Submissions for variant NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

gnomAD frequency: 0.00377  dbSNP: rs41276738

Total submissions: 42

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169683	SCV000221221	pathogenic	Hereditary von Willebrand disease	2024-03-19	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000086620	SCV000322001	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000086620	SCV000334295	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169683	SCV000380622	pathogenic	Hereditary von Willebrand disease	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	2023-10-27	criteria provided, single submitter	clinical testing	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.
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
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	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.
Fulgent Genetics, Fulgent Genetics	RCV000762901	SCV000893311	pathogenic	von Willebrand disease type 1; von Willebrand disease type 3; von Willebrand disease type 2	2021-09-27	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000169683	SCV000899325	pathogenic	Hereditary von Willebrand disease	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 Center for Human Genetics Tuebingen	RCV000086620	SCV001246257	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	VWF: PP1:Strong, PM1, PM5, PS3:Moderate
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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000086620	SCV002011305	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000086620	SCV002020886	pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000336497	SCV002103046	likely pathogenic	von Willebrand disease type 2	2021-11-26	criteria provided, single submitter	clinical testing	PS1_moderate, PS3, PM1
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000000321	SCV002500928	pathogenic	von Willebrand disease type 1		criteria provided, single submitter	clinical testing
Mendelics	RCV000000321	SCV002519962	pathogenic	von Willebrand disease type 1	2022-05-04	criteria provided, single submitter	clinical testing
Laboratory of Hematology, Radboud University Medical Center	RCV000336497	SCV002546263	pathogenic	von Willebrand disease type 2	2021-12-09	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV000000321	SCV002556468	pathogenic	von Willebrand disease type 1	2020-07-13	criteria provided, single submitter	clinical testing	The VWF c.2561G>A variant is classified as Pathogenic (PS3, PS4, PP1, PP2, PP3, PP5)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000336497	SCV002569916	pathogenic	von Willebrand disease type 2		criteria provided, single submitter	clinical testing
Variantyx, Inc.	RCV000000320	SCV002754530	pathogenic	von Willebrand disease type 2N	2022-11-04	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV004547445	SCV004117618	pathogenic	VWF-related disorder	2024-02-02	criteria provided, single submitter	clinical testing	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.
New York Genome Center	RCV000762901	SCV004176035	pathogenic	von Willebrand disease type 1; von Willebrand disease type 3; von Willebrand disease type 2	2023-05-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000086620	SCV004243463	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000336497	SCV004244520	pathogenic	von Willebrand disease type 2	2023-11-30	criteria provided, single submitter	clinical testing	PS3, PM1, PM3_Strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987302	SCV004803450	pathogenic	von Willebrand disorder	2024-01-16	criteria provided, single submitter	clinical testing	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.
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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000086620	SCV001740446	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000086620	SCV001808213	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086620	SCV001954827	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086620	SCV001965898	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000169683	SCV002507237	not provided	Hereditary von Willebrand disease		no assertion provided	literature only
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000336497	SCV002513416	uncertain significance	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing