rs61750117

Variant names:

Your query was ambiguous. Multiple possible variants found:

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: NM_000552.4(VWF):c.4789C>T (p.Arg1597Trp) missense variant has been identified in at least 40 probands reported to have type 2A VWD. This variant has been reported in at least 16 probands meeting PP4 laboratory phenotype criteria. (PS4_VeryStrong; PMIDs: 31939074, 22102197, 26791163, 27214365, 22329792, 14630825, 33807613, 23702511, 25689060, 27766062, 1380739, 16961623, 19277422, 22871923, 23355534). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 11%), low VWF:RCo/VWF:Ag ratio of 0.28, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additionally, a normal RIPA assay was reported for this patient (PP4_moderate, PMID:25689060 Patient 7). The variant has been reported to segregate with VWD type 2A through >2 affected meioses in at least 2 families (PP1_moderate; PMID:22329792, 27766062). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 1 individual with VWD type 2A (PS2_supporting; PMID:27214365). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting), a single allele is present in the European (Finnish) population. ADAMTS susceptibility assay, in 293 EBNA cells and hydrodynamic mouse model, expressing recombinant R1597W VWF showed increased susceptibility indicating that this variant has a damaging effect on protein function and the hydrodynamic model is a strong recapitulation human patients with a multimer profile was skewed toward lower molecular weight multimers, reduced VWF:Ag, and reduced thrombus formation. (PMID:16322474, 29186156, 22372972)(PS3). The computational predictor CADD gives a PHRED score of 27.4, which is above the ClinGen VWD VCEP threshold of >20 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP1_moderate, PP4_moderate, PS4_VeryStrong, PP3, PM2_supporting, PS2_supporting, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114117/MONDO:0015628/081

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13O:2

Conservation

PhyloP100: 2.56

Publications

38 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.4789C>T	p.Arg1597Trp	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4789C>T	p.Arg1597Trp	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.4789C>T	p.Arg1597Trp	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-24695C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

Feb 13, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

It has been reported in heterozygous individuals with von Willebrand disease (VWD) type 2A in the published literature (PMID: 19277422 (2009) and 16322474 (2006)) and has been reported to segregate with VWD type 2A in a large family (PMID: 27766062 (2016)). In addition, functional studies have demonstrated that this variant is damaging to VWF protein functions (PMID: 29186156 (2017), 22372972 (2012), 18986390 (2008), 16322474 (2006)). Therefore, this variant is classified as pathogenic. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Academic Unit of Haematology, University of Sheffield

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 29, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_Strong, PP3, PP5, PM2, PM6, PS3, PS4_Moderate -

Hereditary von Willebrand disease

Pathogenic:2Other:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 16, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: VWF c.4789C>T (p.Arg1597Trp) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251162 control chromosomes (gnomAD). c.4789C>T has been reported in the literature in multiple individuals affected with Von Willebrand Disease and the variant segregated with disease (examples: Ginsburg_1989, Inbal_1992, Starke_2013, and Shen_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence from in vitro and mouse model studies have demonstrated that this variant disrupts the normal activity of the protein (examples: Hassenpflug_2006, Xu_2013 and Pruss_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=6) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

von Willebrand disease type 2

Pathogenic:2

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

- -

Jul 08, 2021

Laboratory of Hematology, Radboud University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Von Willebrand disease type 2A

Pathogenic:2

May 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 13, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

NM_000552.4(VWF):c.4789C>T (p.Arg1597Trp) missense variant has been identified in at least 40 probands reported to have type 2A VWD. This variant has been reported in at least 16 probands meeting PP4 laboratory phenotype criteria. (PS4_VeryStrong; PMIDs: 31939074, 22102197, 26791163, 27214365, 22329792, 14630825, 33807613, 23702511, 25689060, 27766062, 1380739, 16961623, 19277422, 22871923, 23355534). At least one patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (VWF:RCo 11%), low VWF:RCo/VWF:Ag ratio of 0.28, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additionally, a normal RIPA assay was reported for this patient (PP4_moderate, PMID: 25689060 Patient 7). The variant has been reported to segregate with VWD type 2A through >2 affected meioses in at least 2 families (PP1_moderate; PMID: 22329792, 27766062). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in at least 1 individual with VWD type 2A (PS2_supporting; PMID: 27214365). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting), a single allele is present in the European (Finnish) population. ADAMTS susceptibility assay, in 293 EBNA cells and hydrodynamic mouse model, expressing recombinant R1597W VWF showed increased susceptibility indicating that this variant has a damaging effect on protein function and the hydrodynamic model is a strong recapitulation human patients with a multimer profile was skewed toward lower molecular weight multimers, reduced VWF:Ag, and reduced thrombus formation. (PMID: 16322474, 29186156, 22372972)(PS3). The computational predictor CADD gives a PHRED score of 27.4, which is above the ClinGen VWD VCEP threshold of >20 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PP1_moderate, PP4_moderate, PS4_VeryStrong, PP3, PM2_supporting, PS2_supporting, PS3. -

not specified

Pathogenic:1

Dec 06, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The VWF c.4789C>T; p.Arg1597Trp variant (also known as Arg834Trp in the mature protein, rs61750117) has been reported in patients with type 2A Von Willebrand disease (VWD) (Baronciani 2006, Ginsburg 1989, Starke 2013) and segregated with disease in a three-generation family (Shen 2016). In vitro studies have shown that this variant results in increased susceptibility to ADAMTS13 cleavage (Hassenpflug 2006, Pruss 2012, Pruss 2008). It has also been shown that plasma samples from patients carrying this variant lack high molecular weight multimers of Von Willebrand factor (VWF) (Hassenpflug 2006, Starke 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 285) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, several other variants at codon 1597 have been reported in patients with type 2A VWD (Donner 1993, Ginsburg 1993, Melo-Nava 2007, Veyradier 2016). The arginine at codon 1597 is highly conserved in the calcium-binding loop of VWF A2 domain (Xu 2013) and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Based on the above information, this variant is classified as pathogenic. References: Baronciani L et al. von Willebrand factor collagen binding assay in von Willebrand disease type 2A, 2B, and 2M. J Thromb Haemost. 2006 Sep; 4:2088-2090. Donner M et al. Two new candidate mutations in type IIA von Willebrand's disease (Arg834-->Gly, Gly846-->Arg) and one polymorphism (Tyr821-->Cys) in the A2 region of the von Willebrand factor. Eur J Haematol. 1993 Jul; 51:38-44. Ginsburg D et al. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci U S A. 1989 May; 86:3723-3727. Ginsburg D et al. von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1993 Feb 1; 69:177-184. Hassenpflug WA et al. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood. 2006 Mar 15; 107:2339-2345. Melo-Nava BM et al. Molecular study of VWF gene from Mexican Mestizo patients with von Willebrand disease, and the finding of three new mutations. Blood Cells Mol Dis. 2007 Nov-Dec; 39:361-365. Pruss CM et al. Use of a mouse model to elucidate the phenotypic effects of the von Willebrand factor cleavage mutants, Y1605A/M1606A and R1597W. J Thromb Haemost. 2012 May; 10:940-950. Pruss CM et al. ADAMTS13 cleavage efficiency is altered by mutagenic and, to a lesser extent, polymorphic sequence changes in the A1 and A2 domains of von Willebrand factor. Br J Haematol. 2008 Nov; 143:552-558. Shen MC et al. De novo mutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD. Thromb J. 2016 Oct 4; 14:36. Starke RD et al. Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood. 2013 Apr 4; 121:2773-2784. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar; 95:e3038. -

Inborn genetic diseases

Pathogenic:1

Mar 29, 2016

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

PhyloP100

2.6

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.85

MutPred

0.86

Gain of catalytic residue at G1595 (P = 0.0166);

MVP

0.89

MPC

0.52

ClinPred

0.98

GERP RS

5.0

Varity_R

0.92

gMVP

0.95

Mutation Taster

=12/88

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