ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.2561G>A (p.Arg854Gln) (rs41276738)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000169683 SCV000221221 pathogenic von Willebrand disorder 2014-05-12 criteria provided, single submitter clinical testing The p.Arg854Gln has been reported in >20 homozygous and compound heterozygous in dividuals with von Willebrand disease (Gaucher 1991, Peerlinck 1992, Veyradier 2 011). This variant has been identified in 0.45% (298/66730) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs41276738). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . Functional studies indicate the p.Arg854Gln variant may affect protein functio n (Wang 2012, Skipwith 2013). In summary, this variant meets our criteria to be classified as pathogenic for type 2N von Willebrand disease in an autosomal rece ssive manner.
GeneDx RCV000086620 SCV000322001 pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing The R854Q variant in the VWF gene is the most frequent cause of von Willebrand disease (VWD) type 2N (Castaman et al., 2010) 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 (Gaucher et al., 1991; Castaman et al., 2010; Hilbert et al., 2004). One individual has been reported to have an autosomal recessive form of VWD type 1 due to a maternally inherited R854Q variant in trans with a hypomorphic allele, inherited from a father with low VWF antigen and a slightly increased bleeding time (Peerlinck et al., 1992). Functional studies of the R854Q variant, referred to as R91Q due to alternate nomenclature, demonstrate a dramatically diminished capacity of VWF to bind factor VIII (Cacheris et al., 1991; Hilbert et al., 2003). An asymptomatic individual heterozygous for the R854Q variant had normal plasma levels of VWF but a reduced binding ability to factor VIII, while cultured blood outgrowth endothelial cells with the R854Q variant stored VWF properly but produced less VWF than normal cells (Wang et al., 2013). The NHLBI Exome Sequencing Project reports R854Q was present in 48/8600 alleles (0.56%) from individuals of European ancestry, but was not present in the homozygous state in any individual within this population. The R854Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species, and may impact secondary protein structure as these residues differ in some properties. We interpret R854Q as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000086620 SCV000334295 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000169683 SCV000380622 pathogenic von Willebrand disorder 2016-06-14 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000086620 SCV000605594 pathogenic not provided 2017-06-15 criteria provided, single submitter clinical testing The VWF c.2561G>A;p.Arg854Gln variant (also known as Arg91Gln) has been published in the literature in individuals with von Willebrand disease (VWD) type 2N and has been shown to disrupt Factor VIII binding, consistent with VWD type 2N (Veyradier 2011, Wang 2013). The variant is listed in the ClinVar database (Variation ID: 296). This variant is listed in the dbSNP variant database (rs41276738) with an allele frequency of 0.3844 percent (50/12956 alleles) in the Exome Variant Server and 0.3438 percent (953/277192 alleles) in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. References: 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000086620 SCV000610065 pathogenic not provided 2017-04-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000336497 SCV000782768 pathogenic von Willebrand disease type 2 2018-01-19 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000336497 SCV000883107 pathogenic von Willebrand disease type 2 2018-11-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086620 SCV000889897 pathogenic not provided 2020-06-12 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Fulgent Genetics,Fulgent Genetics RCV000762901 SCV000893311 pathogenic Von Willebrand disease, recessive form; von Willebrand disease type 1; von Willebrand disease type 2 2018-10-31 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000169683 SCV000899325 pathogenic von Willebrand disorder 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851593 SCV000899326 likely pathogenic Abnormality of coagulation 2019-02-01 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086620 SCV001246257 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Versiti Diagnostic Laboratories,Versiti, Inc RCV000000320 SCV001250572 pathogenic von Willebrand disease type 2N 2019-11-11 criteria provided, single submitter clinical testing 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.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000336497 SCV001251482 pathogenic von Willebrand disease type 2 criteria provided, single submitter research 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).
Johns Hopkins Genomics, Johns Hopkins University RCV000336497 SCV001425379 pathogenic von Willebrand disease type 2 2020-02-10 criteria provided, single submitter clinical testing 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000086620 SCV001716116 pathogenic not provided 2021-03-26 criteria provided, single submitter clinical testing
OMIM RCV000000320 SCV000020464 pathogenic von Willebrand disease type 2N 2010-05-01 no assertion criteria provided literature only
OMIM RCV000000321 SCV000020465 pathogenic von Willebrand disease type 1 2010-05-01 no assertion criteria provided literature only
Academic Unit of Haematology, University of Sheffield RCV000086620 SCV000118824 not provided not provided no assertion provided not provided
Reproductive Health Research and Development,BGI Genomics RCV000000321 SCV001142429 pathogenic von Willebrand disease type 1 2020-01-06 no assertion criteria provided curation 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.
Birmingham Platelet Group; University of Birmingham RCV001270529 SCV001450828 likely pathogenic Abnormal bleeding; Thrombocytopenia 2020-05-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000086620 SCV001552634 pathogenic not provided no assertion criteria provided clinical testing 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.