ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2554C>T (rs144500145)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188581 SCV000242203 pathogenic not provided 2021-09-23 criteria provided, single submitter clinical testing Published functional studies of R852C demonstrate polymerase assays retained less than 1% that of wildtype polymerase activity, demonstrating a damaging effect (Kasiviswanathan et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24642831, 30167885, 27538604, 19251978, 19478085, 16545482, 17426723, 23545419, 18546365, 20818383, 24985751, 29474836)
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188581 SCV000610294 pathogenic not provided 2017-08-02 criteria provided, single submitter clinical testing
Invitae RCV000633537 SCV000754783 pathogenic Progressive sclerosing poliodystrophy 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 852 of the POLG protein (p.Arg852Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs144500145, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Alpers syndrome (PMID:21880868, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In addition, this variant in combination with another POLG variant has been reported in individuals affected with Alpers syndrome (PMID: 16545482, 22000311), ataxia neuropathy spectrum (PMID: 18546365), Complex IV deficiency (PMID: 20818383, 22494076), and other POLG-related conditions (PMID: 17426723, 18487244). ClinVar contains an entry for this variant (Variation ID: 206528). Experimental studies have shown that this missense change abolishes polymerase activity (PMID: 19478085). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000633537 SCV000886909 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2554C>T (NP_002684.1:p.Arg852Cys) [GRCH38: NC_000015.10:g.89321780G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16545482 . 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.
Fulgent Genetics,Fulgent Genetics RCV000762953 SCV000893385 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000188581 SCV001145154 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Inconclusive segregation with disease.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188581 SCV001149562 uncertain significance not provided 2018-02-01 criteria provided, single submitter clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252349 SCV001428101 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000188581 SCV001808637 uncertain significance not provided no assertion criteria provided clinical testing

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