rs267607353 — VWF S1783A

VWF S1783A — The Bleeding Risk Hidden in a Normal Blood Test

Von Willebrand factor (VWF) performs two simultaneous jobs inside a damaged blood vessel: it rolls out like a molecular carpet to which platelets can stick, and it ferries coagulation Factor VIII¹¹ coagulation Factor VIII
Factor VIII is the plasma protein deficient in haemophilia A; VWF acts as its stabilizing carrier, protecting it from premature destruction in the bloodstream to the site of injury. Both jobs require VWF's three functional domains — A1 (platelet GpIb binding), A3 (collagen binding), and D (Factor VIII binding) — to work in concert. The rs267607353 variant swaps serine for alanine at residue 1783 of the A3 domain, dismantling just one of these functions: the ability to grip collagen in the vessel wall.

The result is a bleeding disorder that standard coagulation panels routinely miss. Multimers look normal. VWF antigen is normal. The ristocetin cofactor assay (VWF:RCo, which tests platelet-binding) is normal. Only a dedicated collagen-binding assay (VWF:CB) reveals the defect — and most haematology labs do not run it unless specifically requested. This is von Willebrand disease type 2M²² von Willebrand disease type 2M
The "M" stands for "multimer-independent," meaning the collagen-binding defect is not due to loss of high-molecular-weight multimers as in type 2A disease, also described as type 2CB (collagen-binding subtype). Carriers can bleed significantly from dental extractions, surgeries, and childbirth while appearing fully normal on routine haematological workup.

The Mechanism

The VWF A3 domain folds into a von Willebrand A fold³³ von Willebrand A fold
A barrel-like beta-sheet structure common to VWF, integrins, and complement proteins; its surface groove coordinates the collagen interaction that positions a specific surface groove to engage collagen types I and III in the extracellular matrix. Serine 1783 sits within this groove. In the wild-type protein, serine's hydroxyl group contributes a hydrogen bond that maintains the precise geometry of the collagen-contact interface. Substituting alanine — which lacks that hydroxyl side chain — disrupts this geometry without altering the overall multimer structure or Factor VIII binding.

Recombinant S1783A VWF expressed and studied by Riddell et al. showed "a pronounced binding defect to both type I and type III collagen" relative to wild-type, while multimer gels were "indistinguishable from wild-type." This mechanistic specificity — collagen binding lost, everything else preserved — is what makes this variant diagnostically elusive and clinically significant.

The Evidence

The key characterization study is Riddell et al., Blood 2009⁴⁴ Riddell et al., Blood 2009
Riddell AF, Gomez K, Millar CM et al. Blood 114(16):3489-96; doi:10.1182/blood-2008-10-184317 — identified S1783A and W1745C as novel A3-domain mutations in three families with bleeding symptoms and normal routine VWD assays; proposed reclassification of isolated collagen-binding defects as a distinct disease subtype. S1783A was identified as a heterozygous variant in a mother-son pair with bleeding symptoms — normal VWF antigen, normal VWF:RCo, normal multimers, but abnormal collagen binding to both collagen I and III. The variant segregated with the phenotype, and the S1783A mutation was absent from the reference allele population. ClinVar (variation 31012) lists the pathogenic classification from OMIM (allelic variant 613160.0042) along with a 2023 Variantyx submission noting variable expressivity consistent with incomplete penetrance.

The importance of dedicated collagen-binding assays is established by Favaloro and Mohammed, 2014⁵⁵ Favaloro and Mohammed, 2014
Favaloro EJ, Mohammed S. Thromb Res 135(6):1307-16, 2014 — comparative evaluation of VWF assay platforms across 600 samples; VWF:CB was most discrepant from VWF:RCo precisely in type 2M patients, confirming VWF:CB is irreplaceable for this subtype. Without a VWF:CB assay in the diagnostic workup, type 2M/2CB cases are systematically missed.

Evidence level is assessed as strong: the causal mechanism is characterised at the recombinant-protein level, the variant segregates with disease in affected pedigrees, ClinVar lists a pathogenic submission, and the collagen-binding assay literature supports the diagnostic framework. However, published case numbers are small (one pedigree for S1783A specifically) and the full penetrance spectrum is not yet established from population-level data.

Practical Actions

For carriers, the priority is to make the invisible visible: the bleeding risk is real but will remain undetected unless haematologists are told to request a VWF collagen-binding assay. Carriers undergoing surgery, dental procedures, or childbirth need a haematologist involved in pre-procedural planning. DDAVP (desmopressin) — the first-line treatment for VWD type 1 — releases endogenous VWF stores but is unlikely to be effective for this variant because the released VWF carries the same structural defect. VWF concentrate (Humate-P, Wilate, or similar) is the preferred treatment option when haemostatic cover is needed, since concentrate VWF has normal collagen-binding activity.

Interactions

VWF S1783A acts through loss of collagen contact rather than reduction in VWF quantity or multimer structure. It does not interact with the ABO blood group variant (rs505922) in the same way that quantitative VWD type 1 does — ABO-associated VWF level modulation is relevant to VWF antigen and clearance, not to A3-domain collagen binding. No compound heterozygosity has been published for S1783A with other A3-domain mutations (such as W1745C at rs61749642 or L1733P), though theoretically compound heterozygosity could produce severe type 3-like collagen-binding loss; this has not been documented in clinical series.