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GeneBe

RPE65

retinoid isomerohydrolase RPE65

Basic information

Region (hg38): 1:68428821-68449954

Previous symbols: [ "RP20" ]

Links

ENSG00000116745NCBI:6121OMIM:180069HGNC:10294Uniprot:Q16518AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • 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
  • RPE65-related recessive retinopathy (Definitive), mode of inheritance: AR
  • RPE65-related dominant retinopathy (Strong), mode of inheritance: AD
  • 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

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Retinitis pigmentosa 20; Leber congenital amaurosis 2AROphthalmologicGene therapy has been described, with increased effectiveness when instituted earlyOphthalmologic13616783; 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 ClinVar and linked to the RPE65 gene.

  • Leber congenital amaurosis 2;Retinitis pigmentosa 20 (304 variants)
  • Retinitis pigmentosa 20;Leber congenital amaurosis 2 (276 variants)
  • Leber congenital amaurosis 2 (196 variants)
  • not provided (155 variants)
  • Leber congenital amaurosis (102 variants)
  • Retinitis pigmentosa (77 variants)
  • Retinitis pigmentosa 20 (33 variants)
  • not specified (23 variants)
  • RPE65-related recessive retinopathy (19 variants)
  • Retinal dystrophy (19 variants)
  • Inborn genetic diseases (13 variants)
  • Retinitis pigmentosa 87 with choroidal involvement (7 variants)
  • RPE65-Related Disorders (6 variants)
  • Retinitis pigmentosa 87 with choroidal involvement;Leber congenital amaurosis 2;Retinitis pigmentosa 20 (5 variants)
  • Autosomal recessive retinitis pigmentosa (5 variants)
  • Congenital isolated adrenocorticotropic hormone deficiency (4 variants)
  • Leber congenital amaurosis 2;Retinitis pigmentosa 20;Retinitis pigmentosa 87 with choroidal involvement (4 variants)
  • Retinitis pigmentosa 20;Leber congenital amaurosis 2;Retinitis pigmentosa 87 with choroidal involvement (3 variants)
  • Retinitis pigmentosa 87 with choroidal involvement;Retinitis pigmentosa 20;Leber congenital amaurosis 2 (2 variants)
  • Abnormality of the eye (2 variants)
  • Cone-rod dystrophy 15 (2 variants)
  • Retinitis Pigmentosa, Recessive (2 variants)
  • Leber congenital amaurosis 2;Retinitis pigmentosa 87 with choroidal involvement;Retinitis pigmentosa 20 (2 variants)
  • RPE65-related condition (2 variants)
  • Congenital blindness;Retinal degeneration;Abnormality of vision;Abnormal electroretinogram (1 variants)
  • Neurodevelopmental disorder (1 variants)
  • Joubert syndrome 9 (1 variants)
  • Leber congenital amaurosis;Retinitis pigmentosa 20;RPE65-Related Disorders (1 variants)
  • - (1 variants)
  • Retinitis pigmentosa 20;Retinitis pigmentosa 87 with choroidal involvement;Leber congenital amaurosis 2 (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
4
clinvar
154
clinvar
7
clinvar
165
missense
26
clinvar
39
clinvar
188
clinvar
2
clinvar
3
clinvar
258
nonsense
24
clinvar
9
clinvar
33
start loss
2
clinvar
2
frameshift
35
clinvar
10
clinvar
45
inframe indel
1
clinvar
5
clinvar
6
splice donor/acceptor (+/-2bp)
16
clinvar
16
clinvar
32
splice region
1
1
15
27
1
45
non coding
15
clinvar
54
clinvar
21
clinvar
90
Total 102 76 212 210 31

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)875931
1-68428861-G-C Retinitis pigmentosa • Leber congenital amaurosis 2 Benign (Jan 13, 2018)298010
1-68428890-A-G Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 13, 2018)875932
1-68429016-T-G Leber congenital amaurosis 2 • Retinitis pigmentosa Uncertain significance (Jan 13, 2018)298011
1-68429040-AT-A Leber congenital amaurosis • Retinitis Pigmentosa, Recessive Uncertain significance (Jun 14, 2016)298012
1-68429096-C-T Retinitis pigmentosa • Leber congenital amaurosis 2 Likely benign (Jan 13, 2018)876922
1-68429146-G-A Leber congenital amaurosis 2 • Retinitis pigmentosa Uncertain significance (Jan 13, 2018)876923
1-68429165-C-T Leber congenital amaurosis 2 • Retinitis pigmentosa Benign (Jan 13, 2018)298013
1-68429188-G-T Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 13, 2018)298014
1-68429216-G-A Leber congenital amaurosis 2 • Retinitis pigmentosa Uncertain significance (Jan 13, 2018)874132
1-68429222-G-A Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 13, 2018)874133
1-68429230-T-G Leber congenital amaurosis 2 • Retinitis pigmentosa Uncertain significance (Jan 12, 2018)875064
1-68429245-T-C Leber congenital amaurosis 2 • Retinitis pigmentosa Benign (Jan 12, 2018)298015
1-68429259-C-T Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 13, 2018)298016
1-68429265-C-T Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 13, 2018)298017
1-68429352-G-T Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 12, 2018)875990
1-68429435-A-G Leber congenital amaurosis 2 • Retinitis pigmentosa Likely benign (Jan 13, 2018)875991
1-68429437-T-C Leber congenital amaurosis 2 • Retinitis pigmentosa Uncertain significance (Jan 12, 2018)875992
1-68429584-T-C Leber congenital amaurosis 2 • Retinitis pigmentosa Uncertain significance (Jan 13, 2018)875993
1-68429648-C-T Retinitis pigmentosa • Leber congenital amaurosis 2 Uncertain significance (Jan 13, 2018)876975
1-68429781-A-T Leber congenital amaurosis 2 • Leber congenital amaurosis 2;Retinitis pigmentosa 20 • not specified • Leber congenital amaurosis • RPE65-related recessive retinopathy • Leber congenital amaurosis 2;Retinitis pigmentosa 20;Retinitis pigmentosa 87 with choroidal involvement Uncertain significance (Feb 18, 2024)870342
1-68429781-A-AT Leber congenital amaurosis 2 Pathogenic (-)973968
1-68429782-T-C Retinitis pigmentosa 20;Leber congenital amaurosis 2 Likely benign (Nov 19, 2022)2941661
1-68429787-TG-T Leber congenital amaurosis 2 • Leber congenital amaurosis 2;Retinitis pigmentosa 20 Pathogenic (Aug 28, 2023)98850
1-68429788-G-T Retinitis pigmentosa 20;Leber congenital amaurosis 2 • Leber congenital amaurosis 2 Pathogenic (Jan 11, 2024)1470027

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
RPE65protein_codingprotein_codingENST00000262340 1421138
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
6.49e-140.20812563801101257480.000437
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.2402842731.040.00001433507
Missense in Polyphen117123.140.950121574
Synonymous-1.541201001.200.00000542988
Loss of Function1.072430.40.7900.00000154369

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.001400.00139
Ashkenazi Jewish0.000.00
East Asian0.00005440.0000544
Finnish0.0003240.000323
European (Non-Finnish)0.0004580.000457
Middle Eastern0.00005440.0000544
South Asian0.0002940.000294
Other0.0004920.000489

dbNSFP

Source: dbNSFP

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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