rs61754002 — VWF Y357X

Von Willebrand Factor Y357X — A Null Allele That Silences Clotting Scaffolding

Von Willebrand factor (VWF) is a large multimeric glycoprotein that performs two essential roles in hemostasis: it anchors platelets to sites of vascular injury, and it acts as a carrier protein that protects coagulation factor VIII (FVIII) from premature degradation in the bloodstream. When a vessel is damaged, VWF unfolds under shear stress, recruits platelets, and delivers FVIII to the clot site for amplification of the coagulation cascade. VWF is synthesized in endothelial cells and megakaryocytes, stored in Weibel-Palade bodies, and released on demand¹¹ VWF is synthesized in endothelial cells and megakaryocytes, stored in Weibel-Palade bodies, and released on demand
VWF biology overview. The rs61754002 variant creates a premature stop codon that eliminates VWF protein from the affected allele entirely — a so-called null allele with no residual function.

The Mechanism

The VWF gene spans chromosome 12p13.31 on the minus strand, encoding a 2813-amino-acid preproprotein across 52 exons. The rs61754002 variant (c.1071C>A on the coding strand; G>T on the genomic plus strand at position 6,072,369 in GRCh38) lies in exon 9, converting codon 357 from tyrosine (TAC) to a stop codon (TAA) — p.Tyr357Ter, also written Y357X. This is a nonsense mutation²² nonsense mutation
a single nucleotide change that creates a premature stop codon, terminating translation early. The truncated transcript is degraded by nonsense-mediated mRNA decay, producing no detectable VWF protein from the affected allele. In heterozygous carriers, VWF plasma levels are driven entirely by the one functional allele; in homozygous or compound heterozygous individuals, VWF is absent or severely reduced.

The Evidence

The original documentation of this variant comes from a French family study that identified a 20-year-old woman with severe VWD initially misclassified as haemophilia A because her two male first cousins had factor VIII gene mutations³³ two male first cousins had factor VIII gene mutations
a separate F8 gene mutation in the same family created diagnostic confusion. She was found to carry compound heterozygosity: one allele with Y357X (creating no VWF protein) and a second allele with C1060R (a missense mutation in the D3 domain that eliminates FVIII binding). The combined effect was very low VWF antigen, undetectable VWF:FVIII binding, and severely reduced FVIII activity — a phenotype resembling haemophilia A but arising from VWF dysfunction, classified as VWD type 2N.

Hilbert et al. (2003)⁴⁴ Hilbert et al. (2003)
Hilbert L et al. Two novel mutations, Q1053H and C1060R, located in the D3 domain of VWF. Br J Haematol. 2003 further characterized the C1060R allele in seven French families with type 2N disease, establishing that D3 domain mutations dramatically reduce VWF:FVIII binding even when located outside the classically defined FVIII-binding tryptic fragment.

Heterozygous carriers of VWF null alleles display a wide range of phenotypes. Pérez-Rodríguez et al. (2006)⁵⁵ Pérez-Rodríguez et al. (2006)
Pérez-Rodríguez A et al. Characterization of recessive severe type 1 and type 3 VWD vs asymptomatic heterozygous carriers. J Thromb Haemost. 2006 found that among obligate carriers of type 3 VWD null alleles, 48% were diagnosed with type 1 VWD and had clinically meaningful bleeding, while the remainder were asymptomatic despite carrying 50% of normal VWF levels. This incomplete penetrance is why carrier testing and standardized bleeding assessment are recommended for any first-degree relative of a type 3 VWD patient.

Practical Actions

For carriers of a single Y357X allele: VWF antigen levels are typically 40–60% of normal, placing many individuals in the "low VWF" or type 1 VWD range. A standardized bleeding assessment — using the ISTH Bleeding Assessment Tool⁶⁶ ISTH Bleeding Assessment Tool
the ISTH-BAT questionnaire scores bleeding history from 12 sites; a score ≥3 in women or ≥2 in men is abnormal — quantifies symptom burden and guides decisions about prophylaxis or treatment around procedures. Desmopressin (DDAVP) can transiently double or triple VWF levels by releasing stored VWF from endothelial Weibel-Palade bodies; response testing should be performed under specialist supervision, as some null-allele carriers respond adequately.

For compound heterozygous or homozygous individuals: VWF replacement using plasma-derived VWF/FVIII concentrates (Alphanate, Humate-P, Wilate) or recombinant VWF (Vonvendi) is the cornerstone of management. Desmopressin is ineffective when both alleles are null. Hematology co-management is required for surgical procedures, trauma, and pregnancy.

Interactions

The Y357X null allele can combine with any second pathogenic VWF variant to produce compound heterozygous disease. When the second allele carries a FVIII-binding domain mutation (such as rs61748497, encoding C1060R — a D3 domain missense that abolishes FVIII binding), the phenotype resembles haemophilia A, and patients are at risk for misdiagnosis. Full VWF gene sequencing should be offered to anyone with confirmed low VWF levels, to identify both alleles and classify the disease subtype accurately.

Blood group O independently lowers VWF antigen levels by 15–25% compared to non-O groups. Carriers of Y357X who also have blood group O may have VWF levels that fall below the type 1 VWD diagnostic threshold (30 IU/dL) even on the heterozygous null-allele background alone.