ClinVar

Description

p.Glu299Val (GAA>GTA): c.896 A>T in exon 2 of the KCNJ2 gene (NM_000891.2). Glu299Val in the KCNJ2 gene has been reported recently as a de novo mutation in a child with SQTS and atrial fibrillation, and was absent from 400 control individuals in this study (Deo M et al., 2013). Functional in vitro studies demonstrated that Glu299Val leads to impaired or absent inward rectification properties of the Kir2.1 potassium channel, and computer simulations predicted that this could result in a shortened QT interval in vivo (Deo M et al., 2013). Glu299Val is a non-conservative amino acid substitution of a negatively-charged Glutamic acid with a neutral Valine at a position that is well conserved across species. Consequently, in silico analysis predicts Glu299Val is damaging to the protein structure/function. Mutations in nearby residues (Gly300Ala, Gly300Asp, Gly300Val, Val302Met) have been reported in association with Andersen-Tawil syndrome, and Met301Lys has been reported in association with SQTS (Hattori T et al., 2011), further supporting the functional importance of this region of the protein. In addition, the Glu299Val 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. In summary, Glu299Lys in the KCNJ2 gene is interpreted as a disease-causing mutation. The variant is found in SQT panel(s).