rs41276738

Variant names:

• chr12-6034812-C-T
• rs41276738
• NM_000552.5:c.2561G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4_Moderate PP1 PM3_Strong PS3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.2561G>A variant in VWF is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 854. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.005857 (based on 7050/1180026 alleles, with 24 homozygotes) in the European non-Finnish population. This allele frequency is above the ClinGen VWD VCEP threshold for VWD Type 2N (<0.005) for PM2_Supporting but below the threshold (>0.01) for BS1 and therefore does not meet any population criterion. At least 9 patients with this variant displayed excessive mucocutaneous bleeding, low FVIII activity, and decreased VWF:FVIII binding, which is highly specific for VWD type 2N (PP4_Moderate, PMID:28971901, PMID:22875612). Four individuals were homozygous for the variant (PMID:28971901, PMID:22875612, PMID:1832934) and one of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Arg816Trp) confirmed in trans (PMID:1832934), additional compound heterozygotes have been reported but were not considered here (PM3_Strong). In one family, the variant segregated with VWD type 2N in the proband and a second affected family member (PP1; PMID:28971901). A hydrodynamic mouse model showed reduced factor VIII stability and impaired binding of factor VIII to VWF, indicating that this variant has a damaging effect on protein function (PMID:28581694)(PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3, PM3_Strong, PP4_Moderate, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114139/MONDO:0015631/090

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (23 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:49 U:1 O:2
• Conservation: PhyloP100: 7.13
• Publications: 85 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.2561G>A	p.Arg854Gln	missense	Exon 20 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.2561G>A	p.Arg854Gln	missense	Exon 20 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2561G>A	p.Arg854Gln	missense	Exon 21 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2561G>A	p.Arg854Gln	missense	Exon 20 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00605

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00340 AC: 856 AN: 251418 AF XY: 0.00353

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00508 AC: 7432 AN: 1461860 Hom.: 23 Cov.: 31 AF XY: 0.00505 AC XY: 3672 AN XY: 727228

African (AFR) AF: 0.00108 AC: 36 AN: 33478

American (AMR) AF: 0.00233 AC: 104 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86254

European-Finnish (FIN) AF: 0.00543 AC: 290 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00597 AC: 6638 AN: 1111988

Other (OTH) AF: 0.00445 AC: 269 AN: 60396

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74492

African (AFR) AF: 0.000914 AC: 38 AN: 41592

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00606 AC: 412 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00492 Hom.: 8

Bravo AF: 0.00351

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00569

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
18	-	-	not provided (19)
10	1	-	von Willebrand disease type 2 (11)
7	-	-	von Willebrand disease type 1 (7)
4	-	-	von Willebrand disease type 2N (4)
3	-	-	Hereditary von Willebrand disease (4)
2	-	-	von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (2)
1	-	-	Abnormality of coagulation (1)
1	-	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)
1	-	-	von Willebrand disease type 3 (1)
1	-	-	von Willebrand disorder (1)
1	-	-	VWF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.49
Sift	Benign	0.062	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.88
MPC		0.72
ClinPred		0.032	T
GERP RS		5.6
Varity_R		0.51
gMVP		0.63
Mutation Taster		=56/44	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41276738; hg19: chr12-6143978; COSMIC: COSV99075179;