ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.679C>T (p.Arg227Trp) (rs121918056)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255169 SCV000322023 pathogenic not provided 2016-10-08 criteria provided, single submitter clinical testing The R227W missense variant in the POLG gene has been reported multiple times previously in individuals with POLG-related disorders who had a second POLG variant identified on the opposite allele (Agostino et al., 2003; Human DNA Polymerase Gamma Mutation Database). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R227W 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, and this substitution occurs at a position that is conserved across species. Therefore, R227W is considered to be a pathogenic variant.
Invitae RCV000525480 SCV000630161 pathogenic Progressive sclerosing poliodystrophy 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 227 of the POLG protein (p.Arg227Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs121918056, ExAC no frequency). This variant has been reported as compound heterozygous in several individuals affected with POLG-related disorders (PMID: 12707443, 22277967, 25281868, 16621917, 19307547, 16957900). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Alpers-Huttenlocher syndrome (PMID: 19307547). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 13515). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014469 SCV000034720 pathogenic Mitochondrial DNA depletion syndrome 4B, MNGIE type 2009-03-24 no assertion criteria provided literature only
Rare Disease Group, Clinical Genetics,Karolinska Institutet RCV000787362 SCV000926324 likely pathogenic Abnormality of corpus callosum 2019-04-09 no assertion criteria provided clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000525480 SCV000886918 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.679C>T (NP_002684.1:p.Arg227Trp) [GRCH38: NC_000015.10:g.89330257G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 . 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. 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. 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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