ArticleGenome medicine2024
High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.
Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
- Overestimating zero-shot fitness prediction: Broad benchmarks mask local failures and practical limitations.bioRxiv : the preprint server for biology · 2026Article
- Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.Molecular medicine (Cambridge, Mass.) · 2026Article
- SynFit: Synergistic Contrastive Learning for Multi-Objective Protein Fitness Prediction and Optimization.bioRxiv : the preprint server for biology · 2026Article
- Structural Evaluation ofCirculation. Genomic and precision medicine · 2026Article
- Determining the intra-residue correlation of missense variant impact using MAVE scores: implications for the ACMG/AMP PM5 criterion for DNA variant classification.Genome medicine · 2026Article
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- The functional landscape of coding variation in the familial hypercholesterolemia geneScience (New York, N.Y.) · 2026Article
- Genetic Risk Factors for Epilepsy: From Familial Studies to Gene Discoveries and Polygenic Risk Scores, Strides Toward Unlocking an Age-Old Question in Epilepsy.Epilepsy currents · 2026Review
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- A Historical Outline of Fluorescence Spectroscopy in Ion Channel Research.Advances in experimental medicine and biology · 2026Review
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
- Proteins need extra attention: improving the predictive power of protein language models on mutational datasets with hint tokens.NAR genomics and bioinformatics · 2025Article
- KCNQ1 Polymorphism in the Context of Ischemic Cardiomyopathy: A Potential Key to Decision-Making for Device Implantation.Clinical cardiology · 2025Article
- Article
- Genetics and Pharmacogenetics of Atrial Fibrillation: A Mechanistic Perspective.JACC. Basic to translational science · 2024Review
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Authors and funding
14 authors.
Funding
Abstract
backgroundKCNE1 encodes a 129-residue cardiac potassium channel (I
methodsIn this study, we leveraged the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein-coding KCNE1 variants.
resultsWe comprehensively assayed KCNE1 variant cell surface expression (2554/2709 possible single-amino-acid variants) and function (2534 variants). Our study identified 470 loss- or partial loss-of-surface expression and 574 loss- or partial loss-of-function variants. Of the 574 loss- or partial loss-of-function variants, 152 (26.5%) had reduced cell surface expression, indicating that most functionally deleterious variants affect channel gating. Nonsense variants at residues 56-104 generally had WT-like trafficking scores but decreased functional scores, indicating that the latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation (with > 70% loss-of-function variants) were in predicted close contact with binding partners KCNQ1 or calmodulin. Our functional assay data were consistent with gold standard electrophysiological data (ρ = - 0.64), population and patient cohorts (32/38 presumed benign or pathogenic variants with consistent scores), and computational predictors (ρ = - 0.62). Our data provide moderate-strength evidence for the American College of Medical Genetics/Association of Molecular Pathology functional criteria for benign and pathogenic variants.
conclusionsComprehensive variant effect maps of KCNE1 can both provide insight into I
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