ArticlePediatric cardiology2019
Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors.
Article in Pediatric cardiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- The importance and clinical utility of reanalysis of exome and genome sequencing data.Kidney research and clinical practice · 2026Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- Reclassification of variants of uncertain significance in neonatal genetic diseases: implications from a clinician's perspective.Journal of human genetics · 2025Article
- Making Sense of Missense: Benchmarking MutScore for Variant Interpretation in Inherited Cardiac Diseases.Molecular diagnosis & therapy · 2025Article
- Appropriate time interval to update ambiguous genetic diagnosis in inherited arrhythmogenic syndromes.iScience · 2025Article
- The Prenatal Diagnosis and Perinatal Management of Congenital Long QT Syndrome: A Comprehensive Literature Review and Recent Updates.Journal of cardiovascular development and disease · 2025Review
- Canadian College of Medical Geneticists: clinical practice advisory document - responsibility to recontact for reinterpretation of clinical genetic testing.Journal of medical genetics · 2024Article
- Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis.Biomedicines · 2024Article
- Article
- Prioritize Variant Reclassification in Pediatric Long QT Syndrome-Time to Revisit.Pediatric cardiology · 2024Article
- Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management.Kidney international reports · 2024Article
- D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.International journal of molecular sciences · 2024Review
- Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy.International journal of molecular sciences · 2024Article
- Variant reclassification and recontact research: A scoping review.Genetics in medicine open · 2024Article
- Diagnostic yield and clinical relevance of expanded germline genetic testing for nearly 7000 suspected HBOC patients.European journal of human genetics : EJHG · 2023Article
- Reevaluation of ambiguous genetic variants in sudden unexplained deaths of a young cohort.International journal of legal medicine · 2023Article
- Characterising the Genetic Landscape of Amyotrophic Lateral Sclerosis: A Catalogue and Assessment of Over 1,000 Published Genetic Variants.Journal of neuromuscular diseases · 2023Article
- Modular networks and genomic variation during progression from stable angina pectoris through ischemic cardiomyopathy to chronic heart failure.Molecular medicine (Cambridge, Mass.) · 2022Article
- Clinical impact of rare variants associated with inherited channelopathies: a 5-year update.Human genetics · 2022Article
- Alanyl-tRNA Synthetase 1 Gene Variants in Hereditary Neuropathy: Genotype and Phenotype Overview.Neurology. Genetics · 2022Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic testing is important to augment clinical diagnosis and inform management of inherited arrhythmias syndromes (IAS), but variants of uncertain significance (VUS) are common and remain a challenge in clinical practice. In 2015, American College of Medical Genetics (ACMG) published updated guidelines for interpretation of genetic results. Despite increasing understanding of human genomic variation, there are no guidelines for reinterpretation of prior genetic test results. Patients at a single tertiary children's hospital with genetic testing for an IAS that demonstrated a VUS were re-evaluated using 2015 ACMG guidelines, clinical information, and publically available databases. Search of the electronic medical record identified 116 patients with genetic testing results available, and 24/116 (21%) harbored a VUS for an IAS. 23 unique VUS were evaluated from 12 genes. Over half of the VUS (12/23 (52%)) were reclassified using 2015 criteria, and 8 (35%) changed to pathogenic and 4 (17%) to benign. Relative risk of reclassification of VUS to a pathogenic variant in a patient with confirmed clinical diagnosis was 4.1 (95% CI 1.23-15.4). Reclassification was not associated with initial testing year. These data demonstrate 52% of VUS in children with IAS are reclassified with application of 2015 ACMG guidelines. Strength of phenotyping is associated with eventual pathogenic classification of genetic variants and periodic re-evaluation of VUS identified on genetic testing for IAS is warranted.
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