Systematic Re-evaluation of SCN5A Variants Associated with Brugada Syndrome

Research output: Contribution to journalArticle

  • External authors:
  • Wern Yew Ding
  • Johan Waktare
  • Dhiraj Gupta
  • Richard Snowdon
  • Mark Hall
  • Robert Cooper
  • Simon Modi
  • Derick Todd
  • Saagar Mahida


BACKGROUND: A large number of SCN5A variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous.

OBJECTIVE: We systematically re-evaluated all SCN5A variants reported in BrS using the 2015 ACMG-AMP guidelines METHODS: A Pubmed/Embase search was performed to identify all reported SCN5A variants in BrS. Standardized bioinformatic re-analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re-evaluation of frequency in the gnomAD database was performed. 14 ACMG-AMP rules were deemed applicable for SCN5A variant analysis.

RESULTS: 480 unique SCN5A variants were identified, the majority of which 425 (88%) were coding variants. 156/425 (37%) variants were classified as pathogenic/likely pathogenic. 258 (60%) were classified as variants of uncertain significance, while a further 11 (3%) were classified as benign/likely benign. When considering the subset of variants that were considered 'null' variants separately, 95% fulfilled criteria for pathogenicity/likely pathogenicity. On the other hand, only 17% of missense variants fulfilled criteria for pathogenicity/likely pathogenicity. Importantly however, only 25% of missense variants had available functional data, which was a major score driver for pathogenic classification.

CONCLUSION: Based on contemporary ACMG-AMP guidelines, only a minority of ion channel variants implicated in BrS fulfil criteria for pathogenicity or likely pathogenicity. This article is protected by copyright. All rights reserved.

Bibliographical metadata

Original languageEnglish
JournalJournal of cardiovascular electrophysiology
Early online date11 Sep 2018
Publication statusPublished - 2018

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