12-6019478-C-G

Variant names:

• chr12-6019478-C-G
• rs61749393
• NM_000552.5:c.3940G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS2_Moderate PS3 PS4_Moderate PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.3940G>C (p.Val1314Leu) missense variant has been reported in at least 3 probands with VWD 2B phenotypes (PS4_moderate; PMIDs: 1419803, 27215777, ISTH 2015 Congress Poster). At least one proband displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and an increased response to LD-RIPA showing gain of function, which together are highly specific for VWD type 2B (PP4_moderate; PMID:1419803). The variant was identified as a de novo occurrence in this patient (PS2_Moderate; PMIDs: 1419803). This variant is absent from gnomAD v4.1 (PM2_Supporting). A Platelet binding assay performed with the Val1314Leu recombinant mutant vWF expressed by COS-7 showed increased binding in the absence of, or at low doses, of ristocetin, indicating that this variant has a gain of function effect on the protein (PMID:8630394; PS3). In summary, the variant meets the criteria to be classified as Likely Pathogenic for von Willebrand disease type 2B based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS3, PS4_moderate, PS2_Moderate, PP4_moderate, and PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114151/MONDO:0015629/081

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 4.20
• Publications: 1 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: 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 11 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.
• 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.3940G>C	p.Val1314Leu	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.3940G>C	p.Val1314Leu	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3940G>C	p.Val1314Leu	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9864G>C		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
2	-	-	Von Willebrand disease type 2B (2)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.60
Sift	Benign	0.034	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0060	B
Vest4		0.22
MutPred		0.80		Loss of sheet (P = 0.0457)
MVP		0.76
MPC		0.27
ClinPred		0.29	T
GERP RS		3.8
Varity_R		0.25
gMVP		0.66
Mutation Taster		=31/69	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: rs61749393; hg19: chr12-6128644;