rs61749384
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000552.5(VWF):c.3916C>T(p.Arg1306Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1306L) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
VWF
NM_000552.5 missense
NM_000552.5 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 3.74
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain 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 ClinVar as [Pathogenic]. Clinvar id is 100301.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, VWF
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
?
Variant 12-6019502-G-A is Pathogenic according to our data. Variant chr12-6019502-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019502-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-6019502-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.3916C>T | p.Arg1306Trp | missense_variant | 28/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.3916C>T | p.Arg1306Trp | missense_variant | 28/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.3916C>T | p.Arg1306Trp | missense_variant | 28/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-25568C>T | intron_variant, non_coding_transcript_variant | 4 | |||||
VWF | ENST00000539641.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 38
GnomAD4 exome
Cov.:
38
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
von Willebrand disease type 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 07, 2022 | The VWF c.3916C>T variant is classified as Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PM5, PP1_Strong) - |
Pathogenic, no assertion criteria provided | clinical testing | Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Apr 26, 2022 | - - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 13, 2023 | 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 affected individuals with Type 2B von Willebrand disease (vWD) (PMIDs: 1672694 (1991), 2010538 (1991), 27029718 (2016), and 31464689 (2019)), causing increased affinity of vWF with platelets (PMID: 15041272 (2003)), the selective loss of high molecular-weight vWF multimers (PMID: 1557393 (1992), and often thrombocytopenia (PMID: 19740526 (2010)). This variant has been reported to occur de novo (PMIDs: 9723578 (1998) and 1419803 (1992)), to segregate with vWD (PMIDs: 19740526 (2010) and 22077376 (2012)), and has been observed in a clinically healthy carrier (PMIDs: 1419803 (1992) and 19740526 (2010)). An in vitro study demonstrated that this variant has increased affinity for platelet receptor glycoprotein than wild type, a higher sensitivity to shear stress which facilitated self-aggregation, and exposure of platelet receptor glycoprotein binding sites (PMID: 23819767 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. 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 | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2017 | The VWF c.3916C>T, p.Arg1306Trp variant (also known as Arg534Trp) is reported in the medical literature in multiple families affected by von Willebrand disease type IIB (Cooney 1991, Lillicrap 1991, Pietu 1991, Randi 1991, Donner 1992, Casana 1998, Ozeki 2010) and co-segregates with affected family members (Lillicrap 1991, Donner 1992, Casana 1998). Functional characterization of the p.Arg1306Trp protein indicates a greater sensitivity to shear stress, leading to a reduction of high molecular weight multimers in plasma (Scaglione 2013). The variant is listed in the ClinVar database (Variation ID:288) and the dbSNP variant database (rs61749384), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at residue 1306 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on protein structure or function. Based on the above information, the variant is classified as pathogenic. References: Casana P et al. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol. 1998 59(1):57-63. Cooney K et al. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest. 1991 87(4):1227-33. Donner M et al. Type IIB von Willebrand's disease: gene mutations and clinical presentation in nine families from Denmark, Germany and Sweden. Br J Haematol. 1992 82(1):58-65. Lillicrap D et al. Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain, in patients with type IIB von Willebrand's disease. Br J Haematol. 1991 79(4):612-7. Ozeki M et al. A family having type 2B von Willebrand disease with an R1306W mutation: Severe thrombocytopenia leads to the normalization of high molecular weight multimers. Thromb Res. 2010 125(2):e17-22. Pietu G et al. Molecular study of von Willebrand disease: identification of potential mutations in patients with type IIA and type IIB. Blood Coagul Fibrinolysis. 1992 3(4):415-21. Randi A et al. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991 87(4):1220-6. Scaglione G et al. The type 2B p.R1306W natural mutation of von Willebrand factor dramatically enhances the multimer sensitivity to shear stress. J Thromb Haemost. 2013 11(9):1688-98. - |
Hereditary von Willebrand disease Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Pathogenic, no assertion criteria provided | research | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Von Willebrand disease type 2B Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Versiti Diagnostic Laboratories, Versiti, Inc | May 14, 2018 | The missense variant VWF c.3916C>T, p.Arg1306Trp (p.R1306W) in exon 28 changes amino acid arginine at codon 1306 to tryptophan. The arginine at this residue is somewhat conserved among species. This amino acid change occurs in the A1 domain, a functional domain that binds GP1ba and collagen (Springer, 2014). This sequence variant has been previously reported in patients with type 2B von Willebrand disease (Cooney, 1991; Randi, 1991; Ozeki, 2010) and has been observed in multiple patients with type 2B VWD in our laboratory cohort. Functional studies of the variant in mammalian cells demonstrated significantly increased platelet binding in the presence and absence of ristocetin (Cooney, 1996) and dramatic enhancement of multimer sensitivity to shear stress. (Scaglione, 2013). To date, this variant has not been reported in the general population (GnomAD, Exome Variant Server). In summary, the collective evidence supports VWF c.3916C>T, p.Arg1306Trp as a pathogenic variant for type 2B von Willebrand disease. - |
Abnormality of coagulation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at D1302 (P = 0.0669);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at