Clinical Domain Working Groups
von Willebrand Disease Variant Curation Expert PanelMembership
von Willebrand Disease (VWD) is classified as a mucocutaneous bleeding disorder that is caused by the deficiency or dysfunction of plasma von Willebrand Factor (VWF). Pathogenic variants in the VWF gene cause VWD.” VWD has six subtypes:
Type 1: Manifests as mild-to-severe mucocutaneous and provoked bleeding
Type 2A: Manifests mild-to-severe mucocutaneous and provoked bleeding
Type 2B: Manifests as mild-to-severe mucocutaneous and provoked bleeding that may be accompanied by thrombocytopenia
Type 2M: Manifests as mild-to-severe mucocutaneous and provoked bleeding
Type 2N: Manifests as excessive bleeding, often mimics the bleeding seen in mild to moderate hemophilia A
Type 3: Manifests as mild-to-severe mucocutaneous, provoked, and musculoskeletal bleeding
The prevalence and inheritance pattern of VWD differs by subtype. Types 1 and 3 are the result of quantitative defects in VWF levels; they are commonly referred to as autosomal dominant and recessive respectively. This is likely due to incomplete penetrance of many of the pathogenic variants leading to quantitative defects; as parents of a child type with type 3 VWD can be, but are not always, diagnosed with type 1 VWD.
Type 2 VWD represents a further group of VWD types where there are qualitative defects in the VWF protein. These types are based on the VWF function that is disrupted. Type 2A, 2B, and 2M are typically inherited in an autosomal dominant pattern with high penetrance of VWF pathogenic variants; however, autosomal recessive inheritance has been reported infrequently in type 2A families. Type 2N VWD is inherited in an autosomal recessive fashion, although there is evidence 2N can be semi-dominant. There are relatively good genotype/phenotype correlations for this gene that can also be used to classify patients into the appropriate type.
The von Willebrand Disease Expert Panel will curate clinically relevant variants using the specified classification rules developed by the group. The VWD VCEP would also like to be able to associate VWF variants with specific VWD types in ClinVar. This will be an added service to the committee as genotyping is often used by clinicians to inform the type, which can alter clinical care and recurrence risks for family members.
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