Even pore-localizing missense variants at highly conserved sites in KCNQ1-encoded Kv7.1 channels may have wild-type function and not cause type 1 long.

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Even pore-localizing missense variants at highly conserved sites in KCNQ1-encoded Kv7.1 channels may have wild-type function and not cause type 1 long QT syndrome: Do not rely solely on the genetic test company's interpretation Ashley Paquin, BA, Dan Ye, MD, David J. Tester, BS, Jamie D. Kapplinger, BA, Michael T. Zimmermann, PhD, Michael J. Ackerman, MD, PhD HeartRhythm Case Reports Volume 4, Issue 2, Pages 37-44 (February 2018) DOI: 10.1016/j.hrcr.2017.04.006 Copyright © 2017 Heart Rhythm Society Terms and Conditions

Figure 1 KCNQ1 topology with A300S variant location. Depicted is a schematic representation of the KCNQ1-encoded potassium channel α subunit (Kv7.1) with A300S localized to the channel's pore region. HeartRhythm Case Reports 2018 4, 37-44DOI: (10.1016/j.hrcr.2017.04.006) Copyright © 2017 Heart Rhythm Society Terms and Conditions

Figure 2 Patient and pedigree summary. Illustrated are the pedigree for our index case (arrow) (A) and a representative ECG tracing (B). The plus sign represents those family members (index case, her father, and her 2 sisters) who were positive for A300S. The negative sign represents the family member (mother) who was negative for A300S. ECG = electrocardiogram; QTc = corrected QT interval. HeartRhythm Case Reports 2018 4, 37-44DOI: (10.1016/j.hrcr.2017.04.006) Copyright © 2017 Heart Rhythm Society Terms and Conditions

Figure 3 Simulations based on the KCNQ1 molecular structure indicate similarities and modest differences for A300S. A: The position within the 3-dimensional tetrameric structure of A300 and 5 additional reference amino acids are indicated—2 along the interior and 2 at sites flanking A300. The view is along the membrane plane, and the “front” half of the tetramer has been hidden for clarity. B: From the extracellular side, the position of reference sites is indicated and 1 monomer of the tetramer colored tan. C: T312 lies at the base of the selectivity filter. The distance between T312 from one monomer to another is used to quantify how open the selectivity filter is. In our simulations, A300S lead to a greater propensity for a more open conformation of the selectivity filter. D: We quantified the distribution of K+ around each reference amino acid; the reference residue number is shown above each subplot and colored as in panel A. RDF = radial distribution function; WT = wild type. HeartRhythm Case Reports 2018 4, 37-44DOI: (10.1016/j.hrcr.2017.04.006) Copyright © 2017 Heart Rhythm Society Terms and Conditions

Figure 4 KCNQ1-A300S missense variant did not alter IKs current density in heterologous TSA201 cells. A: Whole-cell IKs representative tracings from TSA201 cells expressing KCNQ1-WT or KCNQ1-A300S determined from a holding potential of −80 mV and testing potentials from −40 to +80 mV in 10 mV increments with a 4-second duration. B: Current-voltage relationship for IKs KCNQ1-WT (n = 14) and -A300S missense variant (n = 14). All values represent mean ± standard error of the mean. IKs = slow delayed rectifier potassium current; WT = wild type. HeartRhythm Case Reports 2018 4, 37-44DOI: (10.1016/j.hrcr.2017.04.006) Copyright © 2017 Heart Rhythm Society Terms and Conditions