RPE65
retinoid isomerohydrolase RPE65
Basic information
Region (hg38): 1:68428822-68451103
Previous symbols: [ "RP20" ]
Links
Phenotypes
GenCC
Source:
- Leber congenital amaurosis 9 (Definitive), mode of inheritance: AR
- retinitis pigmentosa (Supportive), mode of inheritance: AD
- Leber congenital amaurosis (Supportive), mode of inheritance: AD
- severe early-childhood-onset retinal dystrophy (Supportive), mode of inheritance: AR
- Leber congenital amaurosis 2 (Definitive), mode of inheritance: AR
- Leber congenital amaurosis 2 (Strong), mode of inheritance: AR
- retinitis pigmentosa 20 (Strong), mode of inheritance: AR
- RPE65-related recessive retinopathy (Definitive), mode of inheritance: AR
- RPE65-related dominant retinopathy (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Retinitis pigmentosa 20; Leber congenital amaurosis 2 | AR | Ophthalmologic | Gene therapy has been described, with increased effectiveness when instituted early | Ophthalmologic | 13616783; 9326941; 9326927; 9501220; 12960219; 14962443; 15557452; 18441371; 18809924; 19675341; 18441370; 18774912; 19854499; 20006823; 22323828; 22644094; 23341016; 23341635; 23474247; 27375040; 28712536; 29033008 |
ClinVar
This is a list of variants' phenotypes submitted to
- Leber congenital amaurosis 2 (79 variants)
- Leber congenital amaurosis 2;Retinitis pigmentosa 20 (74 variants)
- RPE65-related recessive retinopathy (56 variants)
- not provided (45 variants)
- Retinitis pigmentosa 20;Leber congenital amaurosis 2 (45 variants)
- Leber congenital amaurosis (31 variants)
- Retinitis pigmentosa 20 (15 variants)
- Retinal dystrophy (14 variants)
- Retinitis pigmentosa (10 variants)
- Leber congenital amaurosis 2;Retinitis pigmentosa 87 with choroidal involvement;Retinitis pigmentosa 20 (6 variants)
- RPE65-related disorder (5 variants)
- Autosomal recessive retinitis pigmentosa (4 variants)
- Inborn genetic diseases (2 variants)
- Retinitis pigmentosa 87 with choroidal involvement;Leber congenital amaurosis 2;Retinitis pigmentosa 20 (1 variants)
- Congenital isolated adrenocorticotropic hormone deficiency (1 variants)
- RPE65-related disorder;Leber congenital amaurosis;Retinitis pigmentosa 20 (1 variants)
- Abnormality of the eye (1 variants)
- Retinitis pigmentosa 20;Retinitis pigmentosa 87 with choroidal involvement;Leber congenital amaurosis 2 (1 variants)
- Abnormality of vision;Abnormal electroretinogram;Congenital blindness;Retinal degeneration (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the RPE65 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 194 | 208 | ||||
| missense | 33 | 53 | 205 | 297 | ||
| nonsense | 39 | 45 | ||||
| start loss | 2 | |||||
| frameshift | 49 | 11 | 60 | |||
| inframe indel | 6 | |||||
| splice donor/acceptor (+/-2bp) | 24 | 18 | 42 | |||
| splice region | 1 | 1 | 17 | 38 | 1 | 58 |
| non coding | 15 | 112 | 21 | 149 | ||
| Total | 148 | 91 | 229 | 309 | 32 |
Highest pathogenic variant AF is 0.000131
Variants in RPE65
This is a list of pathogenic ClinVar variants found in the RPE65 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 1-68428830-G-A | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Apr 27, 2017) | ||
| 1-68428861-G-C | Retinitis pigmentosa • Leber congenital amaurosis 2 | Benign (Jan 13, 2018) | ||
| 1-68428890-A-G | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 13, 2018) | ||
| 1-68429016-T-G | Leber congenital amaurosis 2 • Retinitis pigmentosa | Uncertain significance (Jan 13, 2018) | ||
| 1-68429040-AT-A | Leber congenital amaurosis • Retinitis Pigmentosa, Recessive | Uncertain significance (Jun 14, 2016) | ||
| 1-68429096-C-T | Retinitis pigmentosa • Leber congenital amaurosis 2 | Likely benign (Jan 13, 2018) | ||
| 1-68429146-G-A | Leber congenital amaurosis 2 • Retinitis pigmentosa | Uncertain significance (Jan 13, 2018) | ||
| 1-68429165-C-T | Leber congenital amaurosis 2 • Retinitis pigmentosa | Benign (Jan 13, 2018) | ||
| 1-68429188-G-T | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 13, 2018) | ||
| 1-68429216-G-A | Leber congenital amaurosis 2 • Retinitis pigmentosa | Uncertain significance (Jan 13, 2018) | ||
| 1-68429222-G-A | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 13, 2018) | ||
| 1-68429230-T-G | Leber congenital amaurosis 2 • Retinitis pigmentosa | Uncertain significance (Jan 12, 2018) | ||
| 1-68429245-T-C | Leber congenital amaurosis 2 • Retinitis pigmentosa | Benign (Jan 12, 2018) | ||
| 1-68429259-C-T | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 13, 2018) | ||
| 1-68429265-C-T | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 13, 2018) | ||
| 1-68429352-G-T | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 12, 2018) | ||
| 1-68429435-A-G | Leber congenital amaurosis 2 • Retinitis pigmentosa | Likely benign (Jan 13, 2018) | ||
| 1-68429437-T-C | Leber congenital amaurosis 2 • Retinitis pigmentosa | Uncertain significance (Jan 12, 2018) | ||
| 1-68429584-T-C | Leber congenital amaurosis 2 • Retinitis pigmentosa | Uncertain significance (Jan 13, 2018) | ||
| 1-68429648-C-T | Retinitis pigmentosa • Leber congenital amaurosis 2 | Uncertain significance (Jan 13, 2018) | ||
| 1-68429781-A-T | Leber congenital amaurosis 2 • Retinitis pigmentosa 20;Leber congenital amaurosis 2 • not specified • Leber congenital amaurosis • Retinitis pigmentosa 20;Leber congenital amaurosis 2;Retinitis pigmentosa 87 with choroidal involvement • RPE65-related recessive retinopathy | Uncertain significance (Feb 18, 2024) | ||
| 1-68429781-A-AT | Leber congenital amaurosis 2 | Pathogenic (-) | ||
| 1-68429782-T-C | Retinitis pigmentosa 20;Leber congenital amaurosis 2 | Likely benign (Nov 19, 2022) | ||
| 1-68429787-TG-T | Retinitis pigmentosa 20;Leber congenital amaurosis 2 • Leber congenital amaurosis 2 | Pathogenic (Aug 28, 2023) | ||
| 1-68429788-G-T | Retinitis pigmentosa 20;Leber congenital amaurosis 2 • Leber congenital amaurosis 2 | Pathogenic (Mar 15, 2024) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| RPE65 | protein_coding | protein_coding | ENST00000262340 | 14 | 21138 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 6.49e-14 | 0.208 | 125638 | 0 | 110 | 125748 | 0.000437 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.240 | 284 | 273 | 1.04 | 0.0000143 | 3507 |
| Missense in Polyphen | 117 | 123.14 | 0.95012 | 1574 | ||
| Synonymous | -1.54 | 120 | 100 | 1.20 | 0.00000542 | 988 |
| Loss of Function | 1.07 | 24 | 30.4 | 0.790 | 0.00000154 | 369 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00140 | 0.00139 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.0000544 | 0.0000544 |
| Finnish | 0.000324 | 0.000323 |
| European (Non-Finnish) | 0.000458 | 0.000457 |
| Middle Eastern | 0.0000544 | 0.0000544 |
| South Asian | 0.000294 | 0.000294 |
| Other | 0.000492 | 0.000489 |
dbNSFP
Source:
- Function
- FUNCTION: Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins. Catalyzes the cleavage and isomerization of all-trans- retinyl fatty acid esters to 11-cis-retinol which is further oxidized by 11-cis retinol dehydrogenase to 11-cis-retinal for use as visual chromophore (PubMed:16116091). Essential for the production of 11-cis retinal for both rod and cone photoreceptors (PubMed:17848510). Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid (PubMed:28874556). The soluble form binds vitamin A (all-trans- retinol), making it available for LRAT processing to all-trans- retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis- retinol, a reaction catalyzed by LRAT (By similarity). {ECO:0000250|UniProtKB:Q28175, ECO:0000269|PubMed:16116091, ECO:0000269|PubMed:17848510, ECO:0000269|PubMed:28874556}.;
- Disease
- DISEASE: Leber congenital amaurosis 2 (LCA2) [MIM:204100]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:10090910, ECO:0000269|PubMed:10766140, ECO:0000269|PubMed:11462243, ECO:0000269|PubMed:14611946, ECO:0000269|PubMed:14962443, ECO:0000269|PubMed:15024725, ECO:0000269|PubMed:16205573, ECO:0000269|PubMed:17297704, ECO:0000269|PubMed:17724218, ECO:0000269|PubMed:18682808, ECO:0000269|PubMed:9326927, ECO:0000269|PubMed:9326941, ECO:0000269|PubMed:9801879}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 20 (RP20) [MIM:613794]: 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:11095629, ECO:0000269|PubMed:12960219, ECO:0000269|PubMed:15557452, ECO:0000269|PubMed:22334370, ECO:0000269|PubMed:23878505, ECO:0000269|PubMed:9501220}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in RPE65 are a cause of autosomal dominant retinitis pigmentosa with choroidal involvement (PubMed:21654732). Affected individuals show reduction of central vision, constriction of visual fields, night blindness and chorioretinal atrophy. {ECO:0000269|PubMed:21654732}.;
- Pathway
- Retinol metabolism - Homo sapiens (human);Vitamin A Deficiency;Retinol Metabolism;Vitamin A and Carotenoid Metabolism;Signaling by GPCR;Signal Transduction;The canonical retinoid cycle in rods (twilight vision);Visual signal transduction: Rods;G alpha (i) signalling events;Visual phototransduction;the visual cycle I (vertebrates);GPCR downstream signalling;Visual signal transduction: Cones
(Consensus)
Recessive Scores
- pRec
- 0.256
Intolerance Scores
- loftool
- 0.114
- rvis_EVS
- -0.38
- rvis_percentile_EVS
- 28.01
Haploinsufficiency Scores
- pHI
- 0.139
- hipred
- N
- hipred_score
- 0.282
- ghis
- 0.420
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.743
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Rpe65
- Phenotype
- homeostasis/metabolism phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); pigmentation phenotype; hematopoietic system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);
Gene ontology
- Biological process
- retinoid metabolic process;retina homeostasis;neural retina development;vitamin A metabolic process;regulation of rhodopsin gene expression;visual perception;circadian rhythm;insulin receptor signaling pathway;retinol metabolic process;retinal metabolic process;detection of light stimulus involved in visual perception;oxidation-reduction process;retina morphogenesis in camera-type eye;cellular response to electrical stimulus;zeaxanthin biosynthetic process
- Cellular component
- endoplasmic reticulum membrane;plasma membrane;membrane;organelle membrane;cell body
- Molecular function
- phosphatidylserine binding;retinal isomerase activity;oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen;isomerase activity;phosphatidylcholine binding;metal ion binding;retinol isomerase activity;all-trans-retinyl-palmitate hydrolase, 11-cis retinol forming activity;all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity;cardiolipin binding