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Optimizing Variant Curation Guidelines to Improve Clinical Genetic Testing and Diagnosis of von Willebrand Disease

1University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States, 2Versiti Blood Research Institute, Milwaukee, Wisconsin, United States, 3Banc de Sang i Teixits; Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Catalonia, Spain, 4University of Michigan, Ann Arbor, Michigan, United States, 5Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands., Leiden, Zuid-Holland, Netherlands, 6Versiti / Blood Center of Wisconsin, Milwaukee, Wisconsin, United States, 7University of Hull, Hull, England, United Kingdom, 8University of Washington; Bloodworks Northwest, Seattle, Washington, United States, 9Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada

Abstract Number: PB1081

Meeting: ISTH 2022 Congress

Theme: Diagnostics and OMICs » Laboratory Diagnostics

Background: Genetic testing can be pivotal to accurately diagnosing von Willebrand disease (VWD) to develop appropriate clinical management recommendations. Limiting the number of variants of uncertain significance (VUS) and increasing the number of rigorously curated variants in public databases is vitally important to ensure that all patients receive optimal care.

Aims: The American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) developed a framework to assess variant pathogenicity; however, the guidelines were broadly written. The Clinical Genome Resource (ClinGen), funded by the National Human Genome Research Institute, convened the von Willebrand Disease Variant Curation Expert Panel (VWD VCEP) in June 2019 to develop rule specifications for curating variants in the VWF gene through the ClinGen FDA-approved process.

Methods: The VWD VCEP members meet monthly to specify ACMG-AMP rules for the VWF gene and discuss resulting variant assertions. Current work is focused on type 2 VWD (types 2A, 2B, 2M and 2N), and rules for types 1 and 3 will follow the completion of these rules. Each rule was assessed for appropriateness for the VWF gene and whether adding detailed criteria for its use and/or modifying its strength based on availability of evidence would be of benefit.

Results: Variant curation specifications were applied to 20 ACMG-AMP rule criteria and 8 rules were deemed not applicable to the VWF gene. Criteria modifications included setting allele frequencies in control populations, defining phenotype criteria and conditions for adjusting rule strength. Fifteen VWF variants were chosen for a pilot study to test the rule specifications, comprising of 6 pathogenic/likely pathogenic, 6 VUS and 3 benign/likely benign variants.

Conclusion(s): Results of this effort will aid clinical variant interpretation of the VWF gene and help standardize variant curations across clinical laboratories. Expert level variant curation from this VCEP will be deposited in the ClinVar database for public access.

To cite this abstract in AMA style:

Lee K, Ross J, Christopherson P, Corrales I, Desch K, Eikenboom J, Friedman K, Futchi I, Hankey W, Springer M, Hampshire D, Johnsen J, Lillicrap D. Optimizing Variant Curation Guidelines to Improve Clinical Genetic Testing and Diagnosis of von Willebrand Disease [abstract]. https://abstracts.isth.org/abstract/optimizing-variant-curation-guidelines-to-improve-clinical-genetic-testing-and-diagnosis-of-von-willebrand-disease/. Accessed August 16, 2022.

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