Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Hematology, |
RCV000677341 | SCV000803140 | pathogenic | Thrombotic thrombocytopenic purpura | 2018-07-01 | no assertion criteria provided | clinical testing | ADAMTS13 is the 13th member of the ADAMTS family of metalloproteases (Zheng X 2001). VWF, the substrate of ADAMTS13, is mainly produced in vascular endothelial cells and released into the plasma as unusually large multimers, which readily undergo ADAMTS13 proteolysis (Moake JL 2002). Recent studies demonstrated an association between pathogenesis and severely reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) (Furlan M 1998; Tsai HM, 1998). This enzyme specifically cleaves von Willebrand factor (VWF), a glycoprotein necessary for normal hemostasis. Consequently, reduced ADAMTS13 activity has been included in the diagnostic criteria for TTP (George JN 2014). Congenital TTP is attributable to ADAMTS13 gene mutations (Levy GG 2001; Kokame K,2002), whereas acquired TTP develops as a result of anti- ADAMTS13 autoantibody production (Furlan M 1998; Tsai HM 1998). A number of fragmented red cells were found in a peripheral blood smear of the proband. In addition to being heterozygous of C737R, the proband was proved to be heterozygous of two novel ADAMTS13 mutations (G194V and G1181R, respectively). Scores of the mutations for predicting the probability of a damaging mutation using Sorting Tolerant From Intolerant (SIFT, http://sift.jcvi.org/) and Polymorphism Phenotyping v2 (PolyPhen-2, http://genetics.bwh.harvard.edu/pph2/) were high. The negative effect of the novel ADAMTS13 mutations on the activity of protease was further verified by SELDI-TOF and the activity level of ADAMTS13 was <5% (normal: 68~131%). In summary, the C737R variant meets our criteria to be classified as pathogenic. |