Exploiting ion channel structure to assess rare variant pathogenicity.

ABSTRACT: BACKGROUND:A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants. OBJECTIVE:The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation. METHODS:We used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels. RESULTS:The structural analysis indicates that KCNQ1 Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1 Val162Met is benign. CONCLUSION:Proximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.

SUBMITTER: Kroncke BM 

PROVIDER: S-EPMC5984725 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature