rs61754010 — VWF N528S

Pathogenic missense variant in the VWF propeptide D2 domain that introduces an aberrant N-glycosylation site, disrupting VWF multimerization and Weibel-Palade body storage

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VWF N528S — When the Protein Cannot Pack Itself Away

Von Willebrand factor (VWF) is the first responder at a vascular injury — a multimeric protein that bridges damaged endothelium to platelets and chauffeurs factor VIII through the bloodstream. Its effectiveness depends critically on two things: being built into large multimers, and being stored in Weibel-Palade bodies11 Weibel-Palade bodies
endothelial storage organelles that release VWF on demand when a blood vessel is damaged. The rs61754010 variant — encoding the N528S substitution in the VWF propeptide22 N528S substitution in the VWF propeptide
asparagine-to-serine change at position 528 in the D2 domain — disrupts both processes, producing a qualitative deficiency classified as von Willebrand disease type 2A33 von Willebrand disease type 2A
a subtype characterised by loss of large and intermediate VWF multimers with reduced platelet-dependent function.

The Mechanism

The VWF propeptide (domains D1-D2) acts as a chaperone: it guides the nascent VWF chain through multimerization in the Golgi and escorts the assembled multimers into Weibel-Palade bodies. Position 528 sits in the D2 domain close to a CGLC disulfide-isomerase consensus sequence44 CGLC disulfide-isomerase consensus sequence
a short protein motif that orchestrates disulfide bond formation during VWF assembly. The N528S substitution introduces an additional N-glycosylation site (at Asn-526, two residues upstream) by creating the consensus sequence Asn-X-Ser. The extra sugar chain attached at this site physically interferes with the propeptide-VWF interaction needed for normal multimerization and for targeting the assembled protein to storage granules.

Haberichter et al. demonstrated in expression studies55 Haberichter et al. demonstrated in expression studies
using heterologous cell lines expressing wild-type and N528S VWF constructs that the mutant VWF is neither properly multimerized nor trafficked to storage granules. The propeptide itself folds and traffics normally — only the mature VWF chain is misdirected. The result, as seen in the Turkish family where this mutation was first characterised, is VWD phenotype IIC: absent triplet structure in plasma multimers, complete absence of platelet VWF multimers beyond protomers, and a near-zero response to desmopressin.

The Evidence

The N528S mutation was identified in a consanguineous Turkish family with several affected homozygous members66 consanguineous Turkish family with several affected homozygous members
three documented homozygous patients with significant mucocutaneous and joint bleeding. ClinVar classifies it as Pathogenic for VWD type 2A with four-star expert panel review status (ClinGen VWD Variant Curation Expert Panel, last reviewed August 2024), making it one of the highest-confidence VWF pathogenic classifications in the database.

For type 2A VWD broadly, the evidence on management is well established. Federici & Mannucci reviewed VWD management across subtypes77 Federici & Mannucci reviewed VWD management across subtypes
including outcomes data for desmopressin and VWF concentrate use by subtype, establishing that desmopressin has variable and often insufficient efficacy in type 2A and that plasma-derived VWF concentrates are the mainstay of treatment for significant bleeding. A 100-patient Italian cohort study of plasma VWF/FVIII concentrate88 100-patient Italian cohort study of plasma VWF/FVIII concentrate
across all VWD types including type 2A showed excellent or good haemostatic responses in 95% of spontaneous bleeding episodes and 97% of surgical procedures, with no serious adverse events across 370 treatments.

Practical Actions

For homozygous individuals (an extremely rare scenario given the near-zero population frequency of the C allele), management is as for severe type 2A: VWF concentrate infusion for all bleeding episodes and pre-procedural cover, with desmopressin contraindicated given the absent Weibel-Palade body stores.

Interactions

ABO blood group is a significant modifier of VWF levels in all carriers of VWF variants. Blood group O independently reduces VWF antigen by approximately 25% through enhanced ADAMTS13- mediated clearance, which can compound the qualitative deficit in type 2A and push measurable VWF:RCo activity to levels requiring treatment. Co-inheritance of other VWF variants (compound heterozygosity with a second pathogenic allele on the opposite chromosome) can produce a more severe phenotype than either allele alone. Thrombocytopenia from any cause — including liver disease or immune platelet destruction — further worsens bleeding in VWF- deficient individuals because VWF-platelet co-function is already impaired.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-carrier Normal

No VWF N528S variant detected — von Willebrand factor function unaffected by this variant

You carry two copies of the common T allele at rs61754010, meaning you do not carry the VWF N528S pathogenic variant. This variant is extremely rare globally — the C allele appears in approximately 1 per 60,000 alleles in ExAC data and is absent in large gnomAD cohorts — so the vast majority of people carry two T alleles. Your von Willebrand factor function is not affected by this specific variant. If you or family members have a personal or family history of abnormal mucosal bleeding, other VWF variants or platelet disorders should be evaluated separately by a haematologist.

CT Carrier — Type 2A VWD Carrier

One copy of the pathogenic N528S variant — heterozygous type 2A von Willebrand disease

The N528S propeptide mutation is mechanistically distinct from most type 2A mutations, which lie in the A2 domain (exon 28) and typically affect ADAMTS13-mediated cleavage. N528S disrupts multimerization upstream at the storage stage, preventing proper assembly before the protein even reaches the plasma. This storage-stage mechanism is why desmopressin — which triggers exocytosis of Weibel-Palade bodies — fails to produce adequate VWF release: the granules lack properly multimerized VWF to release.

CC Homozygous — Severe Type 2A VWD Homozygous

Two copies of the pathogenic N528S variant — severe type 2A von Willebrand disease with absent desmopressin response

In the family characterised by Haberichter et al. (PMID 20335223), homozygous N528S individuals showed absent VWF triplet structure on plasma multimer gel, complete absence of platelet VWF multimers beyond protomers (platelet VWF:Ag markedly reduced), and a near-absent response to desmopressin acetate. The propeptide itself was normal — only the mature VWF chain failed to multimerize and enter storage granules. This demonstrated a novel pathogenic mechanism: defective propeptide-VWF interaction post-translationally, upstream of the granule packaging step.

Clinically, homozygous type 2A differs from type 3 in that VWF antigen levels may not be as severely reduced (type 3 can have <1 IU/dL), but functional activity (VWF:RCo) is profoundly impaired because the present VWF is non-functional protomers. Factor VIII levels are variably affected depending on whether the non-functional VWF can still bind and stabilise FVIII in plasma — in some type 2A variants this capacity is partially preserved even when platelet-binding function is lost. Bleeding manifestations include heavy mucosal bleeding, prolonged bleeding from minor wounds, and potentially joint bleeds if FVIII stabilisation is also impaired.