rs267607326

Variant names:

• chr12-6022841-T-C
• rs267607326
• NM_000552.5:c.3437A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PS4 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.3437A>G (p.Tyr1146Cys) missense variant has been reported in at least 22 VWD type 2A patients. The Grpmax filtering allele frequency in gnomAD v4.1 is 0 (based on 1/37812 alleles in the African/African-American population), which is lower than the ClinGen VWD VCEP threshold of<0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.872, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of low VWF activity (VWF:RCo 16, VWF:CB 7) and VWF:Ag of 20 for a low VWF:CB activity/VWF:Ag ratio of 0.35, which is specific for VWD type 2A. (PP4; PMID:24598842). Eight additional VWD 2A patients, with confirmatory lab values including very low VWF:RCo, low VWF:GPIb, and or low VWF activity/ VWF:Ag ratio, have been reported (PMIDs: 22871923, 16985174, 35452508, 20351307; PS4_VeryStrong). Multimer analysis in 293 cells expressing recombinant variant VWF showed reduced high molecular weight multimers indicating that this variant has a damaging effect on protein function (PMID:20351307 Figure 3, PMID:27533707 Figure 2; PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant VWD type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_VeryStrong, PS3, PM2_supporting, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228408/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:8 O:1
• Conservation: PhyloP100: 3.87
• Publications: 7 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: Pathogenic. The variant received 11 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.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.3437A>G	p.Tyr1146Cys	missense	Exon 26 of 52	NP_000543.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3437A>G	p.Tyr1146Cys	missense	Exon 26 of 52	ENSP00000261405.5
	VWF	ENST00000895679.1		c.3437A>G	p.Tyr1146Cys	missense	Exon 27 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+6501A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome AF: 0.00000227 AC: 1 AN: 440372 Hom.: 0 Cov.: 1 AF XY: 0.00 AC XY: 0 AN XY: 232952

African (AFR) AF: 0.0000814 AC: 1 AN: 12290

American (AMR) AF: 0.00 AC: 0 AN: 19324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13530

East Asian (EAS) AF: 0.00 AC: 0 AN: 29802

South Asian (SAS) AF: 0.00 AC: 0 AN: 45314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1922

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 265316

Other (OTH) AF: 0.00 AC: 0 AN: 25430

GnomAD4 genome Cov.: 12

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	von Willebrand disease type 2 (3)
2	-	-	Hereditary von Willebrand disease (2)
1	-	-	not specified (1)
1	-	-	von Willebrand disease type 1 (1)
1	-	-	Von Willebrand disease type 2A (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		3.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.83		Gain of catalytic residue at E1143 (P = 0.0192)
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.95
Mutation Taster		=5/95	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: rs267607326; hg19: chr12-6132007;