rs61748511

Variant names:

• chr12-6022833-A-G
• rs61748511
• NM_000552.5:c.3445T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS3 PS4 PP4_Moderate PP1_Moderate PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.3445T>C variant in VWF is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 1149 in the D3 (multimerization) domain. This variant has been reported in at least 8 apparently unrelated families exhibiting a VWD Type 2A phenotype (PMID:19286880, PMID:8839833, PMID:28971901, PS4). At least 7 patients with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:RCo, activity/VWF:Ag ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A (PP4_moderate, PMID:19286880, PMID:28971901). The variant has been reported to segregate with VWD type 2A through at least 2 affected meioses from 3 different families (PP1_Moderate; PMID:8839833, PMID:19286880, PMID:28971901). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/316464 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Multimerization assays performed with the p.Cys1149Arg recombinant mutant and wild-type vWF expressed by 293T cells showed an overall decrease in secreted multimers, with particular loss of high-molecular weight multimers), indicating that this variant has a damaging effect on protein function (PMID:839833 Fig. 3, PMID:14995987)(PS3). Additional functional characterization studies have found that the variant protein exhibits characteristics of a quantitative VWF defect as well, as it is retained in the endoplasmic reticulum, exerts a partially dominant negative effect on VWF secretion, and is more rapidly cleared from circulation (PMID:11698279, PMID:8839833, PMID:21596755, PMID:16194200). 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: PS4, PP4_Moderate, PP1_Moderate, PS3, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228410/MONDO:0015628/081

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 8.94

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.3445T>C	p.Cys1149Arg	missense_variant	Exon 26 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3445T>C	p.Cys1149Arg	missense_variant	Exon 26 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3445T>C	p.Cys1149Arg	missense_variant	Exon 26 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-28899T>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome AF: 0.00000226 AC: 1 AN: 442410 Hom.: 0 Cov.: 1 AF XY: 0.00 AC XY: 0 AN XY: 233808

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000375

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

von Willebrand disease type 1 Pathogenic:2

Nov 15, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 01, 2021

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

von Willebrand disease type 2 Pathogenic:1

Oct 01, 2021

Laboratory of Hematology, Radboud University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Von Willebrand disease type 2A Pathogenic:1

Jul 09, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000552.5(VWF):c.3445T>C variant in VWF is a missense variant predicted to cause substitution of cysteine by arginine at amino acid 1149 in the D3 (multimerization) domain. This variant has been reported in at least 8 apparently unrelated families exhibiting a VWD Type 2A phenotype (PMID: 19286880, PMID: 8839833, PMID: 28971901, PS4). At least 7 patients with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity measured by VWF:RCo, activity/VWF:Ag ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A (PP4_moderate, PMID: 19286880, PMID: 28971901). The variant has been reported to segregate with VWD type 2A through at least 2 affected meioses from 3 different families (PP1_Moderate; PMID: 8839833, PMID: 19286880, PMID: 28971901). The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/316464 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.971, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). Multimerization assays performed with the p.Cys1149Arg recombinant mutant and wild-type vWF expressed by 293T cells showed an overall decrease in secreted multimers, with particular loss of high-molecular weight multimers), indicating that this variant has a damaging effect on protein function (PMID: 839833 Fig. 3, PMID: 14995987)(PS3). Additional functional characterization studies have found that the variant protein exhibits characteristics of a quantitative VWF defect as well, as it is retained in the endoplasmic reticulum, exerts a partially dominant negative effect on VWF secretion, and is more rapidly cleared from circulation (PMID: 11698279, PMID: 8839833, PMID: 21596755, PMID: 16194200). 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: PS4, PP4_Moderate, PP1_Moderate, PS3, PP3, PM2_Supporting. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.90		Gain of catalytic residue at C1149 (P = 5e-04);
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		1.0
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs61748511; hg19: chr12-6131999;