12-6019501-C-T

Position:

chr12-6019501-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_000552.5(VWF):c.3917G>A(p.Arg1306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1306L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3O:1

Conservation

PhyloP100: 1.22

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 11 ACMG points.

PM1

In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000552.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-6019501-C-A is described in Lovd as [Likely_pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 12-6019501-C-T is Pathogenic according to our data. Variant chr12-6019501-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100300.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6019501-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.3917G>A	p.Arg1306Gln	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.3917G>A	p.Arg1306Gln	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.3917G>A	p.Arg1306Gln	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25567G>A		intron_variant, non_coding_transcript_variant		4
VWF	ENST00000539641.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727134

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with type 2B von Willebrand disease (VWD) (PMIDs: 9198195 (1997), 9858249 (1998), 17598021 (2007), 28971901 (2017)). This variant is located in the glycoprotein Ib (GPIb)-binding site of VWF, and has been shown to allow normal VWF multimerization but cause abnormal increased affinity of plasma VWF for platelets (PMIDs: 9108394 (1997), 9858249 (1998), 20200350 (2010)). Based on the available information, this variant is classified as pathogenic. -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -

von Willebrand disease type 2

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Apr 26, 2022

- -

VWF-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2024

The VWF c.3917G>A variant is predicted to result in the amino acid substitution p.Arg1306Gln. This variant (aka p.Arg543Gln) has been reported in multiple individuals with von Willebrand disease (VWD) type 2B (Hilbert et al. 1998. PubMed ID: 9858249; Szántó et al. 2007. PubMed ID: 17598021; Borràs et al. 2017. PubMed ID: 28971901. Table S7; Sadler et al. 2021. PubMed ID: 33556167. Table S3). In vitro and in vivo functional studies have demonstrated that this variant increases VWF binding affinity toward platelet-bound glycoprotein 1b-alpha (GP1Ba), leading to platelet aggregation (Yago et al. 2008. PubMed ID: 18725999; Rayes et al. 2010. PubMed ID: 20200350; Tischer et al. 2014. PubMed ID: 25185554). Additional studies using an in vivo mouse model found that this variant also increases VWF binding affinity toward macrophage-bound LRP1, leading to increased clearance of mutant VWF from circulation (Wohner et al. 2015. PubMed ID: 25728415). This variant has not been reported in a large population database, indicating this variant is rare. Of note, a different missense variant at the same amino acid position (p.Arg1306Trp) is one of the most commonly reported disease-causing variants in patients with VWD type 2B (for example, see Ozeki et al. 2010. PubMed ID: 19740526; Borràs et al. 2017. PubMed ID: 28971901; Sadler et al. 2021. PubMed ID: 33556167). Taken together, the p.Arg1306Gln variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.51

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.72

Sift

Uncertain

0.014

Sift4G

Uncertain

0.012

Polyphen

0.98

Vest4

0.77

MutPred

0.76

Gain of catalytic residue at R1306 (P = 0.0024);

MVP

0.74

MPC

0.96

ClinPred

0.85

GERP RS

4.1

Varity_R

0.51

gMVP

0.69

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over