Enhancing the Predictive Power of Mutations in the C-Terminus of the KCNQ1-Encoded Kv7.1 Voltage-Gated Potassium Channel

Jamie D. Kapplinger, Andrew S. Tseng, Benjamin A. Salisbury, David J. Tester, Thomas E. Callis, Marielle Alders, Arthur A M Wilde, Michael John Ackerman

Research output: Contribution to journalArticle

11 Scopus citations


Despite the overrepresentation of Kv7.1 mutations among patients with a robust diagnosis of long QT syndrome (LQTS), a background rate of innocuous Kv7.1 missense variants observed in healthy controls creates ambiguity in the interpretation of LQTS genetic test results. A recent study showed that the probability of pathogenicity for rare missense mutations depends in part on the topological location of the variant in Kv7.1’s various structure-function domains. Since the Kv7.1’s C-terminus accounts for nearly 50 % of the overall protein and nearly 50 % of the overall background rate of rare variants falls within the C-terminus, further enhancement in mutation calling may provide guidance in distinguishing pathogenic long QT syndrome type 1 (LQT1)-causing mutations from rare non-disease-causing variants in the Kv7.1’s C-terminus. Therefore, we have used conservation analysis and a large case-control study to generate topology-based estimative predictive values to aid in interpretation, identifying three regions of high conservation within the Kv7.1’s C-terminus which have a high probability of LQT1 pathogenicity.

Original languageEnglish (US)
Pages (from-to)187-197
Number of pages11
JournalJournal of Cardiovascular Translational Research
Issue number3
StatePublished - Apr 1 2015



  • Conservation analysis
  • Estimated predictive value
  • KCNQ1 (Kv7.1)
  • Long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics
  • Genetics(clinical)
  • Molecular Medicine
  • Pharmaceutical Science

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