12-6019502-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PS4PS2_SupportingPP1_ModeratePP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3916C>T (p.Arg1306Trp) variant in VWF has been reported in several dozen vWD type 2B patients (PS4). At least 4 (PMIDs: 1419803, 19740526 and 15041272) have sufficient information reported to meet the PP4_moderate criteria. In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PMID:20371742). This variant is absent from population databases, including gnomADv4.1 (PM2_supporting). It is predicted deleterious by REVEL which gives a score of 0.769, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant has been observed both de novo (PMID:1419803; PS2_supporting) and segregating in multiple families (PMID:15041272 and 1419803; PP1_moderate). In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PS2_supporting, PP1_moderate, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114123/MONDO:0015629/081

Frequency

Genomes: not found (cov: 32)

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15O:2

Conservation

PhyloP100: 3.74

Publications

33 publications found

Variant links:

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

VWF Gene-Disease associations (from GenCC):

hereditary von Willebrand disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
von Willebrand disease type 2B
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
von Willebrand disease 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
von Willebrand disease 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
von Willebrand disease type 2A
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease type 2M
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease type 2N
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VWF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.3916C>T	p.Arg1306Trp	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.3916C>T	p.Arg1306Trp	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.3916C>T	p.Arg1306Trp	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000538635.5 link	n.421-25568C>T		intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1 link	n.*26C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

Academic Unit of Haematology, University of Sheffield

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with Type 2B von Willebrand disease (vWD) (PMIDs: 1672694 (1991), 2010538 (1991), 27029718 (2016), and 31464689 (2019)), causing increased affinity of vWF with platelets (PMID: 15041272 (2003)), the selective loss of high molecular-weight vWF multimers (PMID: 1557393 (1992), and often thrombocytopenia (PMID: 19740526 (2010)). This variant has been reported to occur de novo (PMIDs: 9723578 (1998) and 1419803 (1992)), to segregate with vWD (PMIDs: 19740526 (2010) and 22077376 (2012)), and has been observed in a clinically healthy carrier (PMIDs: 1419803 (1992) and 19740526 (2010)). An in vitro study demonstrated that this variant has increased affinity for platelet receptor glycoprotein than wild type, a higher sensitivity to shear stress which facilitated self-aggregation, and exposure of platelet receptor glycoprotein binding sites (PMID: 23819767 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The VWF c.3916C>T; p.Arg1306Trp variant (rs61749384), also known as Arg534Trp, is reported in the medical literature in multiple families affected by von Willebrand disease type IIB (Cooney 1991, Lillicrap 1991, Pietu 1991, Randi 1991, Donner 1992, Casana 1998, Ozeki 2010) and co-segregates with affected family members (Lillicrap 1991, Donner 1992, Casana 1998). Functional characterization of the p.Arg1306Trp protein indicates a greater sensitivity to shear stress, leading to a reduction of high molecular weight multimers in plasma (Scaglione 2013). This variant is also reported in ClinVar (Variation ID:288), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at residue 1306 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.769). Based on available information, the variant is classified as pathogenic. References: Casana P et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol. 1998 59(1):57-63. PMID: 9723578. Cooney K et al. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest. 1991 87(4):1227-33. PMID: 1672694. Donner M et al. Type IIB von Willebrand's disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden. Br J Haematol. 1992 82(1):58-65. PMID: 1419803. Lillicrap D et al. Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain, in patients with type IIB von Willebrand's disease. Br J Haematol. 1991 79(4):612-7. PMID: 1772783. Ozeki M et al. A family having type 2B von Willebrand disease with an R1306W mutation: Severe thrombocytopenia leads to the normalization of high molecular weight multimers. Thromb Res. 2010 125(2):e17-22. PMID: 19740526. Pietu G et al. Molecular study of von Willebrand disease: identification of potential mutations in patients with type IIA and type IIB. Blood Coagul Fibrinolysis. 1992 3(4):415-21. PMID: 1420817. Randi A et al. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991 87(4):1220-6. PMID: 2010538. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

von Willebrand disease type 2

Pathogenic:4

Apr 26, 2022

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 07, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The VWF c.3916C>T variant is classified as Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PM5, PP1_Strong) -

Von Willebrand disease type 2B

Pathogenic:3

May 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 14, 2018

Versiti Diagnostic Laboratories, Versiti, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant VWF c.3916C>T, p.Arg1306Trp (p.R1306W) in exon 28 changes amino acid arginine at codon 1306 to tryptophan. The arginine at this residue is somewhat conserved among species. This amino acid change occurs in the A1 domain, a functional domain that binds GP1ba and collagen (Springer, 2014). This sequence variant has been previously reported in patients with type 2B von Willebrand disease (Cooney, 1991; Randi, 1991; Ozeki, 2010) and has been observed in multiple patients with type 2B VWD in our laboratory cohort. Functional studies of the variant in mammalian cells demonstrated significantly increased platelet binding in the presence and absence of ristocetin (Cooney, 1996) and dramatic enhancement of multimer sensitivity to shear stress. (Scaglione, 2013). To date, this variant has not been reported in the general population (GnomAD, Exome Variant Server). In summary, the collective evidence supports VWF c.3916C>T, p.Arg1306Trp as a pathogenic variant for type 2B von Willebrand disease. -

Aug 12, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.3916C>T (p.Arg1306Trp) variant in VWF has been reported in several dozen vWD type 2B patients (PS4). At least 4 (PMIDs: 1419803, 19740526 and 15041272) have sufficient information reported to meet the PP4_moderate criteria. In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PMID: 20371742). This variant is absent from population databases, including gnomADv4.1 (PM2_supporting). It is predicted deleterious by REVEL which gives a score of 0.769, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant has been observed both de novo (PMID: 1419803; PS2_supporting) and segregating in multiple families (PMID: 15041272 and 1419803; PP1_moderate). In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PS2_supporting, PP1_moderate, PP3, and PP4_moderate. -

Hereditary von Willebrand disease

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Abnormality of coagulation

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3

Pathogenic:1

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.5

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.63

MutPred

0.79

Gain of catalytic residue at D1302 (P = 0.0669);

MVP

0.84

MPC

0.96

ClinPred

0.98

GERP RS

3.1

Varity_R

0.64

gMVP

0.82

Mutation Taster

=23/77

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over