The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification |
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| Authors: | Joana R. Chora Michael A. Iacocca Lukáš Tichý Hannah Wand C. Lisa Kurtz Heather Zimmermann Annette Leon Maggie Williams Steve E. Humphries Amanda J. Hooper Mark Trinder Liam R. Brunham Alexandre Costa Pereira Cinthia E. Jannes Margaret Chen Jessica Chonis Jian Wang Serra Kim Mafalda Bourbon |
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| Affiliation: | 1. Department of Health Promotion and Prevention of Noncommunicable Diseases, Nacional Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal;2. BioISI - BioSystems & Integrative Sciences Institute, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal;3. Departments of Biomedical Data Science and Pathology, School of Medicine, Stanford University, Stanford, CA;4. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto Ontario, Canada;5. Centre of Molecular Biology and Gene Therapy, University Hospital Brno, Brno, Czech Republic;6. Center for Inherited Cardiovascular Disease, Stanford Health Care, Stanford University, Stanford, CA;7. Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;8. Ambry Genetics, Aliso Viejo, CA;9. Color Health, Inc, Burlingame, CA;10. Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom;11. Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom;12. Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, University of Western Australia, Perth, Western Australia, Australia;13. Department of Medicine, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada;14. Laboratory of Genetics and Molecular Cardiology, Institute of the Hearth (InCor), Faculty of Medicine, São Paulo University, São Paulo, Brazil;15. GeneDx, Inc, Gaithersburg, MD;16. Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada;17. Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic;18. Faculty of Medicine, Masaryk University, Brno, Czech Republic;19. Genomics England, London, United Kingdom;20. University Hospitals Pitié-Salpêtrière/Charles-Foix, Molecular and Chromosomal Genetics Center, Obesity and Dyslipidemia Genetics Unit, Sorbonne University, Paris, France;21. Academic Medical Center, Erasmus University, Rotterdam, Netherlands;22. Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Prevention Research Center, and Diabetes Research Center, School of Medicine, Stanford University, Stanford, CA;23. FH Foundation, Pasadena, CA |
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| Abstract: | PurposeIn 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.MethodsThe multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.ResultsThe consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.ConclusionEstablishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH. |
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| Keywords: | ACMG/AMP ClinGen Familial hypercholesterolemia Variant classification |
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