ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.915C>G (p.Ser305Arg) (rs769410130)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188649 SCV000242272 pathogenic not provided 2020-02-18 criteria provided, single submitter clinical testing Published functional studies demonstrate reduced DNA affinity and nucleotide mismatch excision rate, leading to a reduction in mtDNA content and increase in mtDNA mutation frequency (Qian et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22000311, 19578034, 21824913, 18546365, 21880868, 25914719, 20883824, 30860128)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758271 SCV000886923 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.915C>G (NP_002684.1:p.Ser305Arg) [GRCH38: NC_000015.10:g.89329051G>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:19578034 . 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188649 SCV001250419 pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing
Invitae RCV000758271 SCV001377915 pathogenic Progressive sclerosing poliodystrophy 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 305 of the POLG protein (p.Ser305Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal recessive POLG-related conditions (PMID: 19578034, 20883824, 22000311). ClinVar contains an entry for this variant (Variation ID: 206588). This variant has been reported to affect POLG protein function (PMID: 20883824, 25914719, 26095671). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001332170 SCV001524403 pathogenic Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1 2020-03-26 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID 19578034 etc.]
Institute of Human Genetics, Klinikum rechts der Isar RCV000995844 SCV001150221 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2019-06-06 no assertion criteria provided clinical testing

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