12-6019396-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS3PS4PP4_ModeratePM2_SupportingPP3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.4022G>A (p.Arg1341Gln) variant in VWF has been reported in several dozen vWD type 2B patients. At least one (P8 of PMID:20118404) has sufficient information reported to meet the PP4_moderate criteria, including mucocutaneous bleeding, positive GOF assay, and loss of HMW multimers. An additional four have been curated for inclusion based on at least a LD-RIPA response (PMIDs: 20118404, 8292729; PS4_strong). In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PS3). The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). This variant is predicted deleterious by REVEL gives a score of 0.792, which is above the ClinGen VWD VCEP threshold of >0.644 (PP3). This variant has been observed segregating in multiple families, however insufficient phenotypic information has been reported on those individuals. In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114129/MONDO:0015629/081

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

8

8

3

Clinical Significance

Pathogenic reviewed by expert panel P:6U:1O:2

Conservation

PhyloP100: 1.87

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 12 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.4022G>A	p.Arg1341Gln	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4022G>A	p.Arg1341Gln	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.4022G>A	p.Arg1341Gln	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-25462G>A		intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1 link	n.*132G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.00000399

AC:

1

AN:

250664

Hom.:

0

AF XY:

0.00000737

AC XY:

1

AN XY:

135606

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

2

AN:

1461630

Hom.:

0

Cov.:

38

AF XY:

0.00000138

AC XY:

1

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Feb 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.4022G>A; p.Arg1341Gln variant (rs61749403), also known as Arg578Gln in the mature protein nomenclature, is reported in the literature in multiple individuals and families affected with von Willebrand disease (vWD) Type 2B (Ahmad 2014, Caron 2006, Cooney 1991, Federici 2009, Freitas 2019, Goodeve 2009, Nurden 2010, Piao 1993, Sadler 2022). This variant is reported in ClinVar (Variation ID: 291). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, at least one other variant at this codon (c.4021C>T; p.Arg1341Trp) has been reported in individuals with von Willebrand disease (vWD) Type 2B and is considered pathogenic (Casana 1998, Casonato 2015, Casonato 2016, Casonato 2017, Federici 2009, Nurden 2010, Sadler 2022, Vangenechten 2019). Functional analyses of the variant protein show increased shear-induced platelet aggregation and increased ristocetin and botrocetin induced binding to platelets compared to the wild type protein (Ajzenberg 2000), and reduced protein stability and multimer formation (Federici 2009, Nurden 2010, Tischer 2014). Computational analyses predict that this variant is deleterious (REVEL: 0.792). Based on available information, this variant is considered to be pathogenic. References: Ahmad F et al. Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease. Haemophilia. 2014 Jul;20(4):e311-7. PMID: 24712919. Ajzenberg N et al. Effect of recombinant von Willebrand factor reproducing type 2B or type 2M mutations on shear-induced platelet aggregation. Blood. 2000 Jun 15;95(12):3796-803. PMID: 10845912. Caron C et al. Measurement of von Willebrand factor binding to a recombinant fragment of glycoprotein Ibalpha in an enzyme-linked immunosorbent assay-based method: performances in patients with type 2B von Willebrand disease. Br J Haematol. 2006 Jun;133(6):655-63. PMID: 16704443. Casana P et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol. 1998 Sep;59(1):57-63. PMID: 9723578. Casonato A et al. Higher and lower active circulating VWF levels: different facets of von Willebrand disease. Br J Haematol. 2015 Dec;171(5):845-53. PMID: 26456374. Casonato A et al. Diagnostic Value of Measuring Platelet Von Willebrand Factor in Von Willebrand Disease. PLoS One. 2016 Aug 17;11(8):e0161310. PMID: 27532107. Casonato A et al. Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. PLoS One. 2017 Jun 22;12(6):e0179566. PMID: 28640903. Cooney KA et al. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest. 1991 Apr;87(4):1227-33. PMID: 1672694. Federici AB et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood. 2009 Jan 15;113(3):526-34. PMID: 18805962. Freitas SDS et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia. 2019 Mar;25(2):e78-e85. PMID: 30817071. Goodeve A et al. von Willebrand Disease. 2009 Jun 4 [Updated 2017 Oct 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsÂ® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7014/ Nurden P et al. Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B. Blood. 2010 Apr 1;115(13):2649-56. PMID: 20118404. Piao YC et al. Arg578Gln mutations in the von Willebrand factor gene in three unrelated cases of type IIB von Willebrand disease. Blood Coagul Fibrinolysis. 1993 Oct;4(5):787-9. PMID: 8292729. Sadl -

-

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM1_supporting, PM5, PS3, PS4_moderate -

Von Willebrand disease type 2B

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_000552.5(VWF):c.4022G>A (p.Arg1341Gln) variant in VWF has been reported in several dozen vWD type 2B patients. At least one (P8 of PMID: 20118404) has sufficient information reported to meet the PP4_moderate criteria, including mucocutaneous bleeding, positive GOF assay, and loss of HMW multimers. An additional four have been curated for inclusion based on at least a LD-RIPA response (PMIDs: 20118404, 8292729; PS4_strong). In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PS3). The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). This variant is predicted deleterious by REVEL gives a score of 0.792, which is above the ClinGen VWD VCEP threshold of >0.644 (PP3). This variant has been observed segregating in multiple families, however insufficient phenotypic information has been reported on those individuals. In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PP3, and PP4_moderate. -

von Willebrand disease type 2

Pathogenic:1Uncertain:1

Apr 26, 2022

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

VWF-related disorder

Pathogenic:1

Jun 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.4022G>A variant is predicted to result in the amino acid substitution p.Arg1341Gln. Using legacy nomenclature, this variant has also been referred to in the literature as p.Arg578Gln. This variant has been reported in the heterozygous state in individuals with Von Willebrand disease 2b (Patient B6 in Cooney et al. 1991. PubMed ID: 1672694; Patient 310 in Ahmad et al. 2014. PubMed ID: 24712919; Patient 28 in Supplementary Table 2 in Freitas et al. 2019. PubMed ID: 30817071; Supplemental File 3 in Sadler et al. 2021. PubMed ID: 33556167). A functional study showed that this variant led to increased platelet aggregation under conditions of sheer flow compared to wildtype (Ajzenberg et al. 2000. PubMed ID: 10845912). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6128562-C-T). Another variant impacting the same amino acid (p.Arg1341Trp) has also been documented in patients with Von Willebrand disease 2b (Casana et al. 1998. PubMed ID: 9723578). Based on this evidence, we interpret the c.4022G>A (p.Arg1341Gln) variant as pathogenic. -

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

0.16

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

28

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.84

D

LIST_S2

Uncertain

0.95

D

M_CAP

Pathogenic

0.60

D

MetaRNN

Pathogenic

0.96

D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.0

M

PrimateAI

Uncertain

0.56

T

PROVEAN

Benign

-1.5

N

REVEL

Pathogenic

0.79

Sift

Uncertain

0.017

D

Sift4G

Uncertain

0.015

D

Polyphen

1.0

D

Vest4

0.80

MutPred

0.78

Gain of helix (P = 0.0325);

MVP

0.85

MPC

0.92

ClinPred

0.89

D

GERP RS

5.0

Varity_R

0.58

gMVP

0.71

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: rs61749403; hg19: chr12-6128562;