rs267607326

Positions:

• chr12-6022841-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PP4 PM2_Supporting PS3 PS4

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 criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.87

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3437A>G	p.Tyr1146Cys	missense_variant	26/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3437A>G	p.Tyr1146Cys	missense_variant	26/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3437A>G	p.Tyr1146Cys	missense_variant	26/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-28907A>G		intron_variant, non_coding_transcript_variant		4

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

Gnomad4 AFR exome AF: 0.0000814

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

von Willebrand disease type 2 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	Dec 10, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2010	- -

Hereditary von Willebrand disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2022	Variant summary: VWF c.3437A>G (p.Tyr1146Cys) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 54460 control chromosomes. c.3437A>G has been reported in the literature in multiple individuals affected with Type I and Type II Von Willebrand Disease (example, Goodeve_2007, Castaman_2008, James_2007, Schneppenheim_2010, Manderstedt_2018, Fidalgo_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in inhibition of normal processing, string formation and platelet binding (Brehm_2014), defective intracellular packaging and markedly reduced VWF secretion. Loss of HMW Multimers. Demonstrated a novel FVIII binding defect (White-Adams_2016) and reduced expression (Schneppenheim_2010). One clinical diagnostic laboratory and the NIHR Bioresource Rare Diseases have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 25, 2020

The variant has been reported as a relatively common variant in Type 2A vWD and some Type 1 vWD patients the published literature (PMID: 16985174 (2007), 17190853 (2007), 20351307 (2010), 22871923 (2012), 26986123 (2016), 26988807 (2016), 29388750 (2018), 29742318 (2018), 31249928 (2018), 31064749 (2019)). Functional studies showed that this variant caused defective intracellular packaging, reduced VWF secretion, and a FVIII binding defect as well as loss of large multimers and decreased proteolysis (PMID: 18230755 (2008), 20351307 (2010), 24598842 (2014), 27533707 (2016)). Therefore, the variant is classified as pathogenic. -

von Willebrand disease type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Dec 10, 2020

- -

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

-

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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: rs267607326; hg19: chr12-6132007;