Submission Details

UPK3A was first reported in relation to autosomal dominant Congenital anomaly of the kidney and urinary tract (CAKUT) in 2005 (Jenkins et al., PMID: 15888565). At the time of curation, there were no single gene disorders associated with UPK3A. In the literature, UPK3A was implicated in the pathogenesis of CAKUT, Renal agenesis/Hypoplasia, and Vesicoureteral reflux (VUR). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference/difference in molecular mechanism and inheritance pattern, with CAKUT, VUR, and Renal agenesis/hypoplasia being representative of a CAKUT phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity, CAKUT (MONDO:0019719).8 variants (missense, nonsense, frameshift) that have been reported in 9 probands in publications (PMIDs:16731295 ,22558067, 26489027, 30773290, 32164334, 34979951, 36417404) are included in this curation. The majority of these variants were scored at 0 points due to all high frequencies in populations. This gene-disease association is also supported by an animal model and expression studies. In summary, the evidence supporting the relationship between UPK3A and autosomal dominant Congenital anomaly of the kidney and urinary tract has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role. This classification was approved by the ClinGen CAKUT GCEP on the meeting date 1/9/23 (SOP Version 9).