rs61749384

Positions:

• chr12-6019502-G-A
• chr12-6019502-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS2_Supporting PP1_Moderate PP4_Moderate PP3 PM2_Supporting PS3 PS4

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
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:2
• Conservation: PhyloP100: 3.74

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3916C>T	p.Arg1306Trp	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3916C>T	p.Arg1306Trp	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3916C>T	p.Arg1306Trp	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-25568C>T		intron_variant		4
VWF	ENST00000539641.1	n.*26C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

von Willebrand disease type 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	Dec 10, 2020	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 07, 2022	The VWF c.3916C>T variant is classified as Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PM5, PP1_Strong) -
Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Apr 26, 2022	- -

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 13, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2017	The VWF c.3916C>T, p.Arg1306Trp variant (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). The variant is listed in the ClinVar database (Variation ID:288) and the dbSNP variant database (rs61749384), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at residue 1306 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on protein structure or function. Based on the above 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. 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. 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. 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. 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. 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. 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. Scaglione G et al. The type 2B p.R1306W natural mutation of von Willebrand factor dramatically enhances the multimer sensitivity to shear stress. J Thromb Haemost. 2013 11(9):1688-98. -

Von Willebrand disease type 2B Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	Aug 12, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Versiti Diagnostic Laboratories, Versiti, Inc	May 14, 2018	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. -

Hereditary von Willebrand disease Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Abnormality of coagulation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.79		Gain of catalytic residue at D1302 (P = 0.0669);
MVP		0.84
MPC		0.96
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.64
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs61749384; hg19: chr12-6128668;