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SCARA5 and von Willebrand Disease

In multi‐patient genetic studies evaluating determinants of plasma von Willebrand factor levels, SCARA5 was included among several candidate genes; however, no significant accumulation of rare or pathogenic variants in SCARA5 was observed in Swedish von Willebrand disease (VWD) cohorts (PMID:33145474, PMID:25832887). The genetic analyses did not yield robust segregation data or recurrent variant findings to substantiate a strong gene‑disease correlation. Consequently, the genetic evidence supporting a direct causal role for SCARA5 in VWD remains limited. The absence of clearly deleterious variants, despite the inclusion of SCARA5 in gene panels, suggests a modulatory rather than determinative role in disease pathogenesis.

Conversely, functional studies have provided moderate evidence for the involvement of SCARA5 in the regulation of VWF clearance. Experimental assays demonstrated that SCARA5 acts as an endocytic receptor by binding and internalizing von Willebrand factor in a calcium‑dependent manner, and murine models further indicated a modest impact on the half‑life of VWF when SCARA5 is deficient (PMID:31126000). These findings support a biological role for SCARA5 in modulating VWF plasma levels, consistent with its potential contribution to the VWD phenotype. Key take‑home sentence: Although functional data underscore a role for SCARA5 in VWF clearance, the limited genetic evidence currently restricts its clinical validity for diagnostic decision‑making.

References

  • TH open : companion journal to thrombosis and haemostasis • 2020 • Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients PMID:33145474
  • Journal of thrombosis and haemostasis : JTH • 2015 • CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease PMID:25832887
  • Journal of thrombosis and haemostasis : JTH • 2019 • The scavenger receptor SCARA5 is an endocytic receptor for von Willebrand factor expressed by littoral cells in the human spleen PMID:31126000

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

The association is based on multi‐gene studies where SCARA5 did not exhibit significant enrichment of pathogenic variants in VWD patients (PMID:33145474, PMID:25832887).

Genetic Evidence

Limited

No clear, recurrent SCARA5 variants were reported, and family segregation data is lacking, thereby limiting the genetic evidence for its direct involvement in VWD.

Functional Evidence

Moderate

Robust molecular assays, including in vitro binding and murine models, demonstrate that SCARA5 binds and internalizes VWF, supporting its role in VWF clearance (PMID:31126000).