Submissions for variant NM_139027.6(ADAMTS13):c.1351G>A (p.Ala451Thr)

dbSNP: rs375508823

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002537718	SCV003483910	uncertain significance	not provided	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 451 of the ADAMTS13 protein (p.Ala451Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTS13-related conditions. ClinVar contains an entry for this variant (Variation ID: 988137). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADAMTS13 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003399043	SCV004121772	uncertain significance	not specified	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS13 c.1351G>A (p.Ala451Thr) results in a non-conservative amino acid change located in the cysteine-rich domain 3 (IPR045371) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-06 in 204006 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1351G>A in individuals affected with Thrombotic Thrombocytopenic Purpura and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328113	SCV001449174	uncertain significance	Atypical hemolytic-uremic syndrome	2018-04-05	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.1351G>A variant in the ADAMTS13 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases to be a disease causing variant. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.003% (1 out of 30,794 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this change; SIFT predicts it to be likely pathogenic whereasPolyPhen2 and MutationTaster predicts this variant to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines.