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

The online version of this article (https://doi.org/10.1016/j. gim.2021.09.012) contains supplementary material, which is available to authorized users. 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. Clinical Genome Resource (ClinGen) is primarily funded by the National Human Genome Research Institute through the following 3 grants: U41HG006834, U41HG009649, and U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the following 3 grants: U24HD093483, U24HD093486, and U24HD093487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.R.C. acknowledges her PhD fellowship funded by the Science and Technology Foundation (SFRH/BD/108503/2015). L.T. and T.F. are supported by the Ministry of Health of the Czech Republic (grant NU20-02-00261). S.E.H. is an Emeritus British Heart Foundation Professor and is funded by PG08/ 008 and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. M.T. is supported by a Vanier Canada Graduate Scholarship. L.R.B. is a Michael Smith Foundation for Health Research scholar and a Canada Research Chair in Precision Cardiovascular Disease Prevention. R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes of Health Research (Foundation Grant) and the Heart and Stroke Foundation of Ontario (G-18- 0022147). J.W.K. is supported by the National Institutes of Health through grants P30DK116074 (to the Stanford Diabetes Research Center), R01 DK116750, R01 DK120565, and R01 DK106236 and by the American Diabetes Association (grant #1-19-JDF-108). info:eu-repo/semantics/publishedVersion