Submissions for variant NM_000552.5(VWF):c.3940G>T (p.Val1314Phe)

dbSNP: rs61749393

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	RCV004821266	SCV005442542	pathogenic	Von Willebrand disease type 2B	2024-08-13	reviewed by expert panel	curation	The NM_000552.5(VWF):c.3940G>T (p.Val1314Phe) missense variant has been reported in at least 1 proband with prolonged bleeding time (>20 minutes), decreased binding capacity to GPIb, vWFAg (25 U/dL) associated with the absence of vWFRCo (<5 U/dL) for a ratio of <0.2, and an absence of high molecular weight and intermediate multimers in the plasma. Additional features included decreased levels of VIIIC (30 U/dL) and a total lack of ristocetin platelet aggregation (RIPA) at concentrations of modulator between 0 and 2 mg/mL. His platelet count is around 120 × 10^9/L and decreases to approximately 50 × 10^9/L at the time of bleeding episodes (PP4; PMID: 8298143). As reported by the authors, there is a discrepancy in this patient between an apparent type 2A phenotype and 2B genotype. This discrepancy can be explained as an extremely severe form of type-IIB vWD, where the variant strongly increases the affinity of vWF for platelet GPIb, which might result in plasma in a spontaneous binding of both HMW and intermediate-sized multimers to the platelets. This could explain the thrombocytopenia of the propositus and the clearance of the large and intermediate forms of vWF from the patient’s plasma. The variant was identified as a de novo occurrence in this patient (PS2_moderate; PMIDs: 1419803). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).A GP1b binding assay performed with the recombinant Val1314Phe mutant vWF expressed by COS-7 cells showed spontaneous binding at low doses of ristocetin (PMID: 8298143 and PMID: 8630394), and enhanced binding to platelets in the presence of low-dose ristocetin compared with WT (PMID: 8630394), indicating that this variant has a gain of function effect on the protein (PS3_supporting). Another type 2B variants have been reported at this amino acid residue; Val1314Leu and classified pathogenic by the VWD VCEP (PM5). In summary, the variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS2_moderate, PP3, PP4, PM5, and PM2_supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086710	SCV000884880	likely pathogenic	not provided	2017-07-11	criteria provided, single submitter	clinical testing
Academic Unit of Haematology, University of Sheffield	RCV000086710	SCV000118915	not provided	not provided		no assertion provided	not provided