Low Clinical Penetrance in Causal Mutation Carriers for Cardiac Channelopathies

Whole-exome sequencing identifies Y1495X of SCN5A to be associated with familial conduction disease and sudden death

“…Alternatively, 13 distinct disease-causing genes are implicated in a single OMIM entity, the conduction system disease13, suggesting a more complex genetic heterogeneity than previously thought. The high genetic heterogeneity, variable expressions, reduced penetrance and pleiotropic effects of arrhythmias-related genes have impeded the identification of pathogenic gene141516, especially for channelopathies with rare clinical phenotypes.…”

Brugada syndrome masked by complete left bundle branch block. A clinical and functional study of its association with the p.1449Y>H SCN5A variant.

“…According to a recent re-evaluation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) rules for assessment of pathogenicity, 2,9 the SCN5A variant identified in this report can be classified as pathogenic, since it fulfills the following criteria: (i) the p.1449Y>H variant is a missense variant that leads to the replacement of tyrosine by histidine at position 1449, in the transmembrane S6 region of DIII, which is part of the pore region of the Na v 1.5 channel and, according to the SCN5A variant browser, is a hotspot region for BrS1 (ACMG category PM1, moderate evidence); 8 (ii) other variants producing amino acid changes in the same residue has been previously established as pathogenic and associated to clinical BrS (p.1449Y>S) and also to conduction disease with partial loss of function in in vitro studies (p.1449Y>C; PS1, strong evidence). [9][10][11][12] These results indicate that the conserved Y1449 is crucial for the proper functioning of the Na v 1.5 channel, and that its alteration induces dramatic changes in channel activity; and (iii) p.1449Y>H mutant encodes a not fully functional channel that generates extremely small (2% as compared to the WT) sodium currents, and a decrease more than 50% in the peak current is significantly associated with BrS1 penetrance (PS3, strong evidence). 2,9 Recently, Ciconte et al, 13 demonstrated that BrS carriers of SCN5A pathogenic variants exhibit a more aggressive clinical presentation and a greater epicardial substrate on electrophysiological studies, associating genotype with phenotypic expression.…”

Brugada syndrome masked by complete left bundle branch block: A clinical and functional study of its association with the p.1449Y>H SCN5A variant

“…Nowadays, functional evidence is considered the major score driver for pathogenicity assumption for missense variants. According to a recent re‐evaluation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG‐AMP) rules for assessment of pathogenicity, 2,9 the SCN5A variant identified in this report can be classified as pathogenic, since it fulfills the following criteria: (i) the p.1449Y>H variant is a missense variant that leads to the replacement of tyrosine by histidine at position 1449, in the transmembrane S6 region of DIII, which is part of the pore region of the Na v 1.5 channel and, according to the SCN5A variant browser, is a hotspot region for BrS1 (ACMG category PM1, moderate evidence); 8 (ii) other variants producing amino acid changes in the same residue has been previously established as pathogenic and associated to clinical BrS (p.1449Y>S) and also to conduction disease with partial loss of function in in vitro studies (p.1449Y>C; PS1, strong evidence) 9–12 . These results indicate that the conserved Y1449 is crucial for the proper functioning of the Na v 1.5 channel, and that its alteration induces dramatic changes in channel activity; and (iii) p.1449Y>H mutant encodes a not fully functional channel that generates extremely small (2% as compared to the WT) sodium currents, and a decrease more than 50% in the peak current is significantly associated with BrS1 penetrance (PS3, strong evidence) 2,9 …”