ArticleAmerican journal of human genetics2020
High-Throughput Reclassification of SCN5A Variants.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 1 of them a synthesis that pooled it.
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Who cites it
74 citing papers in PubMed, 1 synthesis or guideline pooled it, 150 citations in OpenAlex.
- 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
- Large serine recombinase-mediated gene insertion for high-throughput screens: advantages, design principles, and applications.Nucleic acids research · 2026Review
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Common genetic variants of the cardiac sodium channel alter patient response to class 1b antiarrhythmics.Journal of precision medicine (Amsterdam, Netherlands) · 2026Article
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Common Genetic Variants of The Cardiac Sodium Channel Alter Patient Response to Class 1b Antiarrhythmics.bioRxiv : the preprint server for biology · 2026Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- Appropriate time interval to update ambiguous genetic diagnosis in inherited arrhythmogenic syndromes.iScience · 2025Article
- How to approach multiple arrhythmias in a young athlete withHeartRhythm case reports · 2025Article
- The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.The Journal of general physiology · 2025Article
- Genetic Background and Clinical Phenotype in an Italian Cohort with Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyopathy (ACM): A Whole-Exome Sequencing Study.International journal of molecular sciences · 2025Article
- Electrophysiological classification ofFrontiers in pharmacology · 2025Article
- The Genetic Basis of Sudden Cardiac Death: From Diagnosis to Emerging Genetic Therapies.Annual review of medicine · 2025Review
- Canadian College of Medical Geneticists: clinical practice advisory document - responsibility to recontact for reinterpretation of clinical genetic testing.Journal of medical genetics · 2024Article
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels.iScience · 2024Article
- ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS.bioRxiv : the preprint server for biology · 2024Article
- Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.Communications biology · 2024Article
- Scalable approaches for generating, validating and incorporating data from high-throughput functional assays to improve clinical variant classification.Human genetics · 2024Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%-50% normalized peak current). The previously unstudied variants were initially classified as likely benign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61). After the patch clamp studies, 16 variants were benign/likely benign, 45 were pathogenic/likely pathogenic, and only 12 were still VUSs. Structural modeling identified likely mechanisms for loss of function including altered thermostability and disruptions to alpha helices, disulfide bonds, or the permeation pore. High-throughput patch clamping enabled reclassification of the majority of tested VUSs in SCN5A.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.