Submissions for variant NM_139027.6(ADAMTS13):c.559G>C (p.Asp187His)

gnomAD frequency: 0.00043  dbSNP: rs148312697

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778929	SCV000915344	likely pathogenic	Upshaw-Schulman syndrome	2017-05-01	criteria provided, single submitter	clinical testing	The ADAMTS13 c.559G>C (p.Asp187His) variant has been reported in two studies in which it was found in a compound heterozygous state in one patient and in a heterozygous state in a second patient in whom an additional variant was not identified, both affected with familial thrombotic thrombocytopenia purpura, onset of which was triggered by pregnancy (De Cock et al. 2015; Delmas et al. 2015). The p.Asp187His variant was identified in 19 of 21,658 control alleles (Lotta et al. 2013; de Vries et al. 2015; Pagliari et al. 2016) and is reported at a frequency of 0.00121 in the Latino population of the Exome Aggregation Consortium. In vitro studies conducted in human embryonic kidney cells showed that the variant reduced ADAMTS13 antigen levels (to 58% of wild type) and activity (to 19% of wild type) as well as reduced the catalytic efficiency of the enzyme, impaired proteolysis of von Willebrand factor, destablized calcium binding, and impaired protein secretion (De Cock et al. 2015; Pagliari et al. 2016). In addition, expression of the p.Asp187His form of the protein, unlike the wild type form, could not rescue the thrombotic thrombocytopenia phenotype of ADAMTS13 null mice (De Cock et al. 2015). In vitro studies also demonstrated the negative effect of another variant at the same position (p.Asp187Ala), providing additional evidence of the functional role of Asp187 in a high affinity calcium binding site important for von Willebrand factor binding and proteolysis (Gardner et al. 2009; de Groot et al. 2010). Based on the evidence, the p.Asp187His variant is classified as likely pathogenic for familial thrombotic thrombocytopenia purpura. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000778929	SCV001526131	uncertain significance	Upshaw-Schulman syndrome	2018-08-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV001507763	SCV001713511	likely pathogenic	not provided	2021-01-11	criteria provided, single submitter	clinical testing	PS3, PM1, PP3
Genetic Services Laboratory, University of Chicago	RCV001507763	SCV002098329	likely pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001507763	SCV002512853	uncertain significance	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Reported in a female with pregnancy-onset TTP who was later found to have reduced ADAMTS13 activity outside the pregnancy period in published literature (De Cock et al., 2015); however, a second ADAMTS13 variant was not identified; Observed with a canonical splice site variant in a pregnant female presenting w/ pre-eclampsia, severe thrombocytopenia, and reduced ADAMTS13 activity in published literature (Delmas et al., 2015), although it is not known if these variants were present on the same allele (in cis) or on opposite alleles (in trans); Identified in a heterozygous child presenting with atypical hemolytic uremic syndrome and nephrotic syndrome in published literature (Bello-Marquez et al., 2020); however, no second ADAMTS13 variant was reported, ADAMTS13 activity was reported to be normal, and variants in other genes were also identified; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on protein secretion and activity (De Cock et al., 2015; Pagliari et al., 2016); This variant is associated with the following publications: (PMID: 27802307, 29669506, 25934476, 23648131, 25442981, 26081109, 32779691, 19047683, 20647566, 34426522)
Invitae	RCV001507763	SCV003261538	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 187 of the ADAMTS13 protein (p.Asp187His). This variant is present in population databases (rs148312697, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with thrombotic thrombocytopenic purpura (PMID: 25442981, 26081109, 30312976). ClinVar contains an entry for this variant (Variation ID: 632074). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ADAMTS13 function (PMID: 25442981, 27802307). 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.
Revvity Omics, Revvity	RCV000778929	SCV004238936	uncertain significance	Upshaw-Schulman syndrome	2023-05-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994114	SCV004813402	uncertain significance	not specified	2024-02-19	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS13 c.559G>C (p.Asp187His) results in a non-conservative amino acid change located in the Peptidase M12B, ADAM/reprolysin domain (IPR001590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 1613864 control chromosomes in the gnomAD database, including 1 homozygote. c.559G>C has been reported in the literature in individuals affected with Thrombotic Thrombocytopenic Purpura or atypical hemolytic uremic syndrome without strong evidence of causality (De Cock_2015, Delmas_2015, Pagliari_2016, Wilson_2020, Bello-Marquez_2021). These reports do not provide unequivocal conclusions about association of the variant with Thrombotic Thrombocytopenic Purpura. At least two publications reports experimental evidence evaluating an impact on protein function, finding that the variant effect results in 10%-<30% of normal activity in vitro (De Cock_2015, Pagliari_2016). The following publications have been ascertained in the context of this evaluation (PMID: 25442981, 27802307, 26081109, 32779691, 35372954). ClinVar contains an entry for this variant (Variation ID: 632074). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000778929	SCV002515518	uncertain significance	Upshaw-Schulman syndrome		no assertion criteria provided	clinical testing