rs121964894

Positions:

chr12-6036488-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS3PM3PP1_ModeratePP4_ModeratePM2_SupportingPP3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5:c.2446C>T variant in VWF is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 816. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.00009000 (based on 10/59984 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.005 (PM2_Supporting). At least 8 patients with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (1.3% or 9.8%) and decreased VWF:FVIII binding (0.00 to 0.1), which is highly specific for VWD type 2N (PMID:28536718, PMID:1832934, PMID:28971901), (PP4_Moderate). Five individuals were homozygous for the variant (PM3) and three were compound heterozygous (PMID:28536718, PMID:28971901, PMID:1832934). The variant has been reported to segregate with VWD type 2N in a proband plus two affected family members (PP1_moderate; PMID:1832934). A hydrodynamic mouse model showed prolonged bleeding time, 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). The computational predictor REVEL gives a score of 0.756, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). 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: PM3, PP1_Moderate, PP3, PP4_Moderate, PS3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114137/MONDO:0015631/090

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

8

9

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:2

Conservation

PhyloP100: 5.16

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

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.

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 linkuse as main transcript	c.2446C>T	p.Arg816Trp	missense_variant	19/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.2446C>T	p.Arg816Trp	missense_variant	19/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.2446C>T	p.Arg816Trp	missense_variant	19/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-42554C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

6

AN:

152154

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

16

AN:

251368

Hom.:

0

AF XY:

0.0000515

AC XY:

7

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

26

AN:

1461776

Hom.:

0

Cov.:

33

AF XY:

0.00000825

AC XY:

6

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

6

AN:

152154

Hom.:

0

Cov.:

33

AF XY:

0.0000404

AC XY:

3

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

0

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

0

ALSPAC

AF:

0.000259

AC:

1

ExAC

AF:

0.0000247

AC:

3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2023	Published functional studies demonstrate a damaging effect, including greatly decreased FVIIIB binding (van den Biggelaar et al., 2009; Qin et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also reported as R53W due to the use of alternative nomenclature; This variant is associated with the following publications: (PMID: 34708896, 26210168, 18728373, 1832934, 7847341, 28971901, 26988807, 21534937, 19088379, 31589614, 24351655) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2023	- -

Hereditary von Willebrand disease

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2019	The p.Arg816Trp variant in VWF has been reported in 6 homozygous, 4 compound heterozygous, and 2 heterozygous (only 1 allele identified) individuals with von Willebrand disease (VWD) and segregated with disease in at least 2 affected individuals from 1 family (Gaucher 1991, Johansson 2011, Qin 2014, Argyris 2016, Fidalgo 2016, Borras 2017). It has also been identified in 9/35418 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Qin 2004). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VWD. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting. -

von Willebrand disease type 2N

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.19

D

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

D

LIST_S2

Uncertain

0.91

D

M_CAP

Pathogenic

0.38

D

MetaRNN

Pathogenic

0.94

D

MetaSVM

Uncertain

0.39

D

MutationAssessor

Uncertain

2.6

M

MutationTaster

Benign

1.0

A

PrimateAI

Uncertain

0.62

T

PROVEAN

Uncertain

-4.4

D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.93

MutPred

0.59

Gain of catalytic residue at P811 (P = 0);

MVP

0.73

MPC

0.73

ClinPred

0.76

D

GERP RS

5.0

Varity_R

0.58

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121964894; hg19: chr12-6145654;