Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000188586 | SCV000242208 | pathogenic | not provided | 2014-03-05 | criteria provided, single submitter | clinical testing | p.Gln879Arg (CAG>CGG): c.2636 A>G in exon 17 of the POLG gene (NM_002693.2). The Gln879Arg missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 5,000 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 Gln879Arg mutation 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. This substitution occurs at a position that is conserved across species in the polymerase domain of the protein and a different missense mutation at the same codon (Gln879His) was identified in a patient with hepatotoxicity and encephalopathy who had another disease-causing mutation on the other chromosome (Horvath et al., 2008; McFarland et al., 2008). Functional studies indicate that Gln879His moderately decreases the polymerase activity of the enzyme, confirming the functional importance of this position in the protein (Kasiviswanathan et al., 2009). The variant is found in INFANT-EPI,DEPLTN-MITOP,CHILD-EPI panel(s). |
| Eurofins Ntd Llc |
RCV000188586 | SCV000858276 | uncertain significance | not provided | 2017-11-20 | criteria provided, single submitter | clinical testing | |
| Wong Mito Lab, |
RCV000758312 | SCV000886970 | pathogenic | Progressive sclerosing poliodystrophy | 2018-10-01 | criteria provided, single submitter | clinical testing | The NM_002693.2:c.2636A>G (NP_002684.1:p.Gln879Arg) [GRCH38: NC_000015.10:g.89321223T>C] 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM2:This variant is absent in key population databases. 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. |
| Labcorp Genetics |
RCV000758312 | SCV001386878 | uncertain significance | Progressive sclerosing poliodystrophy | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 879 of the POLG protein (p.Gln879Arg). This variant is present in population databases (rs368587966, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. 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. |