Submissions for variant NM_139027.6(ADAMTS13):c.581G>T (p.Gly194Val)

gnomAD frequency: 0.00002  dbSNP: rs1554785242

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531387	SCV002998173	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADAMTS13 protein function. ClinVar contains an entry for this variant (Variation ID: 559578). This variant has not been reported in the literature in individuals affected with ADAMTS13-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 194 of the ADAMTS13 protein (p.Gly194Val).
Department of Hematology, 303rd Hospital of the People's Liberation Army	RCV000677303	SCV000802930	pathogenic	Thrombotic thrombocytopenic purpura	2018-06-21	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 c.581G>T, the proband was proved to be heterozygous of two novel ADAMTS13 mutations (c.2209T>C and c.3541G>A, 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 G194V variant meets our criteria to be classified as pathogenic.