GeneBe

rs61748477

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_ModeratePP3PM2_SupportingPS3PM3

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

Publications

10 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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
VWFNM_000552.5 linkc.2372C>T p.Thr791Met missense_variant Exon 18 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.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
VWFENST00000261405.10 linkc.2372C>T p.Thr791Met missense_variant Exon 18 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000538635.5 linkn.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
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251384
AF XY:
0.0000147
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 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
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86254
European-Finnish (FIN)
AF:
0.0000374
AC:
2
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1111986
Other (OTH)
AF:
0.000149
AC:
9
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
African (AFR)
AF:
0.0000241
AC:
1
AN:
41436
American (AMR)
AF:
0.0000655
AC:
1
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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. -

-
Academic Unit of Haematology, University of Sheffield
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

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 -

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
PhyloP100
9.1
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
Mutation Taster
=6/94
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61748477; hg19: chr12-6153527; API