Variant: NM_000552.5(VWF):c.3926T>A (p.Ile1309Asn)

Version: 1.0
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CA383506185

1684483 (ClinVar)

Gene: VWF (HGNC:7450)

Condition: von Willebrand disease type 2B

Inheritance Mode: Autosomal dominant inheritance

UUID: 3f3d0c7b-a702-4ea7-a03a-15e8fc2e2fb8

Approved on: 2025-05-06

Published on: 2025-05-09

HGVS expressions

NM_000552.5:c.3926T>A
NM_000552.5(VWF):c.3926T>A (p.Ile1309Asn)
NC_000012.12:g.6019492A>T
CM000674.2:g.6019492A>T
NC_000012.11:g.6128658A>T
CM000674.1:g.6128658A>T
NC_000012.10:g.5998919A>T
NG_009072.1:g.110179T>A
NG_009072.2:g.110179T>A
ENST00000261405.10:c.3926T>A
ENST00000261405.9:c.3926T>A
ENST00000538635.5:n.421-25558T>A
NM_000552.3:c.3926T>A
NM_000552.4:c.3926T>A

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PP3 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.3926T>A (p.Ile1309Asn) missense variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.886, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Another type 2B missense change (p.I1309V) has been reported at this amino acid residue and has been classified Pathogenic for type 2B VWD by the VWD VCEP (PM5). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of thrombocytopenia and an assay showing gain of function (flow cytometry showed markedly increased baseline activity), which together are highly specific for VWD type 2B. (PP4_moderate, SCV002515788.1). The patient was also reported to a VWF antigen/activity ratio (0.2) consistent with type 2B. In summary, this variant has been classified as likely 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. PM2_supporting, PP3, PM5, PP4_moderate.

Met criteria codes

• PP4_Moderate: At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of thrombocytopenia and an assay showing gain of function (flow cytometry showed markedly increased baseline activity), which together are highly specific for VWD type 2B. (PP4_moderate, SCV002515788.1). The patient was also reported to a VWF activity/antigen ratio (0.2) consistent with type 2B.
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.886, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).
• PM5: Another type 2B missense change (p.I1309V) has been reported at this amino acid residue and has been classified Pathogenic for type 2B VWD by the VWD VCEP.