ArticleAmerican journal of human genetics2022
A calibrated functional patch-clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Likelihood-based calibration improves the clinical utility of JAG1 functional data for variant classification.American journal of human genetics · 2026Article
- Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome.Molecular genetics and genomics : MGG · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- ClinMAVE: a curated database for clinical application of data from multiplexed assays of variant effect.Nucleic acids research · 2026Article
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.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
- Electrophysiological classification ofFrontiers in pharmacology · 2025Article
- Article
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Multisite Validation of a Functional Assay to AdjudicateCirculation. Genomic and precision medicine · 2024Article
- Multiplexed Assays of Variant Effect and Automated Patch-clamping ImprovemedRxiv : the preprint server for health sciences · 2024Article
- Molecular and cellular context influences SCN8A variant function.JCI insight · 2024Article
- Integration of validated functional evidence to support the pathogenicity ofGenetics in medicine open · 2024Article
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study.Interface focus · 2023Article
- 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
- Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance.Human molecular genetics · 2023Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Modern sequencing technologies have revolutionized our detection of gene variants. However, in most genes, including KCNH2, the majority of missense variants are currently classified as variants of uncertain significance (VUSs). The aim of this study was to investigate the utility of an automated patch-clamp assay for aiding clinical variant classification in KCNH2. The assay was designed according to recommendations proposed by the Clinical Genome Sequence Variant Interpretation Working Group. Thirty-one variants (17 pathogenic/likely pathogenic, 14 benign/likely benign) were classified internally as variant controls. They were heterozygously expressed in Flp-In HEK293 cells for assessing the effects of variants on current density and channel gating in order to determine the sensitivity and specificity of the assay. All 17 pathogenic variant controls had reduced current density, and 13 of 14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying evidence of moderate or supporting strength for VUS reclassification. Inclusion of functional assay evidence enabled us to reclassify 6 out of 44 KCNH2 VUSs as likely pathogenic. The high-throughput patch-clamp assay can provide moderate-strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value of developing automated patch-clamp assays for functional characterization of ion channel gene variants.
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Registered trials
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.