rs61750630 — VWF C2362F

VWF C2362F — A Founder Mutation That Silences the Bleeding Brake

Von Willebrand factor is the molecular glue of hemostasis: a multimeric glycoprotein that captures platelets at the site of a vascular injury and shuttles factor VIII through the bloodstream. Without adequate VWF activity, even minor cuts fail to clot properly and surgical bleeding can become life-threatening. The rs61750630 variant — encoding the C2362F substitution¹¹ C2362F substitution
cysteine-to-phenylalanine change in the D4 domain of VWF — is a pathogenic missense change that disrupts protein folding in the endoplasmic reticulum, preventing most of the mutant protein from ever reaching the bloodstream. It was first identified as a founder mutation in northern Italian families with type 3 von Willebrand disease²² founder mutation in northern Italian families with type 3 von Willebrand disease
autosomal recessive severe VWD with near-absent VWF.

The Mechanism

VWF contains a series of cysteine-rich domains that form disulfide bonds critical for proper multimerization and secretion³³ disulfide bonds critical for proper multimerization and secretion
loss of a cysteine removes one bond from an intricate disulfide network. The Cys2362Phe substitution eliminates a cysteine in the D4 domain, disrupting the local disulfide architecture. The misfolded protein is retained in the endoplasmic reticulum rather than trafficked to the Golgi and secreted. Tjernberg et al. showed that cells expressing only VWF-C2362F secrete just 8% of normal VWF antigen levels⁴⁴ Tjernberg et al. showed that cells expressing only VWF-C2362F secrete just 8% of normal VWF antigen levels
compared to wild-type controls. Crucially, it is the loss of the cysteine itself — not the bulky phenylalanine side chain — that causes retention, since the same group showed the defect is structural rather than steric. When mutant and wild-type constructs are co-expressed (mimicking the heterozygous state), secretion reaches approximately 50% of normal, consistent with the mildly reduced VWF levels observed in carriers.

A further complication emerges upon desmopressin (DDAVP) stimulation: although homozygous patients do release some VWF in response to DDAVP, the mutant protein has a 2-fold shortened plasma half-life⁵⁵ 2-fold shortened plasma half-life
suggesting impaired interactions with ADAMTS13 or stabilizing proteins, making DDAVP a poor treatment option for severely affected patients.

The Evidence

Eikenboom et al. characterised eight northern Italian families with recessive VWD⁶⁶ Eikenboom et al. characterised eight northern Italian families with recessive VWD
identifying mutations in 14 of 16 disease-associated VWF alleles. The C2362F substitution appeared in every type 3 VWD patient from a subgroup previously noted for an unusually strong factor VIII response to desmopressin — a clinical phenotype that correlates with the founder haplotype. Haplotype analysis supported a single ancestral origin, making this one of the clearest examples of a VWF founder effect in a defined European population.

The inheritance picture is more nuanced than purely recessive. Bowman et al. studied 34 Canadian families with 31 distinct VWD type 3 mutations⁷⁷ Bowman et al. studied 34 Canadian families with 31 distinct VWD type 3 mutations
including C2362F carriers and found that in approximately half of families, heterozygous parents had bleeding symptoms and reduced VWF levels sufficient to diagnose type 1 VWD — evidence of co-dominant inheritance rather than a purely silent carrier state⁸⁸ co-dominant inheritance rather than a purely silent carrier state
48% of obligate carriers received a clinical VWD diagnosis. This means the risk_allele does not recede invisibly in the heterozygous state.

Given the global allele frequency of approximately 3.4 per million chromosomes in Europeans (gnomAD v4, n = 1,400,916 exomes), the C2362F variant is extremely rare outside of the northern Italian founder population. Homozygosity is essentially unique to that ancestry.

Practical Actions

For heterozygous carriers, the key step is a formal bleeding assessment: measure VWF antigen, VWF activity (ristocetin cofactor), and factor VIII. Levels around 50% of normal are typical; values below 30 IU/dL meet the diagnostic threshold for type 1 VWD and should trigger referral to a haematologist. Carriers should disclose their genetic status before any surgical procedure, dental extraction, or childbirth so a proactive haemostasis plan can be put in place.

For the rare homozygous individual, management follows type 3 VWD guidelines: plasma-derived or recombinant VWF concentrate (Vonvendi, Wilate, Humate-P) is the mainstay of treatment. DDAVP is not effective in type 3 VWD — VWF stores are severely depleted and the small amount released is cleared too rapidly to provide sustained haemostasis. All family members should be offered VWF screening.

Interactions

Carriers of two VWF null alleles (different mutations in trans, i.e. compound heterozygotes) present identically to homozygotes clinically. ABO blood group independently modulates VWF antigen levels — blood group O reduces VWF by approximately 25%, which can compound the haemostatic deficit in carriers who also have blood group O. Concurrent thrombocytopenia or platelet function defects (e.g. variants in GP1BA encoding the VWF receptor, or TBXA2R affecting platelet activation) can further worsen bleeding in VWF-deficient individuals.