ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2558G>A (p.Arg853Gln) (rs796052888)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188583 SCV000242205 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing p.Arg853Gln (CGG>CAG): c.2558 G>A in exon 16 of the POLG gene (NM_002693.2). The R853Q missense mutation in the POLG gene has been reported in a patient with myocerebrohepatopathy spectrum (MCHS) who was compound heterozygous for R853Q and two other missense mutations on the opposite POLG allele (Wong et al., 2008). R853Q is located in the thumb subdomain of the POLG protein and expression studies found that this mutation is associated with less than 1% residual polymerase gamma activity compared to wild type (Kasiviswanathan et al., 2009). Therefore, R853Q is considered a disease-causing mutation. The variant is found in EPILEPSY,MITONUC-MITOP panel(s).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758451 SCV000887161 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2558G>A (NP_002684.1:p.Arg853Gln) [GRCH38: NC_000015.10:g.89321776C>T] 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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 Pathogenic.
Invitae RCV000758451 SCV001401060 likely pathogenic Progressive sclerosing poliodystrophy 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 853 of the POLG protein (p.Arg853Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of autosomal recessive myocerebrohepatopathy (PMID: 18546365). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206529). This variant has been reported to affect POLG protein function (PMID: 19478085, 20185557). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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