NM_000552.5:c.3922C>T

Variant names:

• chr12-6019496-G-A
• rs61749387
• NM_000552.5:c.3922C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PS4 PS2_Supporting PP4_Moderate PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys) missense variant is predicted to cause substitution of arginine by cysteine at amino acid 1308. This variant has been reported in at least 30 probands, of which at least 19 reported sufficient phenotypic information to confirm type 2B VWD. (PS4; PMIDs: 18805962, 22077376, 1419803, 2010538, 16246252). Patient 9 of PMID:2010538, has sufficient information to meet PP4_moerate: lacked HMWM in plasma and had a moderately heightened RIPA (0.6–0.7), as well as low VWF:RCo/VWF:Ag ratio (<0.45), with Platelet-type VWD excluded by mixing experiments to confirm that the defect was in the patient plasma and not in the patient platelets. The variant has been reported to segregate with VWD type 2B through at least 2 affected meioses from 1 family (PP1; PMID:2010538). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VWD type 2B (PPS2_supporting; PMID:2010538). This variant is absent from gnomAD v4.1 (PM2_Supporting). GP1bα binding assay in COS-7 cells expressing recombinant VWF, variant alone or together with WT, showed increased binding at low doses of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID:16246252) (PS3). Similar results have been reported in multiple studies (PMIDs: 26345337, 8630394). The computational predictor REVEL gives a score of 0.673, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant VWD type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3_supporting, PS4_VeryStrong, PM2_supporting, PS2_supporting, PP1, PP3, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114125/MONDO:0015629/081

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:1
• Conservation: PhyloP100: 6.15
• Publications: 38 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 14 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.3922C>T	p.Arg1308Cys	missense	Exon 28 of 52	NP_000543.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3922C>T	p.Arg1308Cys	missense	Exon 28 of 52	ENSP00000261405.5
	VWF	ENST00000895679.1		c.3922C>T	p.Arg1308Cys	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9846C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.4	L
PhyloP100		6.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.1	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.81		Loss of MoRF binding (P = 0.0038)
MVP		0.90
MPC		0.51
ClinPred		0.72	D
GERP RS		4.1
Varity_R		0.32
gMVP		0.80
Mutation Taster		=22/78	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: rs61749387; hg19: chr12-6128662;