ClinVar Miner

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

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Total submissions: 7
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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 2019-08-19 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched 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 Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086795 SCV001148581 uncertain significance not provided 2018-05-01 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

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