rs41276738
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_ModeratePP1PM3_StrongPS3
This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.2561G>A variant in VWF is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 854. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.005857 (based on 7050/1180026 alleles, with 24 homozygotes) in the European non-Finnish population. This allele frequency is above the ClinGen VWD VCEP threshold for VWD Type 2N (<0.005) for PM2_Supporting but below the threshold (>0.01) for BS1 and therefore does not meet any population criterion. At least 9 patients with this variant displayed excessive mucocutaneous bleeding, low FVIII activity, and decreased VWF:FVIII binding, which is highly specific for VWD type 2N (PP4_Moderate, PMID:28971901, PMID:22875612). Four individuals were homozygous for the variant (PMID:28971901, PMID:22875612, PMID:1832934) and one of those individuals was compound heterozygous for the variant and a pathogenic variant (p.Arg816Trp) confirmed in trans (PMID:1832934), additional compound heterozygotes have been reported but were not considered here (PM3_Strong). In one family, the variant segregated with VWD type 2N in the proband and a second affected family member (PP1; PMID:28971901). A hydrodynamic mouse model showed 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). 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: PS3, PM3_Strong, PP4_Moderate, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114139/MONDO:0015631/090
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.2561G>A | p.Arg854Gln | missense_variant | 20/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.2561G>A | p.Arg854Gln | missense_variant | 20/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.2561G>A | p.Arg854Gln | missense_variant | 20/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-40878G>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.00373 AC: 568AN: 152236Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00340 AC: 856AN: 251418Hom.: 5 AF XY: 0.00353 AC XY: 480AN XY: 135894
GnomAD4 exome AF: 0.00508 AC: 7432AN: 1461860Hom.: 23 Cov.: 31 AF XY: 0.00505 AC XY: 3672AN XY: 727228
GnomAD4 genome ? AF: 0.00373 AC: 568AN: 152354Hom.: 3 Cov.: 33 AF XY: 0.00357 AC XY: 266AN XY: 74492
ClinVar
Submissions by phenotype
not provided Pathogenic:15Other:1
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 | Oct 27, 2023 | The VWF c.2561G>A; p.Arg854Gln variant (also known as Arg91Gln) is published in the literature in individuals with von Willebrand disease (VWD) type 2N and is the most common VWD type 2N pathogenic variant (Casonato 2018, Veyradier 2011, Wang 2013). Functional analyses of the variant protein show decreased factor VIII binding, consistent with VWD type 2N (Veyradier 2011, Wang 2013). This variant is reported in ClinVar (Variation ID: 296). This variant is found in the general population with an overall allele frequency of .347% (980/ 282824 alleles, including 5 homozygotes) in the Genome Aggregation Database. The arginine at codon 854 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.487). Considering available information, this variant is classified as pathogenic. References: Casonato A et al. Type 2N von Willebrand disease: Characterization and diagnostic difficulties. Haemophilia. 2018 Jan;24(1):134-140. Veyradier A et al. Validation of the first commercial ELISA for type 2N von Willebrand's disease diagnosis. Haemophilia. 2011. 17(6):944-51. Wang JW et al. Analysis of the storage and secretion of von Willebrand factor in blood outgrowth endothelial cells derived from patients with von Willebrand disease. Blood. 2013. 121(14):2762-72. - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The VWF p.R854Q variant was identified in multiple homozygous or compound heterozygous individuals with autosomal recessive Von Willebrand disease (VWD) type 2N (Casonato_2016_PMID:27532107; Casonato_2007_PMID:17456630; Rodgers_2002_PMID:12162689; Cabrera_2008_PMID:18712522). In one family study, two sisters with borderline VWD type 2N were compound heterozygotes for this variant and p.Q895H; the father and mother were asymptomatic carriers for p.Q895H and p.R854Q, respectively (Cabrera_2008_PMID:18712522). The variant was identified in dbSNP (ID: rs41276738) and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine, GeneDx and 11 other laboratories). The variant was identified in control databases in 980 of 282824 chromosomes (5 homozygous) at a frequency of 0.003465 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 143 of 25122 chromosomes (freq: 0.005692), European (non-Finnish) in 690 of 129142 chromosomes (freq: 0.005343), Other in 26 of 7226 chromosomes (freq: 0.003598), Latino in 74 of 35428 chromosomes (freq: 0.002089), Ashkenazi Jewish in 10 of 10370 chromosomes (freq: 0.000964), African in 21 of 24968 chromosomes (freq: 0.000841) and South Asian in 16 of 30614 chromosomes (freq: 0.000523), but was not observed in the East Asian population. The p.Arg854 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The VWF gene encodes Von Willebrand factor, which interacts with coagulation factor VIII (FVIII) for hemostasis. Functional studies reveal that this variant causes significantly decreased binding between VMF and FVIII compared to wild type (Kroner_1991_PMID:1918030; Rosenberg_2002_PMID:12176890; Dagil_2019_PMID: 31349985). The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this has not been confirmed by RNA analysis. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 14, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2023 | Published functional studies demonstrate a damaging effect with dramatically diminished capacity of VWF to bind factor VIII (PMID: 23636243, 1906877, 12588349); This variant is associated with the following publications: (PMID: 26207643, 26105150, 26764160, 31064749, 20981092, 21489050, 21371195, 22197721, 23636243, 22875612, 22995991, 24029428, 25649154, 16953269, 9684781, 24033266, 20409624, 1906877, 23426949, 1832934, 1581215, 15461624, 25212677, 28436749, 29115006, 29220693, 29431110, 30609409, 30431218, 30722078, 31019283, 32935436, 31980526, 34426522, 31589614, 8115998, 9692396, 33942438, 33556167, 12588349, 20586924) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | VWF: PP1:Strong, PM1, PM5, PS3:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 12, 2020 | In the published literature, this variant has been reported in multiple individuals with autosomal recessive Type 2N von Willebrand disease (Type 2N vWD) (PMID: 1832934 (1991), 9684781 (1998), 12353087 (2002), 15461624 (2004), 20409624 (2010)). Functional studies have shown that this variant greatly reduces the ability of the VWF protein to bind factor VIII (PMID: 1906877 (1991), 15461624 (2004)). Based on the available information, this variant is classified as pathogenic. - |
von Willebrand disease type 2 Pathogenic:7Uncertain:1
Uncertain significance, 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 | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The (p.R854Q) variant in the VWF gene is the most frequent cause of VWD type 2N, which manifests as a mild form of VWD with only moderate bleeding in homozygotes (PMID: 20301765). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Nov 26, 2021 | PS1_moderate, PS3, PM1 - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 09, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 30, 2023 | PS3, PM1, PM3_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 10, 2020 | c.2561G>A (p.Arg854Gln) has been reported in the literature associated with von Willebrand disease, type 2N and functional analysis supports the deleterious nature of this variant. Additionally, this variant (rs41276738) is more prevalent in affected individuals than the healthy population (gnomAD: 980/282824 total alleles; 0.3465%; 5 homozygotes). Sixteen submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic. - |
von Willebrand disease type 1 Pathogenic:5
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_000552.3:c.2561G>A in the VWF gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. The p.Arg854Gln (NM_000552.3:c.2561G>A) variant in the VWF gene is the most frequent cause of von Willebrand disease (VWD) type 2N and has been reported previously in the homozygous state or in trans with another pathogenic variant in multiple unrelated individuals with autosomal recessive VWD type 2N (PMID: 1832934; 21371195; 15461624). Functional studies indicate the p.Arg854Gln variant may affect protein function (PMID: 23636243; 23426949). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 13, 2020 | The VWF c.2561G>A variant is classified as Pathogenic (PS3, PS4, PP1, PP2, PP3, PP5) - |
Hereditary von Willebrand disease Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.2561G>A (p.Arg854Gln) variant is found specifically in patients with type 2N von Willebrand disease (VWD) which manifests as a mild form of VWD with only moderate bleeding in homozygotes. This variant is well-documented as disease-causing for this specific type of VWD, found in up to 73% of type 2N patients to date (Casonato et al. 2013). The variant is also common among Caucasians, being found in over 1% of the general population (Goodeve et al. 2010). Across a selection of the available literature, the p.Arg854Gln variant has been reported in seven studies and found in a total of 72 patients including in 26 in a homozygous state, 12 in a compound heterozygous state and 34 in a heterozygous state in whom a second variant as not been found (Gaucher et al. 1991; Cacheris et al. 1991; Peerlinck et al. 1992; Hilbert et al. 2004; Hilbert et al. 2006; Veyradier et al. 2011; Casonato et al. 2013). The variant was absent from 906 control alleles and is reported at a frequency of 0.014 in the Puerto Rican population of the 1000 Genomes Project. Functional studies have demonstrated that the p.Arg854Gln variant results in reduced binding of FVIII and proteolysis by ADAMTS13 with a normal multimer pattern (Gaucher et al. 1991; Cacheris et al. 1991; Peerlinck et al. 1992; Hilbert et al. 2004; Hilbert et al. 2006; Skipwith et al. 2013; Wang et al. 2013). Based on the collective evidence, the p.Arg854Gln variant is classified as pathogenic for von Willebrand disease. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2024 | The p.Arg854Gln has been reported in the homozygous or compound heterozygous state in >20 individuals with von Willebrand disease (VWD) type 2N (Gaucher 1991 PMID: 1832934, Peerlinck 1992 PMID: 1581215, Veyradier 2011 PMID: 21371195). This variant is a common disease-causing variant for type 2N VWD (Casonato 2013 PMID: 22875612). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 296) and has been identified in 0.6% (7050/1180026) of European chromosomes, including 26 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This is consistent with a recessive carrier frequency and the clinical manifestations of type 2N VWD. In vitro functional studies indicate the p.Arg854Gln variant may affect protein function as it has been shown to decrease binding to factor VIII (Wang 2012 PMID: 23426949, Skipwith 2013 PMID: 23636243). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive type 2N von Willebrand disease. ACMG/AMP criteria applied: PM3_VeryStrong, PS3_Supporting, PM2_Supporting. - |
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
von Willebrand disease type 2N Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Versiti Diagnostic Laboratories, Versiti, Inc | Nov 11, 2019 | The missense variant VWF c.2561G>A, p.Arg854Gln (p.R854Q) in exon 20 changes amino acid arginine at codon 854 to glutamine. The arginine at this residue is highly conserved among species. This amino acid change occurs in the D'D3 domain of the VWF protein, a functional domain that binds factor VIII (Springer, 2014). Pathogenic variants in VWF are associated with autosomal dominant or autosomal recessive von Willebrand disease (VWD), characterized by quantitative or qualitative deficiencies in von Willebrand factor and resulting in prolonged bleeding. Pathogenic missense variants in the D'D3 domain have been shown to cause autosomal recessive type 2N VWD, characterized by low plasma factor VIII levels and a laboratory phenotype that can initially resemble hemophilia A. This sequence variant has is one of the most common reported variants in patients with type 2N VWD (Hilbert, 2004; Goodeve, 2007; Veyradier, 2011; van Meegeren, 2015; Borras, 2017). Functional studies of p.R854Q mutant in mamalian cells showed decreased FVIII binding (Hilbert, 2004; Swystun, 2017). The minor allele frequency of this variant in the general population is 0.003465 (gnomAD). In summary, the collective evidence supports VWF c.2561G>A, p.Arg854Gln as a pathogenic variant for type 2N von Willebrand disease. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Variantyx, Inc. | Nov 04, 2022 | This is a nonsynonymous variant in the VWF gene (OMIM 613160). Pathogenic variants in this gene have been associated with autosomal dominant and autosomal recessive von Willebrand disease (VWD). This variant, also known as p.Arg91Gln, is the most common pathogenic variant associated with autosomal recessive VWD type 2N (VWD2N) (PMID: 15461624, 1832934, 21371195, 22875612, 26764160 31064749, 34355501) (PM3_Very Strong). Functional studies have shown that this variant alters VWF protein function (PMID: 12176890, 1918030, 31349985) (PS3). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). This variant has a 0.6055% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive VWD2N. - |
von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | May 03, 2023 | - - |
von Willebrand disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2024 | Variant summary: VWF c.2561G>A (p.Arg854Gln) results in a conservative amino acid change located in the VWFC domain (IPR001846) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251418 control chromosomes in the gnomAD database, including 5 homozygotes. c.2561G>A has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Von Willebrand Disease type 2N (e.g. Casonato_2013, Fidalgo_2016) and is a common variant associated with type 2N VWD. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing that the variant affects protein function (Wang_2013, Skipwith_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22875612, 26988807, 23636243, 23426949). ClinVar contains an entry for this variant (Variation ID: 296). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Abnormality of coagulation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
VWF-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 02, 2024 | The VWF c.2561G>A variant is predicted to result in the amino acid substitution p.Arg854Gln. This variant (aka p.Arg91Gln) has been reported in the homozygous or compound heterozygous state in many patients with recessive von Willebrand disease (VWD) type 2N (van Meergeren et al. 2015. PubMed ID: 26207643; Castaman et al. 2010. PubMed ID: 20586924; Gaucher et al. 1991. PubMed ID: 1832934; Hilbert et al. 2004. PubMed ID: 15461624). One patient with VWD type 1 was also reported to have the p.Arg854Gln substitution (Peerlinck et al. 1992. PubMed ID: 1581215). Different cellular and biochemical studies indicate the p.Arg854Gln change alters normal VWF protein function (Cacheris et al. 1991. PubMed ID: 1906877; Castaman et al. 2010. PubMed ID: 20586924; Wang et al. 2013. PubMed ID: 23426949; Hilbert et al. 2004. PubMed ID: 15461624). This variant is reported in 0.57% of alleles in individuals of European (Finnish) descent in gnomAD, including several homozygotes. Multiple laboratories classify this variant as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/296/). This variant is interpreted as pathogenic. - |
Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Birmingham Platelet Group; University of Birmingham | May 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at