NM_000552.5:c.3939G>C

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: Likely pathogenic reviewed by expert panel P:2 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 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: 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.

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.3939G>C	p.Trp1313Cys	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.3939G>C	p.Trp1313Cys	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3939G>C	p.Trp1313Cys	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9863G>C		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely 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	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;