Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000552.5(VWF):c.3940G>T (p.Val1314Phe)

CA228498

100308 (ClinVar)

Gene: VWF
Condition: von Willebrand disease type 2B
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f029ee4a-f433-486b-a623-20df4ad77990
Approved on: 2024-08-13
Published on: 2024-08-13

HGVS expressions

NM_000552.5:c.3940G>T
NM_000552.5(VWF):c.3940G>T (p.Val1314Phe)
NC_000012.12:g.6019478C>A
CM000674.2:g.6019478C>A
NC_000012.11:g.6128644C>A
CM000674.1:g.6128644C>A
NC_000012.10:g.5998905C>A
NG_009072.1:g.110193G>T
NG_009072.2:g.110193G>T
ENST00000261405.10:c.3940G>T
ENST00000261405.9:c.3940G>T
ENST00000538635.5:n.421-25544G>T
NM_000552.3:c.3940G>T
NM_000552.4:c.3940G>T

Pathogenic

Met criteria codes 6
PS3 PP4 PP3 PM5 PS2_Moderate PM2_Supporting

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
von Willebrand Disease VCEP
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.
Met criteria codes
PS3
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).
This variant lead to significantly decreased heparin-binding in plasma and corresponding rVWF, reaching 68% of control plasma or WT-rVWF. This is not an assay considered for this criteria. PubMed:11776314
V1314F (referred to here as V551F) rVWF had spontaneous binding to GPIb (22.1% ± 3.5%) and increased binding at low doses of ristocetin (41.3% ± 3.1% at 0.2mg). PubMed:10845912
Found V1314F rVWF exhibited a significantly increased to rADAMTS-13-mediated proteolysis, both in low and in physiological ionic strength conditions as compared with rVWF-WT (fig 5). PubMed:17087728
PP4
The patient, in PMID: 8298143, had 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. As reported by the authors, there is a discrepancy in this patient between an apparent type 2A phenotype and 2B genotype. The patient meets criteria for PP4_moderate for type 2A but this is likely actually a type 2B variant and PP4 is applied at the supporting level based on loss of HMWM. 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.
PP3
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). The computational splicing predictor SpliceAI gives a score of 0.01 for splice donor gain, indicating that the variant likely has no impact on splicing.
PM5
Another type 2B variants have been reported at this amino acid residue; Val1314Leu and classified pathogenic by the VWD VCEP (PM5). Val1314Asp (classified pathogenic by the VWD VCEP) has also been reported but is not included here to avoid circularity.
PS2_Moderate
The Val1314Phe variant (referred to as Val551Phe in PMID: 8298143) was identified in the patient but not in the parents. Additionally, the authors studied the variable number of tandemly repeated (VNTR) DNA sequences in the 3’ hypervariable region of the apolipoprotein B gene of the patient and his parents, and together with the available blood group data, confirmed parental relationships (PS2_moderate).
PM2_Supporting
This variant is absent from gnomAD v4.1 (PM2_Supporting).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.