OC 63.3 - Specifications of ACMG/AMP Variant Curation Guidelines for VWF variants in type 2 von Willebrand disease: Recommendations by ClinGen’s von Willebrand Disease Variant Curation Expert Panel

Tuesday, June 25, 2024

15:15 – 15:30 ICT

Room: Ballroom B3

Presenting Author(s)

Justyne Ross, PhD

Research Associate
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Durham, North Carolina, United States

Co-Author(s)

WH

William Hankey

Research Associate
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
Kristy Lee

Research Professor
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
NB

Nina Borràs

PhD
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain
Pamela Christopherson

Senior Research Coordinator
Blood Research Institute, Versiti BloodCenter of Wisconsin, Milwaukee, WI, US.
Milwaukee, Wisconsin, United States
IC

Irene Corrales

Main researcher, PhD
Laboratori de Coagulopaties Congènites, Banc de Sang i Teixits, Barcelona, Spain
Barcelona, Catalonia, Spain
KD

Karl Desch

Associate Professor
Department of Pediatrics, University of Michigan, Ann Arbor, MI, US.
Ann Arbor, Michigan, United States
SD

Stefanie Dugan

Manager, Hematology Genetics
Diagnostic Laboratories, Versiti BloodCenter of Wisconsin, Milwaukee, WI, US.
Milwaukee, Wisconsin, United States
Jeroen Eikenboom

MD, PhD, prof
Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
KF

Kenneth Friedman

Senior Medical Director, Hematology, Investigator
Blood Research Institute, Versiti BloodCenter of Wisconsin, Milwaukee, WI, US.
Milwaukee, Wisconsin, United States
BC

Blair Compton

Graduate Research Assistant
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
MF

Margaret Fergusson

Coordinator
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
AF

Annabelle Frantz

Coordinator
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
IF

Isabella Futchi

Coordinator
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
MS

Mitchell Springer

Clinical Variant Scientist
Diagnostic Laboratories, Versiti BloodCenter of Wisconsin, Milwaukee, WI, US.
Milwaukee, Wisconsin, United States
LW

Lindsay Worley

Research Assitant
Department of Genetics, University of North Carolina, Chapel Hill, NC, US.
Chapel Hill, North Carolina, United States
DH

Daniel Hampshire

Lecturer in Genetics
Biomedical Institute for Multimorbidity, Centre for Biomedicine, Hull York Medical School, Hull, UK.
Hull, England, United Kingdom
Jill Johnsen, MD

Associate Professor
Department of Medicine, University of Washington, Seattle, WA, US; Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA US
Seattle, Washington, United States
David Lillicrap, MD

Professor Department of Pathology and Molecular Medicine
Molecular Hemostasis Research Group, Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
Kingston, Ontario, Canada

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder but variant interpretations remain challenging due, in part, to multiple VWD types with complex, partially overlapping clinical and laboratory phenotypes. Variants in the von Willebrand Factor (VWF) gene are responsible for six types of VWD, four predominately inherited in an autosomal dominant manner and two recessive. Additionally, some types are caused by specific variants in particular VWF functional domains but others are attributable to variants throughout the gene. These complex mechanisms of disease present substantial challenges.

Aims: To this end, the ClinGen VWD Variant Curation Expert Panel has undertaken the following aims: (1) To increase the accuracy and consistency of VWF variant classification by developing VWD-based specifications to the ACMG/AMP Sequence Variant Interpretation Guidelines (2) To provide FDA-recognized, ClinVar 3-star interpretations of VWF variants.

Methods: Disease-/gene-informed specifications of the guidelines for type 2 VWD included optimization of population frequency cutoffs, identification of regions critical to protein function and appropriate functional assays, as well as recommendations for the use of computational/predictive data and clinical evidence. Guidelines for benign criteria encompass all types of VWD, while pathogenic criteria are specified for type 2, or explicitly subtype 2A, 2B, 2M, and 2N when possible. The specified guidelines were validated with 50 variants, composed of 20 reputed pathogenic variants (5 of each subtype), 15 of unknown significance, and 15 benign.

Results: Through the integration of published data with that of participating diagnostic and research laboratories, there was 80% clinical concordance with previous classifications and fewer variants of uncertain significance. Five variants with conflicting ClinVar interpretations were resolved to likely pathogenic or likely benign categories.

Conclusion(s): These guidelines enable both publication of 3-star ClinVar classifications from the expert panel and independent use by investigators, clinicians, and clinical laboratories, which will ultimately enhance clinical decision-making to improve patient outcomes.