Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001753589 | SCV001994833 | likely pathogenic | Mitochondrial disease | 2021-05-23 | reviewed by expert panel | curation | The c.3313G>C (p.Ala1105Pro) variant in POLG is not in any databases (PM2). This variant has a Revel score of 0.932 (PP3). There are no publications of cases with this variant. There is a case in the literature where the same amino acid position p.Ala1105Thr resulted in three family members affected PEO, ptosis, tremors, muscle weakness, and multiple mtDNA deletions (PS1; PMID: 15351195). In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2, PP3 |
| Gene |
RCV000188617 | SCV000242240 | uncertain significance | not provided | 2024-01-04 | criteria provided, single submitter | clinical testing | Observed in a patient with epilepsy who harbored a second POLG variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Saneto RP 2017, doi:10.1177/2326409817733012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Russell2017[CaseReport]) |
| Labcorp Genetics |
RCV002514035 | SCV003477389 | uncertain significance | Progressive sclerosing poliodystrophy | 2022-08-31 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1105 of the POLG protein (p.Ala1105Pro). This variant is not present in population databases (gnomAD no frequency). 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: 206560). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004586613 | SCV005077407 | uncertain significance | not specified | 2024-04-29 | criteria provided, single submitter | clinical testing | Variant summary: POLG c.3313G>C (p.Ala1105Pro) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3313G>C in individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 206560). Based on the evidence outlined above, the variant was classified as uncertain significance. |