ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2293C>A (p.Pro765Thr) (rs1003442806)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000530237 SCV000630127 uncertain significance Progressive sclerosing poliodystrophy 2017-07-28 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 765 of the POLG protein (p.Pro765Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as heterozygous in an individual with features suggestive of a POLG deficiency (PMID: 21880868) and as homozygous in an individual affected with sensory ataxic neuropathy, ophthalmoplegia, dysarthria and gastroparesis (PMID: 22805437). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000530237 SCV000886959 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2293C>A (NP_002684.1:p.Pro765Thr) [GRCH38: NC_000015.10:g.89322875G>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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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