ClinVar

Description

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.