GeneBe

NM_000552.5:c.3970G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3PS4_ModeratePP4_ModeratePP3PP1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.3970G>A (p.Gly1324Ser) variant is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 1324. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and a decreased GP1b binding assay, which together are highly specific for VWD type 2M (PP4_moderate, PMID:30084138). The variant has been reported to segregate with VWD type 2M through 2 affected meioses from 1 family (PP1; PMID:29341351). At least 3 additional VWD type 2M probands have been reported with this variant (PMIDs: 29341351, 22102201, 1409710; PS4_moderate). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000003650 (based on 2/91074 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.718, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A platelet binding assay in COS-7 cells expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function. In a direct binding assay, the ristocetin-induced binding of rvWF(G1324S) to platelets was markedly reduced compared with rvWF(wt). (PMID:1409710) (PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP1, PP3, PP4_moderate, PS4_moderate. (VCEP specifications version Pilot; date of approval). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114147/MONDO:0015630/081

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

8
6
2

Clinical Significance

Pathogenic reviewed by expert panel P:5O:1

Conservation

PhyloP100: 4.73

Publications

17 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 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.
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
VWFNM_000552.5 linkc.3970G>A p.Gly1324Ser missense_variant Exon 28 of 52 ENST00000261405.10 NP_000543.3
VWFXM_047429501.1 linkc.3970G>A p.Gly1324Ser missense_variant Exon 28 of 52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkc.3970G>A p.Gly1324Ser missense_variant Exon 28 of 52 1 NM_000552.5 ENSP00000261405.5
VWFENST00000538635.5 linkn.421-25514G>A intron_variant Intron 5 of 5 4
VWFENST00000539641.1 linkn.*80G>A downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000798
AC:
2
AN:
250604
AF XY:
0.00000737
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:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461572
Hom.:
0
Cov.:
38
AF XY:
0.00000413
AC XY:
3
AN XY:
727094
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53354
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111816
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
2
2
3
4
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:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41434
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
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:
0.00000474
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:2Other:1
Jul 25, 2024
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in the heterozgyous state in multiple patients with type 2M von Willebrand factor deficiency referred for genetic testing at GeneDx and in published literature, and thought to result in a mild clinical bleeding phenotype (PMID: 29341351, 1409710, 30084138); Published functional studies demonstrate a reduction of VWF activity (PMID: 1409710, 25185554, 29341351); Not observed at significant frequency in large population cohorts (gnomAD); Also known as G561S; This variant is associated with the following publications: (PMID: 25185554, 27761512, 37872709, 29341351, 1409710, 27889474, 34141704, 30084138, 35833249, 26677223, 22102201)

May 12, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The frequency of this variant in the general population, 0.000008 (2/250604 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 2B and Type 2M VWD (PMIDs: 29341351 (2018), 27761512 (2016), 25185554 (2014), 22102201 (2011), and 1409710 (1992)). Functional studies demonstrated that this variant is damaging to protein function (PMIDs: 29341351 (2018), 27761512 (2016), 25185554 (2014), and 1409710 (1992)). 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 likely pathogenic.

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

von Willebrand disease type 2M 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

The NM_000552.4(VWF):c.3970G>A (p.Gly1324Ser) variant is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 1324. At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of a normal multimer pattern, low VWF:RCo/VWF:Ag ratio, and a decreased GP1b binding assay, which together are highly specific for VWD type 2M (PP4_moderate, PMID: 30084138). The variant has been reported to segregate with VWD type 2M through 2 affected meioses from 1 family (PP1; PMID: 29341351). At least 3 additional VWD type 2M probands have been reported with this variant (PMIDs: 29341351, 22102201, 1409710; PS4_moderate). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000003650 (based on 2/91074 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.718, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A platelet binding assay in COS-7 cells expressing recombinant VWF showed decreased binding indicating that this variant has a damaging effect on protein function. In a direct binding assay, the ristocetin-induced binding of rvWF(G1324S) to platelets was markedly reduced compared with rvWF(wt). (PMID: 1409710) (PS3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2M based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PM2_supporting, PP1, PP3, PP4_moderate, PS4_moderate. (VCEP specifications version Pilot; date of approval).

von Willebrand disease type 2 Pathogenic:1
Apr 21, 2021
Genetics and Molecular Pathology, SA Pathology
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T
Eigen
Pathogenic
0.78
Eigen_PC
Uncertain
0.64
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.48
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
3.7
H
PhyloP100
4.7
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.7
N
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.0030
D
Vest4
0.93
ClinPred
0.96
D
GERP RS
5.0
Varity_R
0.47
gMVP
0.84
Mutation Taster
=10/90
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: rs61749398; hg19: chr12-6128614; API