RPE65

retinoid isomerohydrolase RPE65

Basic information

Region (hg38): 1:68428821-68449954

Previous symbols: [ "RP20" ]

Links

ENSG00000116745 ∙ NCBI:6121 ∙ OMIM:180069 ∙ HGNC:10294 ∙ Uniprot:Q16518 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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
• 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: CGD

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 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	154	7	165
missense	26	39	188	2	3	258
nonsense	24	9				33
start loss		2				2
frameshift	35	10				45
inframe indel	1		5			6
splice donor/acceptor (+/-2bp)	16	16				32
splice region	1	1	15	27	1	45
non coding			15	54	21	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)
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 • 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)
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		Leber congenital amaurosis 2 • Leber congenital amaurosis 2;Retinitis pigmentosa 20	Pathogenic (Aug 28, 2023)
1-68429788-G-T		Retinitis pigmentosa 20;Leber congenital amaurosis 2 • Leber congenital amaurosis 2	Pathogenic (Jan 11, 2024)

GnomAD

Source: gnomAD

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: 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

	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