rs61753993 — VWF D141G

Missense variant in von Willebrand factor (p.Asp141Gly) associated with type 1 von Willebrand disease; heterozygous and homozygous carriers may have reduced VWF activity and increased bleeding tendency requiring hematology evaluation

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VWF D141G — A Missense Variant in von Willebrand Factor's Propeptide Region

Von Willebrand factor (VWF) is the molecular bridge between injured blood vessel walls and circulating platelets. Without adequate VWF, even a minor cut can lead to prolonged bleeding. The D141G variant — a single amino acid substitution replacing aspartate with glycine at position 141 of the VWF protein — was catalogued by the International Society on Thrombosis and Haemostasis VWF mutation database and identified in a UK cohort study of type 1 VWD families11 UK cohort study of type 1 VWD families
Cumming et al., Thromb Haemost 2006 — VWF gene sequenced in 32 confirmed UK type 1 VWD families as likely causative of von Willebrand disease in index cases. The variant is extremely rare in the general population and is not well-represented in large population databases such as gnomAD, consistent with a disease-causing rather than neutral polymorphism.

The Mechanism

Position 141 of VWF falls within the D1 propeptide domain22 D1 propeptide domain
The VWF propeptide (D1-D2) is cleaved after secretion and is essential for correct disulfide-bond formation and multimerisation of VWF. Aspartate at position 141 participates in the structural organisation of this domain; substitution with glycine — a conformationally flexible but electrically neutral residue — disrupts the local protein fold. Both SIFT (score 0, deleterious) and PolyPhen-2 (score 0.996, probably damaging)33 SIFT (score 0, deleterious) and PolyPhen-2 (score 0.996, probably damaging)
Ensembl VEP predictions for NM_000552.5:c.422A>G classify D141G as likely deleterious. The consequence may be impaired multimerisation, reduced secretion efficiency, or accelerated clearance of VWF — mechanisms common to type 1 VWD missense variants and collectively resulting in lower circulating VWF:Ag and VWF activity (VWF:RCo).

The VWF gene sits on chromosome 12 (12p13.31) and is transcribed off the minus strand. On a genome file, this variant is reported as T→C on the plus strand (the C allele encoding the Gly141 substitution when translated from the minus-strand coding sequence).

The Evidence

The MCMDM-1VWD European cohort44 MCMDM-1VWD European cohort
Goodeve et al. Blood 2007 — 150 type 1 VWD index cases across 9 European countries found that 70% of type 1 VWD index cases carried identifiable VWF mutations, with missense variants concentrated in the D and C domains responsible for multimerisation and platelet binding. Penetrance is incomplete: some D141G carriers may have VWF levels within the low-normal range (30–50 IU/dL) and minimal symptoms, while others present with VWF:Ag well below 30 IU/dL and frank bleeding diathesis.

The ASH/ISTH/NHF/WFH 2021 joint guidelines55 ASH/ISTH/NHF/WFH 2021 joint guidelines
James et al. Blood Adv 2021 — 11 evidence-based recommendations using GRADE methodology define type 1 VWD as VWF:Ag <30 IU/dL with a positive bleeding history, and recommend structured bleeding assessment tools (ISTH-BAT) for all suspected VWD cases. Carriers of D141G who have never had laboratory testing should have VWF:Ag, VWF:RCo, and FVIII measured to determine their functional phenotype.

Atiq et al. (Blood Adv 2019)66 Atiq et al. (Blood Adv 2019)
122 type 1 VWD patients followed prospectively; desmopressin challenge correlated with subsequent bleeding phenotype demonstrated that the magnitude of VWF and factor VIII rise after desmopressin challenge predicts clinical bleeding severity: patients achieving the highest FVIII quartile at 3 hours post-dose had substantially lower Tosetto bleeding scores. This means the desmopressin challenge test is both diagnostic and prognostic for type 1 VWD carriers.

Practical Actions

Any carrier of D141G who has not had haematological evaluation should request VWF panel testing (VWF:Ag, VWF:RCo, FVIII:C) from their physician and, if results are borderline or low, a referral to a haematologist for desmopressin challenge testing. Before surgical or dental procedures, excessive bleeding should be anticipated and preventive measures discussed with the treating team. Tranexamic acid (an anti-fibrinolytic agent) is effective for mucosal bleeding episodes (nosebleeds, heavy menstrual bleeding) in mild-moderate VWD and can often be managed without haematology input once the diagnosis is confirmed. Desmopressin (DDAVP) is first-line for type 1 VWD when a documented response is confirmed on prior challenge testing.

Interactions

VWF interacts genetically with ABO blood group: O blood group individuals naturally have approximately 25% lower VWF:Ag than non-O groups, which can unmask borderline VWF variants. Carriers of D141G with blood group O may have a more symptomatic phenotype than those with A, B, or AB blood groups. Additionally, high VWF clearance (measurable as elevated VWFpp/VWF:Ag ratio) compounds the functional deficit in type 1 VWD regardless of the causal variant; some D141G carriers may have both a synthesis defect and enhanced clearance contributing to their low VWF levels.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-carrier Normal

Standard VWF sequence — no D141G variant detected

You carry two copies of the common T allele at rs61753993, meaning your VWF gene encodes the normal aspartate amino acid at position 141. This is the wild-type sequence found in the vast majority of people. You do not carry the D141G missense variant associated with type 1 von Willebrand disease at this locus.

CC D141G Homozygous High Risk

Two copies of D141G — homozygous; likely significant VWF deficiency requiring specialist care

Homozygosity for a likely-pathogenic VWF missense variant is clinically significant regardless of the current symptom burden. Some individuals with quantitative VWD (even type 1) may not have had provoking events and may underreport bleeding symptoms — yet face significant haemorrhagic risk during surgery, dental procedures, trauma, childbirth, or anticoagulant therapy. The degree of VWF deficiency in CC homozygotes depends on the specific functional impact of D141G on secretion, multimerisation, and platelet binding, which must be assessed biochemically (VWF:Ag, VWF:RCo, multimer analysis).

If VWF:Ag is below 30 IU/dL with concordantly reduced VWF:RCo, type 1 VWD diagnosis is confirmed. Treatment modalities available to the haematologist include: - Desmopressin (DDAVP): effective if residual VWF secretion can be stimulated; response must be tested prospectively before use in procedures - VWF/FVIII concentrate (plasma-derived or recombinant): for procedures, major bleeding, or DDAVP non-responders - Tranexamic acid: adjunct for mucosal bleeding

Homozygous carriers of a pathogenic VWF variant and a personal or family history of severe bleeding should have genetic counselling, particularly if considering pregnancy.

CT D141G Carrier Carrier

One copy of D141G — heterozygous carrier with potential for reduced VWF activity

Type 1 von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative deficiency of VWF. Heterozygous carriers of missense variants like D141G typically have VWF:Ag levels 30–70% of normal, though the severity depends on the variant's specific functional impact and modifiers including ABO blood group.

The most important initial step is laboratory confirmation: VWF:Ag (antigen level), VWF:RCo (ristocetin cofactor activity — functional measure), and FVIII:C (coagulant activity) should be measured. If any are below the normal reference range, haematology referral is indicated. A desmopressin (DDAVP) challenge test — measuring VWF and FVIII at 1 and 4 hours after a dose of 0.3 μg/kg IV or 300 μg intranasal — is the key predictor of treatment response: those who mount a 3-4 fold rise in VWF:Ag can use DDAVP for bleeding episodes and surgical cover.

Symptoms in type 1 VWD carriers include easy bruising, prolonged nosebleeds, heavy menstrual bleeding, prolonged bleeding after dental extractions, and excessive post-surgical bleeding. An ISTH Bleeding Assessment Tool (ISTH-BAT) score can quantify bleeding history and support the clinical diagnosis.