ArticleCirculation. Cardiovascular genetics2012
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.
Article in Circulation. Cardiovascular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed.
- Common and rare variants in SCN10A modulate the risk of atrial fibrillation.Circulation. Cardiovascular genetics · 2015Trial
- Sudden death-associated KCNH2 variants exert opposing effects on a nuclear subdomain of the cardiac potassium channel hERG1.The Journal of biological chemistry · 2026Article
- Case Report: Association of a rare single nucleotide variant in the KCNH2 gene with drug-induced QT prolongation.Frontiers in genetics · 2026Article
- Sudden Death-AssociatedbioRxiv : the preprint server for biology · 2025Article
- Mutation-Specific Differences in Kv7.1 (International journal of molecular sciences · 2022Review
- Isogenic Sets of hiPSC-CMs Harboring Distinct KCNH2 Mutations Differ Functionally and in Susceptibility to Drug-Induced Arrhythmias.Stem cell reports · 2020Article
- Protein Subdomain Enrichment ofFrontiers in cardiovascular medicine · 2020Article
- Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.Scientific reports · 2019Article
- Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension.Molecular genetics & genomic medicine · 2018Review
- Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.Science advances · 2018Article
- Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.Circulation · 2018Review
- Yield of theCirculation. Genomic and precision medicine · 2018Article
- Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy.European journal of human genetics : EJHG · 2017Article
- Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.Circulation. Cardiovascular genetics · 2017Article
- Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.Science translational medicine · 2016Article
- The genetics underlying acquired long QT syndrome: impact for genetic screening.European heart journal · 2016Article
- The pathogenicity of genetic variants previously associated with left ventricular non-compaction.Molecular genetics & genomic medicine · 2016Article
- Next-Generation Sequencing in Post-mortem Genetic Testing of Young Sudden Cardiac Death Cases.Frontiers in cardiovascular medicine · 2016Review
- Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death.International journal of molecular sciences · 2015Article
- Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel.Circulation. Cardiovascular genetics · 2015Article
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Abstract
backgroundHundreds of nonsynonymous single nucleotide variants (nsSNVs) have been identified in the 2 most common long-QT syndrome-susceptibility genes (KCNQ1 and KCNH2). Unfortunately, an ≈3%
backgroundand KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. METHODS AND
resultsIn this study, 4 tools [(1) conservation across species, (2) Grantham values, (3) sorting intolerant from tolerant, and (4) polymorphism phenotyping] were used to predict pathogenic or benign status for nsSNVs identified across 388 clinically definite long-QT syndrome cases and 1344 ostensibly healthy controls. From these data, estimated predictive values were determined for each tool independently, in concert with previously published protein topology-derived estimated predictive values, and synergistically when ≥3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1, whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the pathogenic status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide-binding domain, the topology-specific estimated predictive value improved from 56% to 91%.
conclusionsAlthough in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical use of the synergistic utility of these tools to enhance the classification of nsSNVs, particularly for Kv11.1's difficult to interpret C-terminal region.
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