Systematic Re-evaluation of SCN5A Variants Associated with Brugada Syndrome

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.