rs61748477

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PM2_SupportingPM3PS3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.2372C>T variant in VWF is a missense variant predicted to cause substitution of threonine by methionine at amino acid 791. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000006150 (based on 2/64030alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold <0.005 for PM2_Supporting, meeting this criterion (PM2_Supporting). At least four patients with this variant displayed excessive mucocutaneous bleeding as well as a low VWF:FVIII/VWF:Ag ratio which is highly specific for VWD type 2N (PP4_moderate, PMIDs: 2018834; 31741138; 22871923; 10706867). This variant has been detected in at least six individuals with VWD type 2N, with absent VWF:FVIII binding, compound heterozygous with a second variant (including Arg854Gln classified Pathogenic by the VWD VCEP without reported confirmation of trans phase 0.5pt PMID:22102197) and two individuals were homozygous for the variant (PMIDs: 2018834; 22871923) (PM3). Factor VIII binding assay in HEK293 expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function (PMID:19088379; PS3_supporting). The computational predictor REVEL gives a score of 0.869, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PS3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114135/MONDO:0015631/090

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

12

5

2

Clinical Significance

Pathogenic reviewed by expert panel P:6O:2

Conservation

PhyloP100: 9.09

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 10 ACMG points.

PS3

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

PM2

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

PM3

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.2372C>T	p.Thr791Met	missense_variant	Exon 18 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2372C>T	p.Thr791Met	missense_variant	Exon 18 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2372C>T	p.Thr791Met	missense_variant	Exon 18 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-50427C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152180

Hom.:

0

Cov.:

34

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

2

AN:

251384

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

27

AN:

1461850

Hom.:

0

Cov.:

61

AF XY:

0.0000193

AC XY:

14

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152180

Hom.:

0

Cov.:

34

AF XY:

0.00

AC XY:

0

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

0

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

1

ALSPAC

AF:

0.00

AC:

0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Jun 04, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.2372C>T (p.Thr791Met) variant has been reported in the published literature in individuals with von Willebrand disease Type 2N (PMIDs: 8500791 (1993), 8903002 (1996), 22871923 (2012), 28536718 (2017), 31939074 (2020), and 33248318 (2021)). Hematological data and functional studies have shown that this variant causes a defect in FactorVIII binding (PMIDs: 1906179 (1991), 22871923 (2012), and 33248318 (2021)) and reduced binding to myosin (PMID: 31935285 (2020)) and fibronectin (PMID: 34136746 (2021)). The frequency of this variant in the general population, 0.000011 (3/282786 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -

Aug 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PP3, PM2_moderate, PS3, PS4_moderate -

-

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

von Willebrand disease type 2N

Pathogenic:2

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.2372C>T variant in VWF is a missense variant predicted to cause substitution of threonine by methionine at amino acid 791. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000006150 (based on 2/64030alleles in European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold <0.005 for PM2_Supporting, meeting this criterion (PM2_Supporting). At least four patients with this variant displayed excessive mucocutaneous bleeding as well as a low VWF:FVIII/VWF:Ag ratio which is highly specific for VWD type 2N (PP4_moderate, PMIDs: 2018834; 31741138; 22871923; 10706867). This variant has been detected in at least six individuals with VWD type 2N, with absent VWF:FVIII binding, compound heterozygous with a second variant (including Arg854Gln classified Pathogenic by the VWD VCEP without reported confirmation of trans phase 0.5pt PMID: 22102197) and two individuals were homozygous for the variant (PMIDs: 2018834; 22871923) (PM3). Factor VIII binding assay in HEK293 expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function (PMID: 19088379; PS3_supporting). The computational predictor REVEL gives a score of 0.869, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PS3, PP3. -

May 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

von Willebrand disease type 2

Pathogenic:1

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Abnormal bleeding

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary von Willebrand disease

Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.35

D

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Uncertain

0.94

D

M_CAP

Pathogenic

0.58

D

MetaRNN

Pathogenic

0.94

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.6

H

PrimateAI

Uncertain

0.59

T

PROVEAN

Uncertain

-3.7

D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.91

MutPred

0.59

Gain of catalytic residue at Q793 (P = 0.0016);

MVP

0.94

MPC

0.76

ClinPred

0.99

D

GERP RS

4.2

Varity_R

0.74

gMVP

0.87

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: rs61748477; hg19: chr12-6153527;