Variant: NM_000552.5(VWF):c.3802C>G (p.His1268Asp)

CA228445

100281 (ClinVar)

Gene: VWF

Condition: von Willebrand disease type 2B

Inheritance Mode: Autosomal dominant inheritance

UUID: bdbc4c65-f676-4c9a-b80a-d6fd2eb3d76f

Approved on: 2024-12-03

Published on: 2024-12-03

HGVS expressions

NM_000552.5:c.3802C>G
NM_000552.5(VWF):c.3802C>G (p.His1268Asp)
NC_000012.12:g.6019616G>C
CM000674.2:g.6019616G>C
NC_000012.11:g.6128782G>C
CM000674.1:g.6128782G>C
NC_000012.10:g.5999043G>C
NG_009072.1:g.110055C>G
NG_009072.2:g.110055C>G
ENST00000261405.10:c.3802C>G
ENST00000261405.9:c.3802C>G
ENST00000538635.5:n.421-25682C>G
ENST00000539641.1:n.600C>G
NM_000552.3:c.3802C>G
NM_000552.4:c.3802C>G

Pathogenic

• Met criteria codes: PP4_Moderate PS4 PS3 PM2_Supporting BP4

• Not Met criteria codes: PM5

Expert Panel

von Willebrand Disease VCEP

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

Evidence submitted by expert panel

von Willebrand Disease VCEP

The NM_000552.5(VWF):c.3802C>G (p.His1268Asp) variant is a missense variant with a REVEL score of 0.29, which meets the VWD VCEP threshold of less than or equal to 0.29 and does not predict a damaging effect on VWF function (BP4). However, a patient with the H1268D variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of a partial loss of high molecular weight multimers and a significant increase in VWF-GPIb showing gain of function which is highly specific for VWF type 2B. Additionally, the patient developed thrombocytopenia during infectious episodes (PMID: 18805962; PP4_Moderate). There are at least 4 additional type 2B probands with this variant and confirmed increased VWF binding (PMID: 8376405, PMID: 16704443, Christopherson, 2020, SCV002515761.1; PS4). The variant is absent from gnomADv4, thus, meeting PM2_Supporting criterion. RIPA assay demonstrated that the variant demonstrated enhanced responsiveness to rVWF-WT at a low concentration of ristocetin. Furthermore, multimer analysis also showed preferential cleavage of HMWMs (PMID: 26345337). The variant also exhibited increased affinity towards the LBD compared to WT AIM-A1 (PS3). In summary, this variant has been classified as Pathogenic for type 2B Von Willebrand Disease based on the ACMG/AMP criteria applied as specified by the von Willebrand Disease Variant Curation Expert Panel. BP4, PP4_Moderate, PM2_Supporting, PS3, PS4.

Met criteria codes

• PP4_Moderate: At lease 1 patient with the H1268D variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of a partial loss of high molecular weight multimers and a significant increase in VWF-GPIb showing gain of function which is highly specific for VWF type 2B. Additionally, the patient developed thrombocytopenia during infectious episodes (PMID: 18805962).
• PS4: There are at least 4 additional type 2B probands with this variant and confirmed increased VWF binding (PMID: 8376405, PMID: 16704443, Christopherson, 2020, SCV002515761.1).
• PS3: RIPA assay using fresh platelets showed that the H1268D variant demonstrated enhanced responsiveness compared with rVWF-WT at a low concentration of ristocetin (0.5 mg/mL). Multimer analysis also showed preferential cleavage of HMW multimers (PMID: 26345337). The H1268 variant showed increased affinity towards the LBD compared to WT AIM-A1 in transfected Expi293FBirA cells (PMID: 33883551).
• PM2_Supporting: This variant is absent from gnomAD v4, thus, meeting PM2_Supporting criterion.
• BP4: The computational predictor REVEL gives a score of 0.29, which meets the ClinGen VWD VCEP threshold of <0.290 (or equal to) and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing (delta scores 0.00).

Not Met criteria codes

• PM5: Two additional variants, p.His1268Asn and His1268Tyr, have been reported at the same codon but have not been curated by the VWD VCEP. Use of PM5 would not change the classification of His1268Asp and will not be pursued at this time.