ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys) (rs1800386)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486974 SCV000565658 uncertain significance not specified 2017-03-07 criteria provided, single submitter clinical testing The Y1584C variant in the Y1584C gene has been reported as the most common variant seen in individuals with type 1 von Willebrand disease, but is noted to have incomplete penetrance (James et al., 2007; O’Brien et al., 2003; Goodeve and James, 2014). The Y1584C variant has been shown to co-segregate with susceptibility of von Willebrand factor to proteolysis, however, Y1584C does not always segregate with a clinical diagnosis of von Willebrand disease (Bowen et al., 2005). The Y1584C variant is 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). The Y1584C variant is observed in 295/66,452 (0.44%) alleles from individuals of European (non-Finnish) background including multiple unrelated homozygous individuals in the ExAC dataset (Lek et al., 2016). The Y1584C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Y1584C as a risk allele.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086795 SCV000602319 likely pathogenic not provided 2020-03-04 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Conflicting predictions of the effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Ambry Genetics RCV000622977 SCV000741424 uncertain significance Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086795 SCV001148581 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283111 SCV001159609 likely pathogenic none provided 2020-07-09 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 contains an entry in ClinVar (Variation ID: 310) and is observed in the general population at an overall frequency of 0.26% (743/282486 alleles, 4 homozygotes) in the Genome Aggregation Database. The tyrosine at codon 1584 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. 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 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. 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. 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. 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. 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. 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.
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,Partners HealthCare Personalized Medicine RCV000678772 SCV001653003 likely pathogenic von Willebrand disorder 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 2021-01-07 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 von Willebrand disorder 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.

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