ArticleCirculation. Cardiovascular genetics2015
Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel.
Article in Circulation. Cardiovascular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 2 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Variability in reported midpoints of (in)activation of cardiac INa.The Journal of general physiology · 2025Pooled it
- The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2023Pooled it
- A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels.Science advances · 2026Article
- Genetic Basis of Brugada Syndrome.Biomedicines · 2025Review
- Structural basis of human NaProceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity.International journal of molecular sciences · 2024Review
- "Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders".BMC cardiovascular disorders · 2024Article
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
- KCNH2A561V Heterozygous Mutation Inhibits KCNH2 Protein Expression via The Activation of UPR Mediated by ATF6.Physiological research · 2023Article
- Review
- Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome.International journal of molecular sciences · 2023Review
- Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.Circulation · 2023Article
- Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with theFrontiers in cardiovascular medicine · 2023Review
- The role of GPD1L, a sodium channel interacting gene, in the pathogenesis of Brugada Syndrome.Frontiers in medicine · 2023Article
- When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of NaCells · 2022Review
- Article
- How Functional Genomics Can Keep Pace With VUS Identification.Frontiers in cardiovascular medicine · 2022Review
- Clinical Spectrum ofGenes · 2021Article
- Ca2+-dependent modulation of voltage-gated myocyte sodium channels.Biochemical Society transactions · 2021Review
- Does function trump bioinformatics in Brugada syndrome-associated SCN5A mutation calling? Patients, computers, and patches.European heart journal · 2021Article
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Authors and funding
9 authors.
Funding
Abstract
backgroundA 2% to 5% background rate of rare SCN5A nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of SCN5A nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools. METHODS AND
resultsSeven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire SCN5A-encoded Na(v)1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3-S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived SCN5A nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs.
conclusionsWe have used a large case/control study to identify regions of Na(v)1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant's pathogenic status.
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