NM_000552.3(VWF):c.4751A>G (p.Tyr1584Cys)

NM_000552.3(VWF):c.4751A>G (p.Tyr1584Cys)

Variant type:
single nucleotide variant
Cytogenetic location:
12p13.3
Genomic location:
  • Chr12:6127833 (on Assembly GRCh37)
  • Chr12:6018667 (on Assembly GRCh38)
Protein change:
Y1584C
HGVS:
  • NG_009072.1:g.111004A>G
  • NM_000552.3:c.4751A>G
  • NC_000012.12:g.6018667T>C (GRCh38)
  • NC_000012.11:g.6127833T>C (GRCh37)
  • NP_000543.2:p.Tyr1584Cys
  • NM_000552.2:c.4751A>G
Links:
NCBI 1000 Genomes Browser:
rs1800386
Molecular consequence:
NM_000552.3:c.4751A>G: missense variant [Sequence Ontology SO:0001583]
Allele frequency:
  • GO-ESP 0.00215 (C)
  • GMAF 0.00080 (C)

Clinical significance

NM_000552.3(VWF):c.4751A>G (p.Tyr1584Cys)

Clinical significance:
risk factor
Review status:
1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
2
Condition(s)
  • von Willebrand disease, type 1, susceptibility to
See supporting ClinVar records

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Recent Activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter
(Last submitted)
Submission accession
risk factor
(Nov 18, 2014)
classified by single submitter
(literature only)
literature only
  • von Willebrand disease, type 1, susceptibility to
germlinePubMed (4)
OMIM
(Dec 30, 2010)
SCV000020482
not providednot classified by submitter
(literature only)
literature onlynot providedAcademic Unit of Haematology University of Sheffield
(Jul 31, 2012)
SCV000119001

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermline, not providednot providednot provided

Academic Unit of Haematology

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

Bowen and Collins (2004) described a patient with type 1 von Willebrand disease in whom the von Willebrand factor showed increased susceptibility to proteolysis by ADAMTS13 (604134). Investigation of additional family members indicated that increased susceptibility was heritable, but it did not track uniquely with type 1 VWD. Sequence analysis showed that increased susceptibility to proteolysis tracked with the Y1584C substitution. A prospective study of 200 individuals yielded 2 Y1584C heterozygotes; for both, plasma VWF showed increased susceptibility to proteolysis.
Bowen et al. (2005) identified heterozygosity for the Y1584C variant in 19 (25%) of 76 UK patients with type 1 VWD. This corresponded to 8 (27%) of 30 total families studied. However, the Y1584C variant did not segregate with disease in 4 families: 5 unaffected individuals carried the variant, whereas 3 affected individuals did not. These findings indicated that Y1584C is not solely causative of type 1 VWD. Eighteen of the 19 patients were ABO blood group (110300) type O, suggesting there may be an interaction between C1584 and blood group O. In vitro studies of plasma showed that Y1584C VWF had increased susceptibility to proteolysis by ADAMTS13, even in those who did not have VWD. Bowen et al. (2005) proposed a mechanism in which Y1584C VWF undergoes increased proteolysis, which may increase bleeding risk in carriers. However, presence for the variant is not causative for the disorder, and may instead represent a risk factor.
Bowen et al. (2005) identified heterozygosity for the Y1584C variant in 19 (25%) of 76 UK patients with type 1 VWD. This corresponded to 8 (27%) of 30 total families studied. However, the Y1584C variant did not segregate with disease in 4 families: 5 unaffected individuals carried the variant, whereas 3 affected individuals did not. These findings indicated that Y1584C is not solely causative of type 1 VWD. Eighteen of the 19 patients were ABO blood group (616093) type O, suggesting there may be an interaction between C1584 and blood group O. In vitro studies of plasma showed that Y1584C VWF had increased susceptibility to proteolysis by ADAMTS13, even in those who did not have VWD. Bowen et al. (2005) proposed a mechanism in which Y1584C VWF undergoes increased proteolysis, which may increase bleeding risk in carriers. However, presence for the variant is not causative for the disorder, and may instead represent a risk factor.
Cumming et al. (2006) identified heterozygosity for the Y1584C variant in 8 (25%) of 32 UK families and in 19 (17%) of 119 related individuals with type 1 VWD. Eighteen (95%) of the 19 individuals were blood group O. Heterozygosity for Y1584C segregated with VWD in 3 families, did not segregate with VWD in 4 families, and showed equivocal results in 2 families. Cumming et al. (2006) concluded that Y1594C is a polymorphism that is frequently associated with type 1 VWD, but shows incomplete penetrance and does not consistently segregate with the disease. The association with blood group type O may be related to the fact that both blood group O and Y1584C are associated with increased proteolysis of VWF by ADAMTS13.
O'Brien et al. (2003) addressed the molecular basis of type 1 von Willebrand disease (193400) in a comprehensive manner through a Canadian population-based study. In 10 Canadian families and 2 families from the UK with type 1 VWD, O'Brien et al. (2003) identified a heterozygous 4751A-G transition in exon 28 of the VWF gene, resulting in a tyr1584-to-cys (Y1584C) substitution. The Y1584C variant was found in 1 of 100 controls, but this individual had low VWF antigen levels, suggesting an affected status. One study participant with the mutation had a normal VWF antigen level and no history of bleeding, suggesting incomplete penetrance, and another who was homozygous for the mutation had significantly decreased VWF antigen levels. The mutation was associated with a common haplotype in a significant portion of patients with the disorder and was in-phase with a splice site variation (5312-19A-C) in some families. In vitro functional expression studies showed that the mutation resulted in increased intracellular retention of the VWF protein, resulting in a quantitative defect. Molecular dynamic simulation on a homology model of the VWF-A2 domain containing the Y1584C mutation showed that no significant structural changes occurred as a result of the substitution, but that a new solvent-exposed reactive thiol group was apparent.

Last Updated: Feb 28, 2015

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