ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000188581 SCV000242203 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing The R852C variant has been observed in multiple individuals with POLG-related disorders who were compound heterozygous for R852C and a second POLG pathogenic variant (Nguyen et al., 2006, Human DNA Polymerase Gamma Mutation Database). It is a non-conservative amino acid substiution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and the substitution occurs at a conserved position in the polymerase domain. Multiple missense variants at the same and nearby residues have been reported in Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, R852C is considered a pathogenic variant.
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.

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