Study: Functional study

Model: HEK293 cell lines

Variant: VWF NM_000552.5: c.7664C>G, p.(Pro2555Arg), described as GOF mutation

rare missense variant, MAF = 0.00007

RefSNP_ID:rs915754316

Not reported in ClinVar

Cells lines were transfected and expressed one of the following: wtVWF, p.Pro2555Arg, both variants, or a negative control variant p.Asp2509Glu

Main result:

p.Pro2555Arg is the first VWF GOF variant that increases platelet aggregate size (AS), which is shear-dependent and independent of fibrinogen (fb). May provide a novel risk factor for thromboembolic disease.

Additional results:

Variant does not affect the binding affinity of the C4 domain for BPIIb/IIIa

VWF stem region mutations can enhance VWF's prothrombotic properties

C4 domain of VWF may be a novel antithrombotic drug target.