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VWF is definitively associated with Type 2M von Willebrand disease, an autosomal dominant bleeding disorder characterized by qualitative defects in platelet-dependent function without loss of high-molecular-weight multimers. Over 100 unrelated probands have been reported across multiple cohorts, with segregation in at least 16 affected relatives ([PMID:17596142]) and concordant in vitro functional data confirming impaired ristocetin-induced binding and preserved multimer distribution. The consistency of genetic and experimental findings over >20 years supports a Definitive ClinGen classification.
Genetic evidence for VWF in Type 2M VWD includes autosomal dominant inheritance, segregation in families, and case series totaling >100 patients. A Canadian cohort study sequenced 16 index cases and 16 additional affected relatives, identifying eight missense mutations within the A1 domain (e.g., c.3943C>T (p.Arg1315Cys)) ([PMID:17596142]). Two unrelated families from the UK and Algeria carried an in-frame deletion of Lys1408 (del K1408, c.4213AAG[3]) in the A1 loop ([PMID:10959688]), and French kindreds harbored recurrent Gly1324 substitutions (G1324A/S) in 4 members ([PMID:12008946]). A cohort of 61 patients in 15 families further confirmed recurrent p.Arg1374His and other A1 domain variants ([PMID:22329792]).
The variant spectrum is dominated by missense changes in the VWF A1 domain, with occasional in-frame deletions (p.Lys1408del), frameshift (p.Pro1648fs*45), and nonsense alleles (p.Gln2470Ter) observed in compound heterozygosity. No deep-intronic or splice variants have been reported for Type 2M VWD. Recurrent variants such as p.Arg1315Cys and p.Arg1374His suggest mutational hotspots in the GPIb binding region.
Phenotypically, patients exhibit a VWF ristocetin cofactor activity/VWF antigen ratio <0.6 with normal multimeric profiles and variable mucocutaneous bleeding. Bleeding scores correlate poorly with VWF levels but may track with specific A1 domain defects. Prevalence in specialized cohorts ranges from 1–2% of VWD referrals, with a founder effect for certain variants in European and North African populations.
Functional studies using recombinant VWF expressed in COS-7 or HEK293T cells demonstrate that Type 2M variants selectively impair GPIb binding in response to ristocetin while preserving botrocetin-induced binding and multimer assembly ([PMID:12588351]; [PMID:23496210]). Mechanistically, missense substitutions disrupt the A1 loop conformation required for normal platelet adhesion, consistent with a loss-of-function dominant effect. Cell-based shear assays confirm normal hemostatic function under physiological flow, underscoring assay-dependent phenotyping.
One variant, p.Pro1467Ser, was associated with low VWF:RCo without bleeding and functional assays showed normal shear-mediated binding, indicating a benign polymorphism and highlighting the need for comprehensive functional evaluation ([PMID:19694940]). Integration of genetic and experimental data establishes VWF A1 domain missense mutations as the cause of Type 2M VWD. Genetic testing of VWF in patients with disproportionate VWF activity deficits and normal multimers enables accurate diagnosis and informs therapy.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongMultiple heterozygous A1 domain missense mutations in >100 patients; AD inheritance; 16 segregations ([PMID:17596142]) Functional EvidenceModerateRecombinant expression of >20 variants demonstrated impaired ristocetin-induced GPIb binding with preserved multimers |