ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1943C>G (p.Pro648Arg) (rs796052906)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188671 SCV000242295 pathogenic not provided 2014-09-12 criteria provided, single submitter clinical testing p.Pro648Arg (CCC>CGC): c.1943 C>G in exon 10 of the POLG gene (NM_002693.2). The P648R missense mutation in the POLG gene has been reported in multiple unrelated individuals with encephalopathy, progressive external ophthalmoplegia, SANDO, or other autosomal recessive POLG-related disorders (Horvath et al., 2006; Ferreira et al., 2011). These individuals were all homozygous for P648R or compound heterozygous for P648R and a second POLG mutation on the other allele. The P648R mutation 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. P648R 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 it alters a conserved residue in the linker region of the protein. Therefore, P648R is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Invitae RCV000702972 SCV000831850 likely pathogenic Progressive sclerosing poliodystrophy 2017-08-15 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 648 of the POLG protein (p.Pro648Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with autosomal recessive progressive external ophthalmoplegia (PEO) and sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndrome (PMID: 16621917, 21550804). ClinVar contains an entry for this variant (Variation ID: 206606). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000702972 SCV000886907 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1943C>G (NP_002684.1:p.Pro648Arg) [GRCH38: NC_000015.10:g.89325456G>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21550804 . 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. PS4:Prevalence of variant in affecteds statistically increased over controls. 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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