ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.5191T>A (p.Ser1731Thr) (rs61750603)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000086830 SCV000322002 likely pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing The S1731T variant in the VWF gene has been reported previously in association with autosomal dominant von Willebrand disease (Ribba et al., 2001). The S1731T variant is observed in 137/66736 (0.205%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). This substitution occurs within the VWFA 3 domain, a main binding site for collagens type I and III, at a nucelotide position that is conserved. In vitro collagen binding studies showed a reduction in binding to both type I and type III collagen, at 45% and 50% of wild type (Flood et al., 2010). We interpret S1731T as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000343743 SCV000380593 uncertain significance von Willebrand disorder 2016-06-14 criteria provided, single submitter clinical testing The c.5191T>A (p.Ser1731Thr) variant has been reported in three studies in which it is found in at least four patients in a heterozygous state (Ribba et al. 2001, Riddell et al. 2009, Veyradier et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00205 in the European (Non-Finnish) population from the Exome Sequencing Project. This frequency is high in comparison to disease prevalence, but may be explained by a milder phenotype or reduced penetrance. Functional studies including expression of the variant in COS-7 cells demonstrated significantly decreased binding of the variant protein to collagen. Analysis in HEK293T cells showed the p.Ser1731Thr variant affects binding to collagen type I but not type III. Additional functional studies utilizing mouse models, HEK293T cell constructs, flow chamber analysis, and collagen thin films in flow assays support normal expression but reduced collagen binding of the p.Ser1731Thr variant (Flood et al. 2010; Shida et al. 2014; Hansen et al. 2011). Based on the limited number of cases but with supporting functional data, the p.Ser1731Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for von Willebrand disease.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826083 SCV000967578 uncertain significance not specified 2020-06-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ser1731Thr variant in VWF has been reported in at least 3 individuals with clinical features of Von Willebrand disease and 1 homozygous individual with Glanzmann thrombasthenia, and segregated with disease in 2 affected relatives from 2 families. However, it was also identified in 1 individual with an alternate molecular cause of disease and 4 asymptomatic relatives (Ribba 2001 PMID: 11583318, Riddell 2009 PMID: 19687512, Veyradier 2016 PMID: 26986123, Owaidah 2019 PMID: 30792900, Al-Doory 2020). This variant has been identified in 2.1% (217/10370) of Ashkenazi Jewish chromosomes and 0.11% (136/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 100420). 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 the p.Ser1731Thr variant may have a partial impact to protein function (Flood 2009 PMID: 20345715, Riddell 2009 PMID: 19687512, Flood 2015 PMID: 25662333); however, these in vitro results may not be biologically relevant. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS3_Supporting, BS1.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086830 SCV001249951 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086830 SCV001470133 uncertain significance not provided 2020-03-20 criteria provided, single submitter clinical testing
Academic Unit of Haematology, University of Sheffield RCV000086830 SCV000119036 not provided not provided no assertion provided not provided

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