ClinVar

Description

Variant summary: KCNJ2 c.919A>G (p.Met307Val) results in a conservative amino acid change located in the Inward rectifier potassium channel, C-terminal domain (IPR041647) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251354 control chromosomes. c.919A>G has been reported in the literature as a de-novo variant/sporadic finding in affected individuals with a report of co-segregation in at-least one family affected with features of Andersen Tawil syndrome (ATS) (example, Liu_2015, Alrashed_2019, Ullah_2019, Luo_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Handklo-Jamal_2020). The most pronounced variant effect results in high sensitivity to PIP2 depletion supporting a lability of/impaired PIP2-Kir2.1 interaction. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.