ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1880G>A (p.Arg627Gln) (rs375305567)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000503435 SCV000596504 likely pathogenic not provided 2015-09-03 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000660508 SCV000782608 pathogenic Progressive sclerosing poliodystrophy 2017-02-15 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000660508 SCV000886906 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1880G>A (NP_002684.1:p.Arg627Gln) [GRCH38: NC_000015.10:g.89325519C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15917273 . 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.
Invitae RCV000660508 SCV000952216 pathogenic Progressive sclerosing poliodystrophy 2019-04-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 627 of the POLG protein (p.Arg627Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs375305567, ExAC 0.01%). This variant has been observed in individuals with POLG-related disease (PMID: 16621917, 15917273, 19752458, 20883824). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (PMID: 17502560). ClinVar contains an entry for this variant (Variation ID: 436359). This variant has been reported to have conflicting or insufficient data to determine the effect on POLG protein function (PMID: 15917273, 24508722, 20153822). 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. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000503435 SCV001250416 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing

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