12-6019472-C-T

Variant names:

• chr12-6019472-C-T
• rs61749397
• NM_000552.5:c.3946G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS2_Moderate PS3 PS4 PP4_Moderate PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.3946G>A variant in VWF is a missense variant predicted to cause substitution of valine by methionine at amino acid 1316. This variant is absent from gnomADv4.1 (PM2_Supporting). This variant has been reported in at least 9 probands showing excessive mucocutaneous bleeding as well as a laboratory phenotype of loss of high molecular weight multimers and/or enhanced platelet aggregation at low doses of ristocetin (PS4_VeryStrong, PMID:19060241, PMID:27885890, PMID:28640903). At least 1 patient showed excessive mucocutaneous bleeding, loss of high molecular weight multimers, and enhanced platelet aggregation at low doses of ristocetin, which together are specific for VWD type 2B, along with consistent features of thrombocytopenia and low VWF antigen/activity ratio (PP4_Moderate, PMID:28640903). Two additional affected patients harbored the variant in an apparent de novo heterozygous state (PS2_Moderate, PMID:7909449, PMID:2010538). The variant has been reported to segregate with VWD type 2B through 3 affected meioses from 1 family (PP1; PMID:19060241). The computational predictor REVEL gives a score of 0.74, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). A knock-in mouse model expressing VWF p.Val1316Met has shown prolonged bleeding time, absence of high-MW multimers, large platelet aggregates, decreased in vitro platelet adhesion to thrombin or collagen, and enhanced in vivo VWF/platelet string formation, indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID:27212476, PS3). 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: PS3, PS4_VeryStrong, PP4_Moderate, PS2_Moderate, PP1, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114127/MONDO:0015629/081

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:2
• Conservation: PhyloP100: 5.25
• Publications: 74 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 15 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.3946G>A	p.Val1316Met	missense	Exon 28 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3946G>A	p.Val1316Met	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3946G>A	p.Val1316Met	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9870G>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000160 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (5)
3	-	-	Hereditary von Willebrand disease (4)
3	-	-	von Willebrand disease type 2 (3)
3	-	-	Von Willebrand disease type 2B (3)
1	-	-	von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.75		Gain of catalytic residue at V1316 (P = 0)
MVP		0.87
MPC		0.93
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.29
gMVP		0.85
Mutation Taster		=51/49	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: rs61749397; hg19: chr12-6128638;