Is variant pathogenicity in the eye of the beholder

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Is variant pathogenicity in the eye of the beholder Is variant pathogenicity in the eye of the beholder? A case of unexplained sudden cardiac arrest highlights the potentially dangerous role of historical rare variant compendia in SCN5A rare variant adjudication Marissa J. Stutzman, Dan Ye, MD, David J. Tester, BS, John R. Giudicessi, MD, PhD, Michael J. Ackerman, MD, PhD HeartRhythm Case Reports Volume 5, Issue 3, Pages 163-168 (March 2019) DOI: 10.1016/j.hrcr.2018.11.019 Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 1 Family pedigree and representative electrocardiogram (ECG) tracings. A: Pedigree. The black symbol represents an affected individual. The white symbols represent unaffected family members. The arrow points to the family index case. B: Representative ECG tracing from the proband. C: Representative ECG tracing from the proband’s father. VF = ventricular fibrillation; VT = ventricular tachycardia. HeartRhythm Case Reports 2019 5, 163-168DOI: (10.1016/j.hrcr.2018.11.019) Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 2 The p.Glu1240Gln-SCN5A variant did not significantly change current density in TSA201 cells. A: The whole-cell SCN5A current representative tracings showing wild-type (WT) and Glu1240Gln from a holding potential of -100 mV to testing potential of +90 mV in 10-mV increments with 24 ms duration. B: Current–voltage relationship for SCN5A-WT (n = 15) and Glu1240Gln variant (n = 16). HeartRhythm Case Reports 2019 5, 163-168DOI: (10.1016/j.hrcr.2018.11.019) Copyright © 2019 Heart Rhythm Society Terms and Conditions

Figure 3 The p.Glu1240Gln-SCN5A variant did not significantly shift V1/2 of inactivation or activation, fast component of recovery from inactivation, or the sodium late current. A: Inactivation curves of SCN5A-WT (n = 15) and Glu1240Gln variant (n = 16). I/Imax represents normalized sodium current. B: Activation curves of SCN5A-WT (n = 15) and Glu1240Gln variant (n = 16). G/Gmax represents normalized conductance. C: Recovery from inactivation for SCN5A-WT (n = 7) and Glu1240Gln variant (n = 7) from a holding potential of -120 mV to prepulse of -20 mV with 700 ms duration, with increased recovery interval, followed by a test pulse of -20 mV with 20 ms duration. D: Summary data of SCN5A-WT (n = 11) and Glu1240Gln variant (n = 9) with respect to the late/persistent sodium current. HeartRhythm Case Reports 2019 5, 163-168DOI: (10.1016/j.hrcr.2018.11.019) Copyright © 2019 Heart Rhythm Society Terms and Conditions