Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000188668 | SCV000242292 | likely pathogenic | not provided | 2017-04-07 | criteria provided, single submitter | clinical testing | A published L623W variant that is likely pathogenic has been identified in the POLG gene. The L623W variant has been reported previously in an individual with mitochondrial DNA depletion who also had a second POLG variant on the other allele (Bortot et al., 2009). 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 L623W 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, and multiple missense variants in nearby residues have been reported in association with POLG-related disorders (Stenson et al., 2014; Human DNA Polymerase Gamma Mutation Database), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Baylor Genetics | RCV001336494 | SCV001529894 | uncertain significance | Progressive sclerosing poliodystrophy | 2018-01-29 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Labcorp Genetics |
RCV001336494 | SCV002129424 | uncertain significance | Progressive sclerosing poliodystrophy | 2024-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 623 of the POLG protein (p.Leu623Trp). This variant is present in population databases (rs758438414, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 19195941, 29655203). ClinVar contains an entry for this variant (Variation ID: 206603). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. 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. |