ArticleCirculation2024
Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve
Abstract read
In one paragraph
Article in Circulation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
–field-weighted citation impact
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
27 citing papers in PubMed.
- Quantitative analysis of trafficking defects induced by heterozygous expression of hERG voltage sensor domain variants.Channels (Austin, Tex.) · 2026Article
- NS1643 enhances the activity of T1019PfsX38 and Q1070X hERG channels associated with long QT syndrome type 2.Pflugers Archiv : European journal of physiology · 2026Article
- Likelihood-based calibration improves the clinical utility of JAG1 functional data for variant classification.American journal of human genetics · 2026Article
- Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes.Cardiovascular research · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- C-terminal long-QT type 1 R562S-Kv7.1 variant, the first variant in helix C impairing β-adrenergic response of the slow delayed rectifier K+ channel.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- HaloTag-based approach to quantify subcellular localization of TRPV3 channels.Biophysical journal · 2026Article
- Sudden death-associated KCNH2 variants exert opposing effects on a nuclear subdomain of the cardiac potassium channel hERG1.The Journal of biological chemistry · 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
- SPARC: a structural pathogenicity algorithm for risk classification of hERG variants.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- Identification and functional assessment of a KCNH2 compound heterozygosity in a patient with presumed idiopathic ventricular fibrillation ascertains the diagnosis of long QT syndrome type 2.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- 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
- Case Report: Association of a rare single nucleotide variant in the KCNH2 gene with drug-induced QT prolongation.Frontiers in genetics · 2026Article
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- High-throughput screens identify genotype-specific therapeutics for channelopathies.JCI insight · 2025Article
Corrections and comments
- Commented on by
- Update of
Authors and funding
42 authors.
Matthew J O'Neill *Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN (M.J.O., X.B.).ORCID 0000-0003-2014-7950
Chai-Ann Ng *Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia (C.-A.N., Q.S., C.-Y.T., J.I.V.).ORCID 0000-0002-3120-5450
Takanori AizawaDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.A., A.K.).ORCID 0000-0001-5192-3962
Luca SalaIRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).ORCID 0000-0002-4129-6632
Sahej BainsDepartment of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.).ORCID 0000-0002-1357-7656
Annika WinboDepartment of Physiology (A.W., B.M.K.), University of Auckland, New Zealand.ORCID 0000-0002-9323-3166
Rizwan UllahVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Qianyi ShenMark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia (C.-A.N., Q.S., C.-Y.T., J.I.V.).
Chek-Ying TanSchool of Clinical Medicine, University of New South Wales Sydney, Darlinghurst, New South Wales, Australia (C.-A.N., J.I.V.).
Krystian KozekVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0002-6951-9404
Loren R VanagsVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Devyn W MitchellVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0001-8508-3324
Alex ShenVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0009-0001-8430-8357
Yuko WadaVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0001-8533-8040
Asami KashiwaDepartment of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.A., A.K.).ORCID 0000-0001-9562-8981
Lia CrottiIRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).ORCID 0000-0001-8739-6527
Federica DagradiIRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).ORCID 0000-0002-1090-3292
Giulia MusuIRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).
Carla SpazzoliniIRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).ORCID 0000-0003-1209-0157
Raquel NevesDepartment of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.).ORCID 0000-0003-2619-0036
J Martijn BosDepartment of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.).ORCID 0000-0002-3635-2003
John R GiudicessiDepartment of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.).ORCID 0000-0001-5871-0265
Xavier BledsoeMedical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN (M.J.O., X.B.).ORCID 0000-0002-6091-9372
Eric R GamazonDivision of Genetic Medicine (E.R.G.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Megan C LancasterVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0002-2697-3762
Andrew M GlazerVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0002-3938-4713
Bjorn C KnollmannVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0003-4956-9735
Dan M RodenVanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology (R.U., K.K., L.R.V., D.W.M., A.S., Y.W., L.C., M.C.L., A.M.G., B.C.K., D.M.R.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Jochen WeileDepartment of Medicine and Surgery, University Milano Bicocca, Milan, Italy. Department of Molecular Genetics, University of Toronto, Canada (J.W., F.R.).
Frederick RothDepartment of Medicine and Surgery, University Milano Bicocca, Milan, Italy. Department of Molecular Genetics, University of Toronto, Canada (J.W., F.R.).
Joe-Elie SalemSorbonne University, APHP, INSERM, Clinical Pharmacology, Hopital Pitié-Salpétière Department of Medicine (J.-E.S.), University of Auckland, New Zealand.ORCID 0000-0002-0331-3307
Nikki EarleDepartment of Cardiology, Waikato Hospital, Hamilton, New Zealand (N.E., R.S.).ORCID 0000-0003-1663-2195
Rachael StilesDepartment of Cardiology, Waikato Hospital, Hamilton, New Zealand (N.E., R.S.).
Taylor AgeeDepartment of Chemistry, Mississippi State University, Starkville (T.A., C.N.J.).ORCID 0000-0002-6179-7653
Christopher N JohnsonDepartment of Chemistry, Mississippi State University, Starkville (T.A., C.N.J.).ORCID 0000-0002-5307-798X
Minoru HorieDepartment of Cardiovascular Medicine, Shiga University of Medical Science, Japan (M.H.).ORCID 0000-0002-9029-2339
Jonathan R SkinnerSydney Children's Hospital Network, University of Sydney, Australia (J.R.S.).ORCID 0000-0002-3653-0412
Michael J AckermanDepartment of Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (S.B., R.N., J.M.B., J.R.G., M.J.A.).ORCID 0000-0002-8011-3333
Peter J SchwartzIRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.S., L.C., F.D., G.M., C.S., P.J.S.).ORCID 0000-0003-0367-1048
Seiko OhnoDepartment of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan (S.O.).ORCID 0000-0003-1209-8896
Jamie I VandenbergMark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, Australia (C.-A.N., Q.S., C.-Y.T., J.I.V.).ORCID 0000-0002-3859-3716
Brett M KronckeDepartment of Physiology (A.W., B.M.K.), University of Auckland, New Zealand.
Funding
Tumor Immunology and Microenvironment Research ProgramP30CA068485 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Ben Ho Park · 1995 to 2026
$172.8MTranslational Analysis CoreP30DK058404 · NIDDK · VANDERBILT UNIVERSITY MEDICAL CENTER · PI MARY Kay WASHINGTON · 2002 to 2026
$29.9MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007347 · NIGMS · VANDERBILT UNIVERSITY · PI WILLIAMS, CHRISTOPHER S. · 1985 to 2023
$26.3MCLINICAL PHARMACOLOGY TRAINING PROGRAMT32GM007569 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Bjorn C Knollmann · 1985 to 2026
$12.4MSystematically mapping variant effects for cardiovascular genesR01HL164675 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI ASHLEY, EUAN A, RODEN, DAN M · 2022 to 2025
$8.1MToward a Mechanism-Based Approach to Treating Cardiac ArrhythmiaR35HL144980 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI KNOLLMANN, BJORN C · 2019 to 2025
$7.1MMedical Scientist Training ProgramT32GM152284 · NIGMS · VANDERBILT UNIVERSITY · PI Christopher S. Williams · 2024 to 2026
$4.8MIntegrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT PenetranceR01HL160863 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Brett M Kroncke · 2022 to 2026
$2.9MHigh-throughput discovery of disease-associated ion channel variantsR35GM150465 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Andrew M. Glazer · 2023 to 2026
$1.8MA pipeline for identifying disease-causing variants in transmembrane proteinsR00HG010904 · NHGRI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI GLAZER, ANDREW M. · 2022 to 2024
$737kAberrant Splicing in the Cardiac ArrhythmiasF30HL163923 · NHLBI · VANDERBILT UNIVERSITY · PI O'NEILL, MATTHEW · 2022 to 2023
$61kNCI NIH HHS P30 CA068485NHGRI NIH HHS R00 HG010904NHLBI NIH HHS F30 HL163923NHLBI NIH HHS R01 HL160863NHLBI NIH HHS R01 HL164675NHLBI NIH HHS R35 HL144980NIDDK NIH HHS P30 DK058404NIGMS NIH HHS R35 GM150465NIGMS NIH HHS T32 GM007347NIGMS NIH HHS T32 GM007569NIGMS NIH HHS T32 GM152284
Abstract
backgroundLong QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by
methodsWe quantified cell-surface trafficking of 18 796 variants in
resultsVariant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and corrected QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88]).
conclusionsHigh-throughput
Indexed as
ERG1 Potassium ChannelLong QT SyndromePatch-Clamp TechniquesAdultFemaleHumansMaleMiddle AgedMutation, MissenseRisk AssessmentERG1 Potassium ChannelKCNH2 protein, humanarrhythmiasautomated patch clampingLQTSmultiplexed assay of variant effectrisk stratification
Identifiers
What Socratic holds
Textmetadata
LicenceTDM
Read underepoch 390
Registered trials
None linked
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 Socratic graph.