NM_000552.5:c.3944G>T

Variant names:

• chr12-6019474-C-A
• rs61749396
• NM_000552.5:c.3944G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PM5_Supporting PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Arg1315Leu variant has a REVEL score of 0.854, which is above the VWD VCEP threshold of > 0.644 and therefore, the variant predicts a damaging effect on VWF function (PP3). There is at least one proband with excessive bleeding as well as low activity/VWF:Ag ratio, which together are specific for VWD type 2A (PMID:28971901). It should be noted that this variant has been associated with both VWD type 2A (PMID:16985174) as well as type 2M (PMID:22329792); therefore, it has been published in the literature as VWD type “2M/2A” as it has been demonstrated to exhibit characteristics of both type 2A and 2M (PMID:35452508). The variant is absent from gnomADv4, thus, meeting PM2_supporting criteria. The p.Arg1315His variant located in the same codon has been classified as likely pathogenic for VWD type 2M by the VWD VCEP (PM5_Supporting). Additional variants, p.Arg1315Gly and p.Arg1315Cys were found at the same codon but have not been curated by the VWD VCEP and therefore were not used in the assessment of PM5. Functional data, including simulation data is present for the variant but does not meet our specifications to be counted towards PS3. The p.Arg1315Leu variant has been reported in at least 3 additional probands meeting PP4 criteria (PS4_moderate). Taken together, the variant has been classified as likely pathogenic for VWD type 2 by the Von Willebrand Disease variant curation expert panel. PP3, PP4_moderate, PM2_suppporting, PM5_supporting, PS4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228506/MONDO:0013304/081

• 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: 6.99
• Publications: 5 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 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.3944G>T	p.Arg1315Leu	missense	Exon 28 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3944G>T	p.Arg1315Leu	missense	Exon 28 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-25540G>T		intron	N/A
	VWF	ENST00000539641.1	TSL:3	n.*54G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

von Willebrand disease type 2 Pathogenic:2

Apr 01, 2025

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Arg1315Leu variant has a REVEL score of 0.854, which is above the VWD VCEP threshold of > 0.644 and therefore, the variant predicts a damaging effect on VWF function (PP3). There is at least one proband with excessive bleeding as well as low activity/VWF:Ag ratio, which together are specific for VWD type 2A (PMID: 28971901). It should be noted that this variant has been associated with both VWD type 2A (PMID: 16985174) as well as type 2M (PMID: 22329792); therefore, it has been published in the literature as VWD type “2M/2A” as it has been demonstrated to exhibit characteristics of both type 2A and 2M (PMID: 35452508). The variant is absent from gnomADv4, thus, meeting PM2_supporting criteria. The p.Arg1315His variant located in the same codon has been classified as likely pathogenic for VWD type 2M by the VWD VCEP (PM5_Supporting). Additional variants, p.Arg1315Gly and p.Arg1315Cys were found at the same codon but have not been curated by the VWD VCEP and therefore were not used in the assessment of PM5. Functional data, including simulation data is present for the variant but does not meet our specifications to be counted towards PS3. The p.Arg1315Leu variant has been reported in at least 3 additional probands meeting PP4 criteria (PS4_moderate). Taken together, the variant has been classified as likely pathogenic for VWD type 2 by the Von Willebrand Disease variant curation expert panel. PP3, PP4_moderate, PM2_suppporting, PM5_supporting, PS4_moderate.

Apr 26, 2022

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.84		Gain of catalytic residue at E1320 (P = 2e-04)
MVP		0.92
MPC		1.0
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.93
Mutation Taster		=5/95	disease causing

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: rs61749396; hg19: chr12-6128640;