ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3151G>A (p.Gly1051Arg) (rs121918049)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685758 SCV000813255 uncertain significance Progressive sclerosing poliodystrophy 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1051 of the POLG protein (p.Gly1051Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121918049, ExAC 0.001%). This variant has not been reported in the literature in individuals with a POLG-related disease. However, a different variant (c.3151G>C) giving rise to the same protein effect observed here (p.Gly1051Arg) has been reported biallelic with another pathogenic POLG variant (in trans) to segregate with autosomal recessive progressive external ophthalmoplegia in a family (PMID: 14745080). Experimental studies have shown that this missense change mildly impairs protein function (PMID: 17980715, 20185557). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000685758 SCV000887121 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3151G>A (NP_002684.1:p.Gly1051Arg) [GRCH38: NC_000015.10:g.89319053C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:14745080 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Likely Pathogenic.

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