rs61750579 — VWF V1607D

Pathogenic missense variant in von Willebrand factor A2 domain adjacent to the ADAMTS13 cleavage site; the Asp substitution renders VWF hypersusceptible to proteolysis, depleting high-molecular-weight multimers and causing autosomal dominant type 2A von Willebrand disease with mucocutaneous bleeding

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VWF V1607D — A Cleavage Site Variant That Unmakes the Bleeding Brake

Von Willebrand factor is the primary bridge between a damaged blood vessel wall and the platelet plug that stops bleeding. It circulates as a series of multimers of varying size; the largest, high-molecular-weight (HMW) multimers are the most haemostatically active because they unfurl under shear stress to capture platelets at injury sites. Size is regulated by ADAMTS1311 ADAMTS13
A metalloprotease that cleaves VWF at the Tyr1605-Met1606 bond in the A2 domain, converting ultra-large multimers into smaller circulating forms. The rs61750579 variant encodes the Val1607Asp substitution22 Val1607Asp substitution
valine-to-aspartate change at position 1607, immediately C-terminal to the ADAMTS13 scissile bond — one of the most mechanistically direct causes of type 2A von Willebrand disease (VWD) identified to date.

The Mechanism

The A2 domain of VWF normally folds so that the Tyr1605-Met1606 scissile bond is buried and inaccessible to ADAMTS13 in the absence of mechanical force. When large shear stress stretches VWF at sites of high flow, the A2 domain transiently unfurls, exposing the cleavage site for regulated proteolysis. The Val1607Asp substitution introduces a charged aspartate residue immediately adjacent to this bond, destabilising the folded A2 domain and promoting a constitutively open conformation33 destabilising the folded A2 domain and promoting a constitutively open conformation
structural studies using FRET constructs showed that most type 2A mutations — including those at the cleavage site — separate the domain's N and C termini without requiring applied force. The result is that ADAMTS13 can cleave VWF continuously, even without mechanical provocation. HMW multimers are selectively degraded, leaving only small multimers in circulation that are unable to support effective platelet adhesion under physiological shear conditions.

Hassenpflug et al. expressed all 13 known A2 domain VWD type 2A mutations in recombinant form44 Hassenpflug et al. expressed all 13 known A2 domain VWD type 2A mutations in recombinant form
using a standardised proteolysis assay with ADAMTS13 at physiological concentrations and found that 11 of 13 mutants showed increased susceptibility to cleavage compared to wild-type VWF — a finding that mirrors the selective HMW multimer loss seen in patients' plasma. V1607D was among the mutations that increased proteolytic susceptibility. The biochemical outcome — accelerated cleavage — exactly accounts for the absent HMW multimers that define VWD type 2A on gel electrophoresis.

The Evidence

Type 2A VWD caused by the Val1607Asp variant is classified as pathogenic in ClinVar (VCV000000286)55 pathogenic in ClinVar (VCV000000286)
Three independent submitters, with classification criteria provided; OMIM allelic variant 613160.0003. ClinVar records document the selective loss of HMW VWF multimers in individuals carrying this variant, consistent with ADAMTS13 hyperactivity at the mutant A2 domain.

Structural modelling by Pozzi et al.66 Pozzi et al.
2012, Biophysical Chemistry showed that the Val1607Asp mutation — in contrast to oxidative modifications at the nearby Met1606 residue that impair cleavage — shifts the VWF-ADAMTS13 interaction toward accelerated proteolysis, producing a net haemorrhagic phenotype. The model correctly predicts the clinical observation that these patients bleed rather than clot.

Inheritance is autosomal dominant77 autosomal dominant
one mutant allele is sufficient to produce disease, because VWF multimers assembled from a mixture of wild-type and mutant subunits are still hypersusceptible to ADAMTS13 if even one Val1607Asp subunit is incorporated. This distinguishes type 2A VWD from the recessive type 3 VWD — heterozygous carriers of V1607D have full clinical disease, not a silent carrier state.

Practical Actions

Diagnosis of VWD type 2A requires a panel of laboratory tests: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo or VWF:GPIbR), factor VIII coagulant activity (FVIII:C), and VWF multimer analysis. The hallmark is a discordant VWF:RCo to VWF:Ag ratio below 0.6 (more activity loss than antigen loss), with absent HMW multimers on gel electrophoresis.

Desmopressin (DDAVP) releases stored VWF from endothelial Weibel-Palade bodies but is only partially effective in type 2A VWD. Atiq et al. found that only ~31% of type 2 VWD patients achieve complete desmopressin response88 Atiq et al. found that only ~31% of type 2 VWD patients achieve complete desmopressin response
compared to 100% of type 1 VWD patients without VWF gene variants, and response is highly variant-dependent. For the V1607D mutation — where accelerated proteolysis rapidly degrades the released VWF — the haemostatic benefit from DDAVP is typically short-lived and incomplete. A formal DDAVP trial under clinical supervision is required to determine individual response before relying on it for procedures.

For bleeds and surgical prophylaxis where desmopressin is insufficient, plasma-derived or recombinant VWF concentrate (Vonvendi, Wilate, Humate-P) restores all multimer sizes and is the established treatment. Antifibrinolytic agents (tranexamic acid) are effective adjuncts for mucosal bleeding.

Interactions

ABO blood group independently modulates circulating VWF levels — blood group O reduces VWF by approximately 25% through increased ADAMTS13-mediated clearance. Carriers of V1607D who also have blood group O (tagged by rs505922) may have compounded VWF deficiency beyond what the genotype alone predicts.

The rs1800380 variant (VWF p.Arg854Gln, type 2N VWD) affects the factor VIII binding domain of VWF rather than the A2 domain; compound heterozygotes carrying both V1607D and R854Q would have combined quantitative, qualitative, and FVIII-transport defects, requiring specialist assessment. Other VWF A2 domain variants (rs61750630 and related exon 28 mutations) can co-occur in the same gene and produce compound phenotypes.

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-carrier Normal

No V1607D variant detected — normal VWF A2 domain at this position

You carry two copies of the reference A allele at rs61750579, meaning you do not carry the VWF Val1607Asp pathogenic variant. This variant is extremely rare (no frequency data in major population databases — consistent with a disease-causing allele under strong purifying selection). Your von Willebrand factor A2 domain is not affected by this specific substitution. If you or family members have a personal or family history of abnormal mucosal or surgical bleeding, other VWF variants or platelet function disorders should be evaluated separately.

AT VWD Type 2A High Risk

One copy of Val1607Asp — autosomal dominant type 2A von Willebrand disease

The Val1607Asp substitution introduces a negatively charged aspartate residue immediately adjacent to the Tyr1605-Met1606 bond that ADAMTS13 cleaves during normal VWF processing. This destabilises the normally protective fold of the A2 domain, exposing the cleavage site constitutively rather than only under mechanical shear. ADAMTS13 cleaves the mutant VWF continuously, preventing the accumulation of the haemostatically active high-molecular-weight multimers. On laboratory testing, VWF ristocetin cofactor activity (VWF:RCo) is reduced more than VWF antigen (VWF:Ag), producing a VWF:RCo/VWF:Ag ratio below 0.6, and VWF multimer gel electrophoresis shows absent HMW multimers — the diagnostic hallmarks of type 2A VWD.

Desmopressin (DDAVP) may provide partial, transient haemostatic benefit by releasing stored VWF from endothelial cells, but the released VWF is rapidly degraded by ADAMTS13, limiting its duration of action. A formal supervised DDAVP trial is required to determine whether response is adequate for a planned procedure. For major surgical haemostasis, VWF concentrate is the reliable treatment.

The variant is extremely rare in population databases, consistent with its pathogenic classification. Any first-degree relative (parent, sibling, child) of a carrier has a 50% chance of carrying the same allele.

TT Homozygous — Severe Type 2A VWD Homozygous

Two copies of Val1607Asp — homozygous type 2A von Willebrand disease with profoundly impaired VWF multimer assembly

In heterozygous carriers, multimers assembled from a mixture of wild-type and Val1607Asp subunits are partially compromised. In homozygotes, every VWF subunit carries the destabilised A2 domain, meaning that every multimer assembled and secreted into plasma is immediately susceptible to ADAMTS13 cleavage without the protection that normally requires mechanical unfolding. The resulting phenotype is expected to be more severe than typical heterozygous type 2A VWD — potentially approaching the functional VWF loss seen in type 3 VWD for HMW-multimer-dependent haemostasis, while VWF antigen levels may remain near-normal or only modestly reduced (since the protein is secreted but rapidly degraded in plasma rather than retained intracellularly as in type 3).

DDAVP releases Weibel-Palade body VWF stores but this VWF is also Val1607Asp and subject to the same accelerated ADAMTS13 proteolysis. Haemostatic coverage is expected to be minimal and short-lived. Management must rely on plasma-derived or recombinant VWF concentrate providing exogenous normal-multimer VWF, and possibly on ADAMTS13 inhibitory strategies under specialist guidance.