ClinVar Miner

Submissions for variant NM_000552.5(VWF):c.3854C>T (p.Ser1285Phe)

dbSNP: rs61749380
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen RCV000000339 SCV005442562 likely pathogenic von Willebrand disease type 2M 2024-12-03 reviewed by expert panel curation The NM_000552.5(VWF):c.3854C>T variant in VWF is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 1285. This variant is absent from gnomAD v4.1 (PM2_supporting). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (<0.5), and markedly reduced ristocetin-induced VWF binding to GPIb, which together are highly specific for VWD type 2M. (PP4_moderate, PMID: 12588351). The computational predictor REVEL gives a score of 0.946, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The A1 domain from this variant exhibited complete loss of shear-flow-dependent platelet adhesion (PMID: 25185554, PS3).This variant is classified as Likely Pathogenic for von Willebrand disease type 2M based on the ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_Moderate, PP3, PS3.
OMIM RCV000000339 SCV000020483 pathogenic von Willebrand disease type 2M 2003-02-01 no assertion criteria provided literature only
Academic Unit of Haematology, University of Sheffield RCV000086691 SCV000118895 not provided not provided no assertion provided not provided

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