Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000435544 | SCV000515377 | pathogenic | not provided | 2016-12-20 | criteria provided, single submitter | clinical testing | A pathogenic variant has been identified in the KCNJ2 gene. The M301L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. Although M301L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, pathogenic missense variants at the same residue (M301K, M301R), and pathogenic/likely pathogenic missense variants in nearby residues (E299V, G300V, G300D) have been reported in the Human Gene Mutation Database in association with KNCJ2-related disorders (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.In summary, M301L in the KCNJ2 gene is interpreted as a pathogenic variant. |
| Labcorp Genetics |
RCV000535723 | SCV000645192 | uncertain significance | Andersen Tawil syndrome; Short QT syndrome type 3 | 2017-03-13 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine with leucine at codon 301 of the KCNJ2 protein (p.Met301Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNJ2-related disease. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). |