ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1874C>T (p.Pro625Leu) (rs1064794214)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478890 SCV000568232 likely pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing The P625L variant has been reported previously in an individual with seizures, developmental delay, hypotonia, ataxia, spasticity, muscle weakness, and an abnormal muscle biopsy; however, a second POLG variant was not identified in this individual (Tang et al., 2011). 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 P625L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. A different missense variant at the same position (P625R) as well as missense variants in nearby residues (L623W, R627W, R627Q) have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database; Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758441 SCV000887150 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1874C>T (NP_002684.1:p.Pro625Leu) [GRCH38: NC_000015.10:g.89325525G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21880868 . 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 RCV000758441 SCV001534699 uncertain significance Progressive sclerosing poliodystrophy 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 625 of the POLG protein (p.Pro625Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 419975). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; 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.

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