RP1
protein-codingRP1 axonemal microtubule associated, the group of Doublecortin superfamily
Gene summary
This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~362.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008377
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0800400
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0800399
Submitter: ClinGen
*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).
Inheritance Pattern: AR
Disease ID:MONDO:0800399
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008377
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0008377
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0800400
Submitter: ClinGen
*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).
Inheritance Pattern: AD
Disease ID:MONDO:0008377
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0800399
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008377
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008377
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0800400
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006269.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 12 | 292 | 10 | 315 | |
| missense | 3 | 17 | 1047 | 59 | 6 | 1132 |
| nonsense | 78 | 41 | 4 | 123 | ||
| start loss | 0 | |||||
| frameshift | 140 | 64 | 6 | 210 | ||
| splice donor/acceptor (+/-2bp) | 2 | 7 | 9 | |||
| Total | 223 | 130 | 1069 | 351 | 16 | 1789 |
Highest pathogenic variant AF is 0.00014689002
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006260.1 | 3 | MANE Select | |
| Ensembl | ENSP00000220676.1 | 3 | MANE Select | |
| RefSeq | NP_001362583.1 | 29 | Standard | |
| Ensembl | ENSP00000489857.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- visual perception
- phototransduction, visible light
- axoneme assembly
- intracellular signal transduction
- photoreceptor cell outer segment organization
Molecular Function
- protein binding
- microtubule binding
Cellular Component
- photoreceptor outer segment
- photoreceptor inner segment
- microtubule
- microtubule associated complex
- axoneme
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000220676
- Coding exons
- 3
- Length
- 14768
- Individuals with no LoFs
- 125529
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 219
- Defined
- 125748
- p
- 0.000871
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.894 | 1169 | 1.09e+3 | 1.08 | 0.0000553 | 14374 |
| Missense (PolyPhen) | 167 | 182.08 | 0.91716 | 2415 | ||
| Synonymous | 0.218 | 390 | 396 | 0.986 | 0.0000210 | 4037 |
| Loss of Function | 3.39 | 30 | 57.8 | 0.519 | 0.00000295 | 901 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0011 | 0.0011 | notable |
| Latino/Admixed American | 0.00069 | 0.00069 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0030 | 0.0030 | notable |
| Finnish | 0.00046 | 0.00046 | rare |
| European (Non-Finnish) | 0.00072 | 0.00071 | rare |
| South Asian | 0.00075 | 0.00075 | rare |
| Other | 0.0011 | 0.0011 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Microtubule-associated protein regulating the stability and length of the microtubule-based axoneme of photoreceptors. Required for the differentiation of photoreceptor cells, it plays a role in the organization of the outer segment of rod and cone photoreceptors ensuring the correct orientation and higher-order stacking of outer segment disks along the photoreceptor axoneme (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Retinitis pigmentosa 1 (RP1) [MIM:180100]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:10391211, ECO:0000269|PubMed:10484783, ECO:0000269|PubMed:11095597, ECO:0000269|PubMed:15863674, ECO:0000269|PubMed:15933747, ECO:0000269|PubMed:19956407, ECO:0000269|PubMed:20664799, ECO:0000269|PubMed:22052604, ECO:0000269|PubMed:22334370}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.102
Intolerance Scores
- LoFtool
- 0.497
- RVIS EVS
- 0.85
- RVIS percentile EVS
- 88.38
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0265
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |