ClinVar Genomic variation as it relates to human health

The ADAMTS13 c.1370C>T (p.Pro457Leu) variant has been reported in at least two studies in which it is found in a compound heterozygous state in two individuals with familial thrombotic thrombocytopenia purpura and in a heterozygous state in an unaffected parent of each individual (Assink et al. 2003; Manea et al. 2007a). The p.Pro457Leu variant was absent from 50 control samples (Assink et al. 2003), but is reported at a frequency of 0.005899 in the European (Finnish) population of the Genome Aggregation Database with one homozygote present in the European (non-Finnish) population. One of the affected individuals was shown to have less than 5% enzyme activity compared to 50% activity seen in the unaffected parent, and in vitro studies showed impaired secretion and very low activity of the secreted variant proteins (Manea et al. 2007a; Manea et al. 2007b). Based on the evidence, the p.Pro457Leu 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.

Published functional studies demonstrate a damaging effect with impaired secretion and reduced enzyme activity (Manea et al., 2007b; Katneni et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28866379, 21228398, 23346910, 17187257, 34426522, 28748566, 32183147, 32531546, 30046676, 17627784, 12753286)

Variant summary: ADAMTS13 c.1370C>T (p.Pro457Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 202740 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not comparable to an estimated frequency for a pathogenic variant in ADAMTS13 causing Thrombotic Thrombocytopenic Purpura allowing no conclusion about variant significance. c.1370C>T has been reported in the literature in at-least one compound heterozygous individual affected with Thrombotic Thrombocytopenic Purpura whose obligate carrier parents demonstrated 50% ADAMTS13 activity levels (example, Assink_2003, Manea_2007). It has also been reported as a single copy or an unspecified genotype in individuals with other unclear phenotypes such as congenital heart disease, acutely resolving episodes of TTP and in cohorts of individuals undergoing WES for rare bleeding disorders (example, Fidalgo_2017, Kateni_2017, Leinoe_2017). These data do not allow any firm conclusions about variant significance. This variant continues to be cited as a pathogenic variant associated with strong evidence for hereditary TTP (example, Hoon Rim_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ADAMTS13 activity although the primary data supporting this finding were not provided (example, Manea_2007). However, western blot analysis demonstrated a complete absence of ADAMTS13 using monoclonal and polyclonal antibodies against this protein. The following publications have been ascertained in the context of this evaluation (PMID: 12753286, 30046676, 32183147, 28866379, 28748566, 17187257, 23715102). Six clinical diagnostic laboratories have submitted conflicting clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; likely pathogenic, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

BS1, PS3_supporting

ACMG Criteria: PS3, PM1, PM3, PP5; Variant was found in heterozygous state

This individual is heterozygous for the c.1370C>T variant in the ADAMTS13 gene which results in an amino acid substitution of proline to leucine at residue 457, p.(Pro457Leu). This variant has been previously reported as a compound heterozygote with another ADAMTS13 variant, in a patient with congenital thrombotic thrombocytopenic purpura (TTP) initially by Assink et al. 2003 Kidney Int 63:1995-9, PMID:12753286. The patient was shown to have less than 5% ADAMTS13 activity compared to 50% activity seen in the father who was heterozygous for the p.Pro457Leu variant (Manea et al. 2007 Eur J Pediatr 166:249-257 PMID:17187257). In vitro studies of the p.Pro457Leu mutant showed reduced activity compared to the wild type (Manea et al. 2007 Br J Haematol 138:651-652, PMID: 176227784). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.57% (119 out of 20, 848 alleles Finnish European population). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be a likely pathogenic according to the ACMG guidelines (Evidence used: PS3, PM3, PP3).

The ADAMTS13 c.1370C>T variant is predicted to result in the amino acid substitution p.Pro457Leu. This variant has been reported in the compound heterozygous state in individuals with thrombotic thrombocytopenic purpura (TTP) (see Patient 3 in Assink et al. 2003. PubMed ID: 12753286; Manea et al. 2007. PubMed ID: 17627784). Functional evidence indicates this variant affects secretion and activity of ADAMTS13 protein and therefore it is possible this variant increases susceptibility for TTP in heterozygous carriers (Katneni et al. 2017. PubMed ID: 28866379; Manea et al. 2007. PubMed ID: 17627784). This variant is reported in 0.57% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.