rs61753993 — VWF D141G

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.