Submissions for variant NM_000552.5(VWF):c.4751A>G (p.Tyr1584Cys)

gnomAD frequency: 0.00237  dbSNP: rs1800386

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086795	SCV000565658	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Reported as the most common variant seen in individuals with type 1 von Willebrand disease, with possible codominant inheritance, but is noted to have incomplete penetrance (James et al., 2007; OBrien et al., 2003; Goodeve and James, 2017); Described as a susceptibility variant, increasing the risk to develop von Willebrand disease type 1, but not sufficient to make a diagnosis of von Willebrand disease in the absence of clinical features (Bowen et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15842375, 22197721, 22995991, 19506354, 27920237, 28091443, 27380589, 34708896, 31064749, 23355534, 21346256, 14525793, 23426949, 12649144, 17610557, 15755288, 16985174, 17190853, 16634747, 27596108, 26988807, 17080221, 30817071, 30722078, 34426522, 33556167, 33113216, 35753512, 33477601, 35505650, 34828413)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086795	SCV000602319	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in more frequently in individuals with Type I von Willebrand disease (vWD) than unaffected individuals (PMID: 12649144 (2003), 17119126 (2007)), 28091443 (2017)). Functional studies have shown that this variant causes decreased VWF protein levels, decreased VWF protein function, (PMID: 16985174 (2007), 23355534 (2013), 23426949 (2013), 25103891 (2014)), and increased susceptibility of the VWF protein to proteolysis (PMID: 14525793 (2004), 19506354 (2009), 21346256 (2011)). This variant has also been described as having reduced penetrance and a mild or moderate phenotypic effect (PMID: 16985174 (2007)).Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000622977	SCV000741424	uncertain significance	Inborn genetic diseases	2014-06-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086795	SCV001148581	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086795	SCV001159609	likely pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	The VWF c.4751A>G; p.Tyr1584Cys variant (rs1800386) has been described in numerous individuals and families affected with von Willebrand disease type I (Bowen 2004, James 2007, O’Brien 2003). While this variant segregates with disease in multiple families, it also exhibits incomplete penetrance in some families (Bowen 2005, O’Brien 2003). This variant is reported in ClinVar (Variation ID: 310). It is found in the general population at an overall allele frequency of 0.26% (743/282486 alleles, 4 homozygotes) in the Genome Aggregation Database. The tyrosine at codon 1584 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.639). Functional studies indicate that this variant protein results in decreased protein synthesis and increased cellular retention in vitro, with increased susceptibility of VWF proteolysis in vivo (Bowen 2005, O’Brien 2003, Pruss 2011). Correlative studies further suggest that in individuals carrying this variant, VWF:Ag levels are lowest in those with blood group O (Davies 2007). Based on available information, the p.Tyr1584Cys variant is considered to be likely pathogenic. REFERENCES Bowen D et al. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood. 2004 Feb 1;103(3):941-7. PMID: 14525793. Bowen D et al. The prevalence of the cysteine1584 variant of von Willebrand factor is increased in type 1 von Willebrand disease: co-segregation with increased susceptibility to ADAMTS13 proteolysis but not clinical phenotype. Br J Haematol. 2005 Mar;128(6):830-6. PMID: 15755288. Davies JA et al. Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group. Blood. 2007;109(7):2840-2846. PMID: 17119126. James P et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54. PMID: 17190853. O'Brien L et al. Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. Blood. 2003 Jul 15;102(2):549-57. PMID: 12649144. Pruss C et al. Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models. Blood. 2011 Apr 21;117(16):4358-66. PMID: 21346256.
Johns Hopkins Genomics, Johns Hopkins University	RCV001255177	SCV001431531	likely pathogenic	von Willebrand disease type 2	2020-08-28	criteria provided, single submitter	clinical testing	This VWF variant is a known risk factor allele and has been reported in numerous individuals with von Willebrand disease. Functional assays have shown that this variant results in a decrease of protein production and expression when compared to wildtype. VWF c.4751A>G is located within the A2 collagen functinal domain. This variant (rs1800386) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%): gnomAD: 743/282486 alleles; 0.26%, 4 homozygotes). VWF c.4751A>G has been reported in ClinVar. We consider this variant to be likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000678772	SCV001653003	likely pathogenic	Hereditary von Willebrand disease	2020-07-03	criteria provided, single submitter	clinical testing	The p.Tyr1584Cys variant in VWF has been reported in >15 individuals with Von Willebrand Disease (VWD) and segregated with disease in at least 3 affected individuals from 3 families. However, this variant has also been associated with a milder phenotype and may display reduced penetrance, as not all individuals who harbor the variant are clinically affected (O'Brien 2003 PMID: 12649144, Bellissimo 2012 PMID: 22197721, Daidone 2017 PMID:27380589, Vangenechten 2019 PMID: 30722078, Freitas 2019 PMID: 30817071). It has also been identified in 0.402% (519/128972) of European chromosomes, including 4 homozygous observations, by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar (Variation ID: 310). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (O'Brien 2003 PMID: 12649144, Pruss 2011 PMID: 21346256); however, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes decreased thrombus formation (Pruss 2011 PMID: 21346256). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic with reduced penetrance for autosomal dominant VWD. ACMG/AMP Criteria applied: PS3, PS4_Moderate, PP1.
Mayo Clinic Laboratories, Mayo Clinic	RCV000086795	SCV001716113	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	BS4, PP5_moderate, PS3, PS4_moderate
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001843449	SCV002103087	risk factor	von Willebrand disease type 1	2022-01-26	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001843449	SCV002500930	likely pathogenic	von Willebrand disease type 1		criteria provided, single submitter	clinical testing
Mendelics	RCV001843449	SCV002519959	pathogenic	von Willebrand disease type 1	2022-05-04	criteria provided, single submitter	clinical testing
Laboratory of Hematology, Radboud University Medical Center	RCV001843449	SCV002546327	pathogenic	von Willebrand disease type 1	2022-05-31	criteria provided, single submitter	research
Laboratory of Hematology, Radboud University Medical Center	RCV001255177	SCV002546328	pathogenic	von Willebrand disease type 2	2022-05-31	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000678772	SCV002555870	likely pathogenic	Hereditary von Willebrand disease	2022-06-14	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4751A>G (p.Tyr1584Cys) results in a non-conservative amino acid change located in the 2nd type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251146 control chromosomes in the gnomAD database, including 4 homozygotes. c.4751A>G has been reported in the literature as the most common variant found in individuals affected with type 1 Von Willebrand Disease and it has been found in many individuals and families affected with the disease (e.g. O'Brien_2003, Bowen_2005, James_2007, Borras_2017, Freitas_2019, Vangenechten_2019), however, in many families a reduced penetrance, and a milder disease phenotype was described (e.g. O'Brien_2003, Bowen_2005, Bellissimo_2012). Experimental studies have demonstrated that the Y1584C variant results in decreased biosynthesis and secretion in vitro (e.g. O'Brien_2003), together with an increased susceptibility to proteolysis by ADAMTS13 (e.g. Pruss_2011). Additionally, in a mouse model the variant protein had decreased plasma levels, and resulted in reduced thrombus formation (Pruss_2011). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=2, likely pathogenic n=4, VUS n=2, risk factor n=1). Based on the evidence outlined above, the variant seems to be associated with the disease with an incomplete penetrance, and therefore was classified as likely pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280857	SCV002569249	likely pathogenic	Thrombus		criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000086795	SCV002818167	likely pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000086795	SCV003823666	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313770	SCV004013004	uncertain significance	Thrombocytopenia		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415599	SCV004116538	likely pathogenic	VWF-related condition	2023-06-30	criteria provided, single submitter	clinical testing	The VWF c.4751A>G variant is predicted to result in the amino acid substitution p.Tyr1584Cys. This variant has been reported to segregate with disease phenotype in several families with von Willebrand Disease (VWD) Type I and was also found in apparent controls who were later found to have some symptoms of VWD (O’Brien et al. 2003. PubMed ID: 12649144; Bellissimo et al. 2012. PubMed ID: 22197721; Bowen and Collins. 2004. PubMed ID: 14525793). The p.Tyr1584Cys substitution has been reported to make VWF protein more susceptible to ADAMTS13 – mediated proteolysis (Bowen and Collins. 2004. PubMed ID: 14525793; Pruss et al. 2013. PubMed ID: 21346256) and has been associated with decreased levels of VWF protein, especially in patients with blood group O (Davies et al. 2009. PubMed ID: 19506354). The c.4751A>G variant displays variable penetrance among patients from the studies mentioned above, and taken together, available data indicate that this variant is likely to cause or at least increase risk of disease. We categorize this variant as likely pathogenic; however, in the absence of clinical features, it may not be sufficient to make a clinical diagnosis of VWD.
Genetics and Molecular Pathology, SA Pathology	RCV001255177	SCV004175541	uncertain significance	von Willebrand disease type 2	2021-07-06	criteria provided, single submitter	clinical testing
OMIM	RCV000000338	SCV000020482	risk factor	von Willebrand disease, type 1, susceptibility to	2006-11-01	no assertion criteria provided	literature only
Academic Unit of Haematology, University of Sheffield	RCV000086795	SCV000119001	not provided	not provided		no assertion provided	not provided
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678772	SCV000804951	pathogenic	Hereditary von Willebrand disease	2013-12-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000086795	SCV001552673	uncertain significance	not provided		no assertion criteria provided	clinical testing	The VWF p.Tyr1584Cys variant is commonly reported in associated with type 1 von Willebrand disease (VWD) and was originally identified in 21/150 patients with type 1 VWD from 70 families, however not all family members with the variant was affected with VWD suggesting incomplete penetrance (O'Brien_2003_PMID:12649144). The variant was also identified in 19/76 patients with VWD from 30 families, however the variant did not co-segregate with disease in four families, suggesting incomplete penetrance and that the variant may increase risk but not necessarily be causal for disease (Bowen_2005_PMID:15755288). The variant was identified in dbSNP (ID: rs1800386), LOVD 3.0 and in ClinVar (classified as likely pathogenic by Quest Diagnostics Nichols Institute San Juan Capistrano, pathogenic by Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital and as a VUS by GeneDx and Ambry Genetics). The variant was not identified in Cosmic. The variant was found in control databases in 743 of 282486 chromosomes (4 homozygous) at a frequency of 0.00263 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 519 of 128972 chromosomes (freq: 0.004024), European (Finnish) in 86 of 25048 chromosomes (freq: 0.003433), Other in 22 of 7212 chromosomes (freq: 0.00305), Ashkenazi Jewish in 29 of 10358 chromosomes (freq: 0.0028), Latino in 60 of 35414 chromosomes (freq: 0.001694), African in 14 of 24934 chromosomes (freq: 0.000562) and South Asian in 13 of 30610 chromosomes (freq: 0.000425); it was not observed in the East Asian population. A case study of a man diagnosed with mild haemophilia A and type 1 VWD identified the VWF Y1584C variant as well as a variant in the FVIII gene (A723T); his daughter also had both mutations and had a slightly higher bleeding score than normal while his father carried just the VWF Y1584C variant and had a normal bleeding score (Daidonee_2017_27380589). This variant was identified in another patient with mild hemophilia A who also had a variant in the FVIII gene (R2150C) (Boylan_2015_25780857). A study of a Nigerian population with a history of bleeding suggested that the Y1584C variant was significantly associated with bleeding compared to controls (Ezigbo_2017_28091443). Functional studies of the Y1584C variant have demonstrated conflicting results. One functional study of the Y1584C variant suggested normal function compared to wild-type as well as another functional study using patient derived blood outgrowth endothelial cells did not show any impaired function in the Y1584C mutant compared to healthy control cells (Growneveld_2014_PMID:25103891; Wang_2013_PMID:23426949). However another functional study of the Y1584C variant from patient blood outgrowth endothelial cells demonstrated impaired function including reduced VWF mRNA and protein expression compared to wild-type (Starke_2013_PMID:23355534). Further, mouse and cell models of the Y1584C variant suggested impaired function compared to wild-type (Pruss_2011_PMID:21346256). The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict the loss of a 5' splice site. However this is not a known splice site and is only predicted by 2 of 4 programs (MaxEntScan, GeneSplicer) to be a 5' splice site with the wildtype allele. No in silico splicing programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a change in splicing at the consensus sequence. The p.Tyr1584 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000086795	SCV001742426	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000086795	SCV001930307	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086795	SCV001959685	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086795	SCV001965759	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000678772	SCV002507241	not provided	Hereditary von Willebrand disease		no assertion provided	literature only