rs267607326

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PS3PM2_SupportingPP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.3437A>G (p.Tyr1146Cys) missense variant has been reported in at least 22 VWD type 2A patients. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/37812 alleles in the African/African-American population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.872, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of low VWF activity (VWF:RCo 16, VWF:CB 7) and VWF:Ag of 20 for a low VWF:CB activity/VWF:Ag ratio of 0.35, which is specific for VWD type 2A. (PP4; PMID:24598842). Eight additional VWD 2A patients, with confirmatory lab values including very low VWF:RCo, low VWF:GPIb, and or low VWF activity/ VWF:Ag ratio, have been reported (PMIDs: 22871923, 16985174, 35452508, 20351307; PS4_VeryStrong). Multimer analysis in 293 cells expressing recombinant variant VWF showed reduced high molecular weight multimers indicating that this variant has a damaging effect on protein function (PMID:20351307 Figure 3, PMID:27533707 Figure 2; PS3). 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: PS4_VeryStrong, PS3, PM2_supporting, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228408/MONDO:0015628/081

Frequency

Genomes: not found (cov: 12)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

15

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 3.87

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

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.

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.3437A>G	p.Tyr1146Cys	missense_variant	Exon 26 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.3437A>G	p.Tyr1146Cys	missense_variant	Exon 26 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.3437A>G	p.Tyr1146Cys	missense_variant	Exon 26 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-28907A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

12

GnomAD4 exome

AF:

0.00000227

AC:

1

AN:

440372

Hom.:

0

Cov.:

1

AF XY:

0.00

AC XY:

0

AN XY:

232952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000814

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

von Willebrand disease type 2

Pathogenic:3

Jun 10, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

- -

Hereditary von Willebrand disease

Pathogenic:2

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 25, 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.3437A>G (p.Tyr1146Cys) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 54460 control chromosomes. c.3437A>G has been reported in the literature in multiple individuals affected with Type I and Type II Von Willebrand Disease (example, Goodeve_2007, Castaman_2008, James_2007, Schneppenheim_2010, Manderstedt_2018, Fidalgo_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in inhibition of normal processing, string formation and platelet binding (Brehm_2014), defective intracellular packaging and markedly reduced VWF secretion. Loss of HMW Multimers. Demonstrated a novel FVIII binding defect (White-Adams_2016) and reduced expression (Schneppenheim_2010). One clinical diagnostic laboratory and the NIHR Bioresource Rare Diseases have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified

Pathogenic:1

Sep 25, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported as a relatively common variant in Type 2A vWD and some Type 1 vWD patients the published literature (PMID: 16985174 (2007), 17190853 (2007), 20351307 (2010), 22871923 (2012), 26986123 (2016), 26988807 (2016), 29388750 (2018), 29742318 (2018), 31249928 (2018), 31064749 (2019)). Functional studies showed that this variant caused defective intracellular packaging, reduced VWF secretion, and a FVIII binding defect as well as loss of large multimers and decreased proteolysis (PMID: 18230755 (2008), 20351307 (2010), 24598842 (2014), 27533707 (2016)). Therefore, the variant is classified as pathogenic. -

von Willebrand disease type 1

Pathogenic:1

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Von Willebrand disease type 2A

Pathogenic:1

Aug 13, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000552.4(VWF):c.3437A>G (p.Tyr1146Cys) missense variant has been reported in at least 22 VWD type 2A patients. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/37812 alleles in the African/African-American population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.872, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of low VWF activity (VWF:RCo 16, VWF:CB 7) and VWF:Ag of 20 for a low VWF:CB activity/VWF:Ag ratio of 0.35, which is specific for VWD type 2A. (PP4; PMID: 24598842). Eight additional VWD 2A patients, with confirmatory lab values including very low VWF:RCo, low VWF:GPIb, and or low VWF activity/ VWF:Ag ratio, have been reported (PMIDs: 22871923, 16985174, 35452508, 20351307; PS4_VeryStrong). Multimer analysis in 293 cells expressing recombinant variant VWF showed reduced high molecular weight multimers indicating that this variant has a damaging effect on protein function (PMID: 20351307 Figure 3, PMID: 27533707 Figure 2; PS3). 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: PS4_VeryStrong, PS3, PM2_supporting, PP3, PP4. -

not provided

Other:1

-

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.49

D

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

24

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Pathogenic

0.75

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.9

H

PrimateAI

Uncertain

0.71

T

PROVEAN

Pathogenic

-8.8

D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.85

MutPred

0.83

Gain of catalytic residue at E1143 (P = 0.0192);

MVP

0.92

MPC

1.1

ClinPred

1.0

D

GERP RS

4.9

Varity_R

0.96

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267607326; hg19: chr12-6132007;