 2016-12-14 criteria provided, single submitter clinical testing The R709X variant in the POLG gene has been reported previously in association with progressive external ophthalmoplegia, in two unrelated affected individual who were heterozygous for the R709X variant and another variant (Di Fonzo et al., 2003; Del Bo et al., 2003). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R709X 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. We interpret R709X as a pathogenic variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758415 SCV000887111 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2125C>T (NP_002684.1:p.Arg709Ter) [GRCH38: NC_000015.10:g.89323847G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:14635118 . 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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