Young, WJ;
Maung, S;
Ahmet, S;
Kirkby, C;
Ives, C;
Schilling, RJ;
Lowe, M;
(2024)
The frequency of gene variant reclassification and its impact on clinical management in the inherited arrhythmia clinic.
Heart Rhythm
10.1016/j.hrthm.2024.01.008.
(In press).
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Abstract
Background: Genetic testing in the inherited arrhythmia clinic informs risk stratification, clinical management, and family screening. Periodic review of variant classification is recommended as supporting evidence accrues over time. However, there is limited reporting of real-world data on the frequency and impact of variant reclassification. Objective: The purpose of this study was to determine the burden of variant reclassification in our inherited arrhythmia clinic and the impact on clinical management. Methods: Genetic testing reports for patients referred to our clinic from 2004–2020 were reviewed. Reported variants were reinvestigated using ClinVar, VarSome, and a literature review. Classification was updated using the American College of Medical Genetics and Genomics (ACMG) criteria and tested for association with arrhythmic events and modification of medical management. Results: We identified 517 patients (median age 37 years) who underwent gene panel testing. A variant of uncertain significance (VUS) was reported for 94 patients (18.2%) and more commonly identified when using large gene panels (P <.001). A total of 28 of 87 unique VUSs (32.2%) were reclassified to pathogenic/likely pathogenic (n = 11) or benign/likely benign (n = 17). Of 138 originally reported pathogenic variants, 7 (5.1%) lacked support using ACMG criteria. Variant reclassification was not associated with arrhythmic events; however, it did impact genotype-specific counseling and future therapeutic options. Conclusion: In our large real-world patient cohort, we identify a clinically important proportion of both pathogenic variants and VUSs with evidence for reclassification. These findings highlight the need for informed pretest counseling, a regular structured review of variants reported in genetic testing, and the potential benefits to patients for supporting genotype-guided therapy.
| Type: | Article |
|---|---|
| Title: | The frequency of gene variant reclassification and its impact on clinical management in the inherited arrhythmia clinic |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.hrthm.2024.01.008 |
| Publisher version: | http://dx.doi.org/10.1016/j.hrthm.2024.01.008 |
| Language: | English |
| Additional information: | © 2024 Heart Rhythm Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
| Keywords: | Channelopathy, Genetic testing, Inherited arrhythmia, Reclassification, Variant of uncertain significance |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10188739 |
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