RP1 was first reported in relation to autosomal dominant (or semidominant) retinitis pigmentosa (RP) in 1999 (Pierce et al., PMID: 10391211 & Sullivan et al. PMID: 10391212). RP1 was later reported in relation to autosomal recessive RP in 2005 (Khaliq et al., PMID: 15863674). It appears that the majority of RP1 variants located in the region encoding the middle of the RP1 protein between c.1981 (p.661) to c.2749 (p.917) are associated with dominant RP, while the variants in the N-terminal portion from c.1 (p.1) to c.1837 (p.613) and the C-terminal from c.2816 (p.939) to c.6471 (p.2157) are mostly associated with recessive RP (summarized in Wang et al., PMID: 33681214). Patients with recessive RP generally exhibit much more severe phenotypes than patients with dominant RP. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we split retinitis pigmentosa 1 (OMIM: 180100) into two disease entities, RP1-related dominant retinopathy (MONDO:0800400) and RP1-related recessive retinopathy. The split curation for RP1-related recessive retinopathy has been curated separately. The RP1 protein is a member of the doublecortin family and is present in the ciliary axoneme of both rods and cones (reviewed in Nikopoulos et al, PMID: 31253780). Several nonsense and frameshift variants have been curated. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The variants in RP1-related dominant retinopathy are thought to escape nonsense-mediated decay (NMD) and their mechanism of pathogenicity appears to be dominant negative (reviewed in Nanda et al., PMID: 30731082). This gene-disease relationship is also supported by expression studies. In summary, RP1 is definitively associated with RP1-related dominant retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on September 1st, 2022 (SOP Version 9).
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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