ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2857C>T (p.Arg953Cys) (rs11546842)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000175301 SCV000226768 uncertain significance not provided 2015-02-06 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758266 SCV000886914 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2857C>T (NP_002684.1:p.Arg953Cys) [GRCH38: NC_000015.10:g.89320890G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. 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. 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 Pathogenic.
Invitae RCV000758266 SCV000961971 uncertain significance Progressive sclerosing poliodystrophy 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 953 of the POLG protein (p.Arg953Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs11546842, ExAC 0.01%). This variant has been observed as homozygous or as compound heterozygous with another variant in the POLG gene in individuals clinical features of progressive external ophthalmoplegia (PMID: 22334187, 21880868). This variant is also known as 13906C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 194838). Experimental studies in yeast have shown that this missense change does not significantly alter the function of the POLG protein when compared to wild type (PMID: 20185557). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000175301 SCV001145158 likely pathogenic not provided 2019-05-23 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive.

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