*NPHP3 *was first reported in relation to autosomal recessive nephronophthisis in 2003 (Olbrich et al., PMID: 12872122), after direction by linkage analysis and homozygosity mapping by Omran et al in 2000 (PMID: 10631142). There are a number of different disease entities described as associated with *NPHP3 *in OMIM, including nephronophthisis, renal-hepatic-pancreatic-dysplasia and Meckel syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism OR inheritance pattern between these different disease entities. Therefore, these disease entities have been lumped into one disease which we suggest is referred to as ‘nephronophthisis – NPHP3’. Multiple variants (missense, in-frame, indel and predicted protein truncating variants) have been reported across multiple probands in multiple publications (PMIDs: 12872122, 19177160) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies and animal models (mice and zebrafish) (PMIDs: 12872122, 18371931, 20462968). In summary, *NPHP3 *is strongly associated with autosomal recessive nephronophthisis (NPHP-NPHP3). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP on 07/24/2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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