ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.925C>T (p.Arg309Cys) (rs886041592)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000292336 SCV000330282 pathogenic not provided 2016-07-22 criteria provided, single submitter clinical testing The R309C pathogenic variant in the POLG gene has been reported previously in the homozygous state in an individual with chronic intestinal pseudo-obstruction, abnormal MRI signaling of the white matter, and mitochondrial proliferation and defective cytochrome C oxidase histochemical staining on muscle biopsy (Amiot et al., 2009). It has also been reported in trans with another missense variant in an individual with sensory and motor neuropathy, ophthalmoparesis and stroke (Lam et al., 2015). Functional studies in a yeast strain with R309C (R265C) exhibited respiratory deficiency and increase of mitochondrial genome stability, which is due to loss of POLG enzyme function (Kaliszewska et al., 2015). The R309C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Additionally, other missense variants at this same residue (R309L, R309H) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R309C variant was not observed in approximately 6500 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 R309C as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000292336 SCV000860343 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000292336 SCV001250418 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000985201 SCV001133226 pathogenic Progressive sclerosing poliodystrophy 2019-09-26 no assertion criteria provided clinical testing

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