The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification

Joana R Chora¹, Michael A Iacocca², Lukáš Tichý³, Hannah Wand⁴, C Lisa Kurtz⁵, Heather Zimmermann⁶, Annette Leon⁷, Maggie Williams⁸, Steve E Humphries⁹, Amanda J Hooper¹⁰, Mark Trinder¹¹, Liam R Brunham¹¹, Alexandre Costa Pereira¹², Cinthia E Jannes¹², Margaret Chen¹³, Jessica Chonis¹³, Jian Wang¹⁴, Serra Kim⁷, Tami Johnston⁶, Premysl Soucek¹⁵, Michal Kramarek¹⁵, Sarah E Leigh¹⁶, Alain Carrié¹⁷, Eric J Sijbrands¹⁸, Robert A Hegele¹⁴, Tomáš Freiberger¹⁵, Joshua W Knowles¹⁹, Mafalda Bourbon²⁰; ClinGen Familial Hypercholesterolemia Expert Panel

Affiliations

¹ Department of Health Promotion and Prevention of Noncommunicable Diseases, Nacional Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal; BioISI - BioSystems & Integrative Sciences Institute, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
² Departments of Biomedical Data Science and Pathology, School of Medicine, Stanford University, Stanford, CA; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto Ontario, Canada.
³ Centre of Molecular Biology and Gene Therapy, University Hospital Brno, Brno, Czech Republic.
⁴ Departments of Biomedical Data Science and Pathology, School of Medicine, Stanford University, Stanford, CA; Center for Inherited Cardiovascular Disease, Stanford Health Care, Stanford University, Stanford, CA.
⁵ Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁶ Ambry Genetics, Aliso Viejo, CA.
⁷ Color Health, Inc, Burlingame, CA.
⁸ Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom.
⁹ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.
¹⁰ Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, University of Western Australia, Perth, Western Australia, Australia.
¹¹ Department of Medicine, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹² Laboratory of Genetics and Molecular Cardiology, Institute of the Hearth (InCor), Faculty of Medicine, São Paulo University, São Paulo, Brazil.
¹³ GeneDx, Inc, Gaithersburg, MD.
¹⁴ Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁵ Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic; Faculty of Medicine, Masaryk University, Brno, Czech Republic.
¹⁶ Genomics England, London, United Kingdom.
¹⁷ University Hospitals Pitié-Salpêtrière/Charles-Foix, Molecular and Chromosomal Genetics Center, Obesity and Dyslipidemia Genetics Unit, Sorbonne University, Paris, France.
¹⁸ Academic Medical Center, Erasmus University, Rotterdam, Netherlands.
¹⁹ Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Prevention Research Center, and Diabetes Research Center, School of Medicine, Stanford University, Stanford, CA; FH Foundation, Pasadena, CA.
²⁰ Department of Health Promotion and Prevention of Noncommunicable Diseases, Nacional Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal; BioISI - BioSystems & Integrative Sciences Institute, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal. Electronic address: mafalda.bourbon@insa.min-saude.

PMID: 34906454
DOI: 10.1016/j.gim.2021.09.012

Free article

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification

Joana R Chora et al. Genet Med. 2022 Feb.

Free article

. 2022 Feb;24(2):293-306.

doi: 10.1016/j.gim.2021.09.012. Epub 2021 Nov 30.

Authors

Affiliations

¹ Department of Health Promotion and Prevention of Noncommunicable Diseases, Nacional Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal; BioISI - BioSystems & Integrative Sciences Institute, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
² Departments of Biomedical Data Science and Pathology, School of Medicine, Stanford University, Stanford, CA; Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto Ontario, Canada.
³ Centre of Molecular Biology and Gene Therapy, University Hospital Brno, Brno, Czech Republic.
⁴ Departments of Biomedical Data Science and Pathology, School of Medicine, Stanford University, Stanford, CA; Center for Inherited Cardiovascular Disease, Stanford Health Care, Stanford University, Stanford, CA.
⁵ Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁶ Ambry Genetics, Aliso Viejo, CA.
⁷ Color Health, Inc, Burlingame, CA.
⁸ Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, United Kingdom.
⁹ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.
¹⁰ Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, University of Western Australia, Perth, Western Australia, Australia.
¹¹ Department of Medicine, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
¹² Laboratory of Genetics and Molecular Cardiology, Institute of the Hearth (InCor), Faculty of Medicine, São Paulo University, São Paulo, Brazil.
¹³ GeneDx, Inc, Gaithersburg, MD.
¹⁴ Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
¹⁵ Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic; Faculty of Medicine, Masaryk University, Brno, Czech Republic.
¹⁶ Genomics England, London, United Kingdom.
¹⁷ University Hospitals Pitié-Salpêtrière/Charles-Foix, Molecular and Chromosomal Genetics Center, Obesity and Dyslipidemia Genetics Unit, Sorbonne University, Paris, France.
¹⁸ Academic Medical Center, Erasmus University, Rotterdam, Netherlands.
¹⁹ Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Prevention Research Center, and Diabetes Research Center, School of Medicine, Stanford University, Stanford, CA; FH Foundation, Pasadena, CA.
²⁰ Department of Health Promotion and Prevention of Noncommunicable Diseases, Nacional Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal; BioISI - BioSystems & Integrative Sciences Institute, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal. Electronic address: mafalda.bourbon@insa.min-saude.

PMID: 34906454
DOI: 10.1016/j.gim.2021.09.012

Abstract

Purpose: In 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.

Methods: The 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.

Results: The 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.

Conclusion: Establishment 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.

Keywords: ACMG/AMP; ClinGen; Familial hypercholesterolemia; LDLR; Variant classification.

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Conflict of interest statement

Conflict of Interest R.A.H. reports consulting fees from Acasti Pharma Inc, Aegerion Pharmaceuticals, Akcea/Ionis Pharmaceuticals, Amgen Inc, HLS Therapeutics Inc, Novartis AG, Pfizer Inc, Regeneron Pharmaceuticals Inc, and Sanofi. All other authors declare no conflicts of interest.

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The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification

Affiliations

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification

Authors

Affiliations

Abstract

Conflict of interest statement

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Miscellaneous