Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Wong Mito Lab, |
RCV000758327 | SCV000886991 | likely pathogenic | Progressive sclerosing poliodystrophy | 2018-10-01 | criteria provided, single submitter | clinical testing | The NM_002693.2:c.3509T>G (NP_002684.1:p.Leu1170Arg) [GRCH38: NC_000015.10:g.89317510A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic. |
| Labcorp Genetics |
RCV000758327 | SCV001226732 | uncertain significance | Progressive sclerosing poliodystrophy | 2024-07-30 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1170 of the POLG protein (p.Leu1170Arg). This variant is present in population databases (rs796052913, gnomAD 0.01%). 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: 206618). 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) performed at Invitae 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. |
| 3billion, |
RCV000758327 | SCV002573355 | uncertain significance | Progressive sclerosing poliodystrophy | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.87). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Victorian Clinical Genetics Services, |
RCV000758327 | SCV005399214 | uncertain significance | Progressive sclerosing poliodystrophy | 2020-05-21 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified, NM_002693.2(POLG):c.3509T>G in exon 22 of the POLG gene. This substitution is predicted to create a major amino acid change from a leucine to an arginine at position 1170 of the protein; NP_002684.1(POLG):p.(Leu1170Arg). The leucine at this position has high conservation (100 vertebrates, UCSC), and is located within the DNA polymerase family A domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, FATHMM, PROVEAN). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). This variant has been reported once as likely pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |