ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3436C>T (p.Arg1146Cys) (rs2307440)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000513124 SCV000171115 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing The R1146C variant in the POLG gene has been reported previously as heterozygous in a patient with progressive external ophthalmoplegia (Gonzalez-Vioque et al., 2006). The R1146C variant is observed in 36/126616 (0.028%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The R1146C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1146C as a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513124 SCV000608733 likely benign not provided 2017-02-01 criteria provided, single submitter clinical testing
Invitae RCV000545884 SCV000630148 uncertain significance Progressive sclerosing poliodystrophy 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1146 of the POLG protein (p.Arg1146Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs2307440, ExAC 0.02%). This variant has been reported as heterozygous and homozygous in individuals affected with mitochondrial disease (PMID: 16401742, 20843780, 21880868). ClinVar contains an entry for this variant (Variation ID: 21313). Experimental studies have shown that this missense change negatively affects the proofreading function of the POLG protein (PMID: 25462018). In summary, this variant has uncertain impact on POLG function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000513124 SCV000843334 uncertain significance not provided 2018-07-24 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000545884 SCV000887300 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3436C>T (NP_002684.1:p.Arg1146Cys) [GRCH38: NC_000015.10:g.89318587G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16401742 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Mendelics RCV000545884 SCV001139676 benign Progressive sclerosing poliodystrophy 2019-05-28 criteria provided, single submitter clinical testing
GeneReviews RCV000020477 SCV000040914 benign Mitochondrial diseases 2012-10-11 no assertion criteria provided curation Converted during submission to Benign.

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