Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Columbia University Laboratory of Personalized Genomic Medicine, |
RCV000258005 | SCV000297744 | likely pathogenic | Acute liver failure | 2016-06-01 | criteria provided, single submitter | clinical testing | Parents are heterozygous and phenotypically normal. The patient is homozygous and has severe mtDNA depeletion. POLG2 encodes the accessory subunit of DNA polymerase and is involved in mtDNA replication. |
| Gene |
RCV000432548 | SCV000530691 | likely pathogenic | not provided | 2016-08-02 | criteria provided, single submitter | clinical testing | The R182W variant in the POLG2 gene has been reported in the homozygous state in an individual with infantile fulminant liver failure and mitochondrial depletion in liver and muscle. This individual's heterozygous parents were reportedly unaffected (Varma et al., 2016). The R182W variant was not observed in approximately 6500 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 R182W variant 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R182W as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV000432548 | SCV003442508 | uncertain significance | not provided | 2023-06-19 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects POLG2 function (PMID: 30157269). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 252958). This missense change has been observed in individual(s) with POLG2-related conditions (PMID: 27592148). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 182 of the POLG2 protein (p.Arg182Trp). |
| OMIM | RCV000824678 | SCV000965602 | pathogenic | Mitochondrial DNA depletion syndrome 16A | 2021-07-15 | no assertion criteria provided | literature only | |
| Clinical Genetics Laboratory, |
RCV002290967 | SCV002583325 | uncertain significance | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 | 2021-11-02 | no assertion criteria provided | clinical testing |