Submission Details

The relationship between NUP93 (or Nuclear Pore Complex Protein 93) and AR Nephrotic syndrome type 12 was evaluated using the ClinGen Clinical Validity Framework. The NUP93 gene encodes a protein that regulates the flow of proteins between the nucleus and the cytoplasm. It also regulates the podocyte migration and proliferation through Smad4 signalling. It is expressed ubiquitously including in the kidney cortex and medulla, and in podocytes and in the developing kidney. NUP93 was first reported in relation to nephrotic syndrome by Braun in 2016 (PMID: 26878725). This is the only disease associated with pathogenic variants in this gene. The clinical presentation is with the development of the nephrotic syndrome at years 1- 6 and kidney failure a few years later. Pathogenic variants include truncating variants, splice site variants and missense changes that are associated with human disease. The mechanism of pathogenicity is Loss of Function. The gene-disease association is supported by experimental expression, protein interaction data, functional alterations in non-patient cells and in non-human model organisms and with rescue experiments in cell lines. In summary, NUP93 is definitively associated with AR nephrotic syndrome. This has been demonstrated in both the clinical diagnostic and research setting, and has been upheld over time. This assessment was performed according to the ClinGen Gene Clinical Validity SOP version 9 and was approved by the Glomerulopathy Working Group on 26 July 2022.