ClinVar

Description

The M301R pathogenic variant in the KCNJ2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The M301R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies of the M301R variant showed the homozygous channels were non-functional, whereas the heterozygous channels demonstrated decreased inward rectification, and the variant was classified as a gain of function pathogenic variant (Hattori et al., 2012). The M301R 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. Multiple missense variants in the same and nearby residues (including E299V, G300A, M301L, V302M, E303K) have been reported in the Human Gene Mutation Database in association with KCNJ2-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret M301R as a pathogenic variant