rs267607352 — VWF W1745C

VWF W1745C — The Bleeding Disorder a Normal Blood Test Won't Find

Von Willebrand factor (VWF) is a molecular intermediary between damaged vessel walls and circulating platelets. When an endothelial surface tears, collagen fibres in the extracellular matrix are exposed. VWF must grip that collagen through its A3 domain¹¹ A3 domain
The A3 domain occupies residues 1686-1874 of mature VWF; it folds into a classical von Willebrand A barrel structure that positions a surface groove to engage fibrillar collagen types I and III before platelets can be recruited to seal the wound. The W1745C variant — a tryptophan-to-cysteine substitution at position 1745 — sits within this collagen-binding groove and dismantles exactly that one function without visibly disturbing anything else.

The consequence is a bleeding disorder that routine haematology labs routinely miss. VWF antigen levels are normal. The most widely used functional test — the ristocetin cofactor assay (VWF:RCo), which measures platelet-binding — is normal. Multimers are normal. Only a dedicated VWF collagen-binding assay (VWF:CB)²² VWF collagen-binding assay (VWF:CB)
Measures how well VWF adheres to immobilised type I or III collagen; the single most sensitive assay for detecting isolated A3-domain defects reveals the defect. This condition is classified as von Willebrand disease type 2M³³ von Willebrand disease type 2M
The "M" stands for multimer-independent — the bleeding defect does not arise from loss of high-molecular-weight multimers but from a qualitative functional impairment of platelet adhesion, also designated type 2CB (collagen-binding subtype). Carriers can bleed significantly from dental extractions, surgery, and childbirth while appearing fully normal on pre-operative screening panels.

The Mechanism

The VWF A3 domain adopts a von Willebrand A fold⁴⁴ von Willebrand A fold
A barrel-like beta-sheet common to VWF domains, integrins, and complement proteins; the convex face presents the collagen-binding groove with critical hydrophobic and polar contacts that presents a curved surface groove for collagen engagement. Tryptophan 1745 provides a bulky aromatic side chain that makes hydrophobic and geometric contacts within the collagen-binding interface. Substituting cysteine — a much smaller, flexible, sulphydryl- bearing residue — eliminates those contacts and likely introduces a free thiol that could form aberrant disulphide bonds, destabilising the local groove architecture without disrupting the overall protein fold, multimerisation, or Factor VIII binding capacity.

Recombinant W1745C VWF expressed in HEK293T cells by Riddell et al. showed a pronounced collagen-binding defect to both type I and type III collagen⁵⁵ Riddell et al. showed a pronounced collagen-binding defect to both type I and type III collagen
Riddell AF et al., Blood 2009; mutations were reproduced by site-directed mutagenesis and characterised in vitro; VWF:CB was severely reduced while multimer analysis was indistinguishable from wild-type, while VWF multimer patterns were indistinguishable from wild-type. Among the three A3-domain mutations characterised in that study, W1745C and S1783A both caused pronounced binding defects to both collagen types, whereas S1731T primarily affected type I collagen — demonstrating that distinct residues in the A3 groove mediate binding to the two collagen subtypes.

The Evidence

The primary characterisation is Riddell et al., Blood 2009⁶⁶ Riddell et al., Blood 2009
Riddell AF, Gomez K, Millar CM, Mellars G, Gill S, Brown SA, Sutherland M, Laffan MA, McKinnon TAJ. Blood. 2009 Oct 15;114(16):3489-96 — three families investigated; W1745C identified in one individual in compound heterozygosity with R760H; site-directed mutagenesis confirmed A3-domain collagen-binding loss with normal multimers. The individual carrying W1745C had compound heterozygosity (W1745C on one allele, R760H on the other) and showed a VWF:CB/VWF:Ag ratio of 0.3 — severely reduced, consistent with a dominant collagen-binding defect — alongside a normal multimer pattern and normal VWF:RCo. The authors proposed that isolated collagen-binding defects should be classified as a distinct VWD subtype, laying the clinical-diagnostic framework that would eventually produce the type 2M/2CB designation.

ClinVar variation 100421⁷⁷ ClinVar variation 100421
ClinGen Von Willebrand Disease Variant Curation Expert Panel classification; last evaluated August 13, 2024; four-star review status; criteria PS3, PP4, PM2_Supporting, PP3 applied classifies W1745C as Likely Pathogenic for VWD type 2M following expert panel review in August 2024. The evidence supporting classification includes the in vitro collagen-binding data, the clinical observation of decreased VWF:CB/VWF:Ag ratio in the index patient, and supporting computational evidence (PP3). The variant is entirely absent from gnomAD population databases (one allele observed in 805,812 in gnomAD exomes — effectively zero population frequency), consistent with strong negative selection.

The importance of including VWF:CB in the diagnostic workup for any bleeding history is established by Favaloro and Mohammed, 2014⁸⁸ Favaloro and Mohammed, 2014
Favaloro EJ, Mohammed S. Thromb Res 135(6):1307-16, 2014 — comparative evaluation of VWF assay platforms; VWF:CB was most discrepant from VWF:RCo precisely in type 2M/2CB patients, confirming its essential role in detecting A3-domain collagen-binding defects. Without a specific collagen-binding assay, this mutation class is systematically undetectable by standard VWD laboratory panels.

Practical Actions

For any carrier, the immediate priority is to make a concealed diagnosis visible: the VWF:CB assay must be explicitly requested. Once the defect is documented, the key clinical decision involves haemostatic coverage for procedures. DDAVP (desmopressin) — the first-line agent for type 1 and many type 2 VWD variants — releases endogenous VWF stores from endothelial Weibel-Palade bodies, but the released VWF carries the W1745C mutation and is expected to bind collagen poorly. VWF concentrate (Humate-P, Wilate, or recombinant VWF such as Vonvendi) provides functionally normal collagen-binding VWF and is the appropriate haemostatic cover when a carrier needs a procedure.

Interactions

W1745C was co-identified alongside S1783A at rs267607353⁹⁹ S1783A at rs267607353
The companion A3-domain variant from the same 2009 characterisation study; also causes pronounced binding defect to both type I and III collagen; OMIM 613160.0042 — another A3-domain variant in the same collagen-binding groove. Compound heterozygosity of two A3-domain defects (e.g. W1745C on one allele and S1783A or another A3 variant on the other) would be expected to produce near-complete loss of collagen-binding activity and a more severe bleeding phenotype, though no published case of such a combination has been described. The index patient carrying W1745C was compound heterozygous with R760H, a type 1 VWD variant in the D3 domain — this combination reduced VWF:CB/VWF:Ag to 0.3 — suggesting that heterozygous W1745C alone may not fully account for all bleeding symptom severity when other VWF variants are co-inherited. ABO blood group (O type lowers VWF levels ~25%) is the standard VWF modifier, but ABO effects operate through VWF clearance rate, not collagen binding, so the ABO interaction is less clinically relevant for this qualitative A3-domain defect than it is for quantitative VWD variants.