rs61754010

Variant names:

• chr12-6057995-T-C
• rs61754010
• NM_000552.5:c.1583A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM3 PS3 PP4_Moderate PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.1583A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 528. This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant has been reported homozygous in two homozygous (PM3) probands meeting the VWD type 2A phenotypic criteria (PP4_moderate, PS4_suporting; PMID:20335223; 9714529). The variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID:20335223). There is evidence of defective VWF storage with no response to desmopressin and very little VWF:Ag released after administration. Expression in 293 EBNA cells showed that homozygous N528S-VWF secretion was 7.5% of WT, with a multimer pattern lacking medium and HMWMs (PMID:20335223 Fig. 4; PS3). Expression in AtT-20 cells showed that the N528S-VWF is not multimerized and is not trafficked to storage granules. In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PP1, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114178/MONDO:0015628/081

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 7.46
• Publications: 14 publications found

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

ACMG classification

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.
• PP1: 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	c.1583A>G	p.Asn528Ser	missense_variant	Exon 14 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1583A>G	p.Asn528Ser	missense_variant	Exon 14 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1583A>G	p.Asn528Ser	missense_variant	Exon 14 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+52520A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250246 AF XY: 0.00

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Von Willebrand disease type 2A 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.1583A>G variant in VWF is a missense variant predicted to cause substitution of asparagine by serine at amino acid 528. This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant has been reported homozygous in two homozygous (PM3) probands meeting the VWD type 2A phenotypic criteria (PP4_moderate, PS4_suporting; PMID: 20335223; 9714529). The variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed in one family (PP1; PMID: 20335223). There is evidence of defective VWF storage with no response to desmopressin and very little VWF:Ag released after administration. Expression in 293 EBNA cells showed that homozygous N528S-VWF secretion was 7.5% of WT, with a multimer pattern lacking medium and HMWMs (PMID: 20335223 Fig. 4; PS3). Expression in AtT-20 cells showed that the N528S-VWF is not multimerized and is not trafficked to storage granules. In summary, this variant meets the criteria to be classified as pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP4_moderate, PM3, PP1, PS3. -

Jun 03, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

von Willebrand disease type 2 Pathogenic:1

Apr 26, 2022

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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	Benign	0.22
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.5
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.63		Gain of catalytic residue at N528 (P = 0);
MVP		0.89
MPC		0.65
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.79
gMVP		0.91
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61754010; hg19: chr12-6167161;