rs61749392

Variant names:

• chr12-6019479-C-G
• rs61749392
• NM_000552.5:c.3939G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PP4_Moderate PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Trp1313Cys variant has a REVEL score of 0.629, which is below the VWD VCEP threshold of > 0.644 and therefore, the variant does not predict a damaging effect on VWF function. The variant is absent from gnomADv4, thus, meeting PM2_Supporting criteria. There is at least one proband with the variant exhibiting a risk of excessive bleeding, RIPA assay showing GOF, and a loss of HMWM which is consistent with VWD type 2B (PP4_Moderate). This patient is also a carrier for the p.Val1565Leu variant (PMID:35772170) which has been classified as Benign by the VWD VCEP. "Genotyping previously confirmed the diagnosis in each patient with type 2B VWD" (PMID:35772170). Functional data demonstrated that mammalian CHO-K1 cells transfected with mutant plasmid (p.W1313C) exhibited a 10-fold affinity to GPIb in the presence of ristocetin compared to wildtype cells (PMID:2011604) (PS3). This variant has been reported in at least 1 additional proband meeting PP4 laboratory phenotype criteria (PS4_supporting); PMIDs: 31939074. Taken together, the variant has been classified as likely pathogenic for VWD type 2B by the Von Willebrand Disease variant curation expert panel. PP4_Moderate, PM2_Supporting, PS3, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114121/MONDO:0015629/081

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.152
• Publications: 4 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: Likely_pathogenic. The variant received 8 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.
• 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.3939G>C	p.Trp1313Cys	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3939G>C	p.Trp1313Cys	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	c.3939G>C	p.Trp1313Cys	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-25545G>C		intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1	n.*49G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Von Willebrand disease type 2B Pathogenic:1

May 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.15
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.6	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.29
MutPred		0.77		Loss of MoRF binding (P = 0.0201);
MVP		0.85
MPC		0.70
ClinPred		0.49	T
GERP RS		-8.2
Varity_R		0.21
gMVP		0.80
Mutation Taster		=65/35	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

Other links and lift over

dbSNP: rs61749392; hg19: chr12-6128645;