ClinVar Miner

Submissions for variant NM_139025.4(ADAMTS13):c.1423C>T (p.Pro475Ser) (rs11575933)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767050 SCV000617792 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing The P475S variant in the ADAMTS13 gene has been reported in a deceased female infant with diarrhea negative hemolytic uremic syndrome and ADAMTS13 activity that was 54% of normal levels (Choi et al., 2011). This variant is also reported often in the literature as a polymorphism with a suspected northeastern Asian origin of the variant (Nakagawa et al., 2016). The P475S variant is observed in 169/3336 alleles (5.1%) from individuals of Latino background and 117/4614 alleles (2.5%) from individuals of East Asian background in the ExAC dataset, with 4 homozygous control individuals reported from all ExAC populations (Lek et al., 2016). The P475S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. Crystal structure analysis indicates that the P475S mutant destabilizes the protein leading to reduced substrate affinity and moderately reduced catalytic efficiency of the ADAMTS13 enzyme (Akiyama et al., 2013). In cell transfection studies, the P475S variant resulted in very low enzyme activity (Kokame et al., 2002). We interpret P475S as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000006170 SCV000478321 likely benign Upshaw-Schulman syndrome 2016-06-14 criteria provided, single submitter clinical testing
OMIM RCV000006170 SCV000026352 pathogenic Upshaw-Schulman syndrome 2002-09-03 no assertion criteria provided literature only
PreventionGenetics RCV000251648 SCV000315859 likely benign not specified criteria provided, single submitter clinical testing

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