ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188649 SCV000242272 pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing The S305R pathogenic variant has been reported previously in multiple individuals with Alpers syndrome and other POLG-related disorders who had a second pathogenic variant on the other allele (Blok et al., 2009; Baruffini et al., 2011; Human DNA Polymerase Gamma Mutation Database). Additionally, studies in yeast cells demonstrated that the S305R allele results in complete loss of functional mitochondria (Qian et al, 2014). The S305R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The S305R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret S305R as a pathogenic variant.
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.
Institute of Human Genetics,Klinikum rechts der Isar RCV000995844 SCV001150221 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2019-06-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188649 SCV001250419 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Invitae RCV000758271 SCV001377915 pathogenic Progressive sclerosing poliodystrophy 2019-10-21 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.