Submission Details

RP1 was first reported in relation to an inherited retinal dystrophy, 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 middle region 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 and RP1-related recessive retinopathy (MONDO:0800399). The split curation for RP1-related dominant 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 and more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity for variants in RP1-related recessive retinopathy appears to be LOF. This gene-disease relationship is also supported by expression studies and knock-out mouse models. In summary, RP1 is definitively associated with RP1-related recessive retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina GCEP on July 7, 2022 (SOP v9).