ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Academic Unit of Haematology, University of Sheffield RCV000086620 SCV000118824 not provided not provided no assertion provided not provided
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000086620 SCV000334295 pathogenic not provided 2015-09-14 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
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
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.
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.
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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000336497 SCV000782768 pathogenic von Willebrand disease type 2 2018-01-19 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
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086620 SCV000889897 pathogenic not provided 2015-06-04 criteria provided, single submitter clinical testing

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