EYS

Summary

EYS (EGF-like photoreceptor maintenance factor, HGNC:21555) is a protein-coding gene on chromosome 6q12, encoding Protein eyes shut homolog (Q5T1H1). Required to maintain the integrity of photoreceptor cells.

The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 346007 — RefSeq curated summary.

At a glance

• Gene–disease (curated): EYS-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 30
• Clinical variants (ClinVar): 5,427 total — 654 pathogenic, 411 likely-pathogenic
• Phenotypes (HPO): 36
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001142800

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21555
Approved symbol	EYS
Name	EGF-like photoreceptor maintenance factor
Location	6q12
Locus type	gene with protein product
Status	Approved
Aliases	dJ1018A4.2, bA166P24.2, SPAM, bA307F22.3, dJ303F19.1, bA74E24.1
Ensembl gene	ENSG00000188107
Ensembl biotype	protein_coding
OMIM	612424
Entrez	346007

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000330816, ENST00000342421, ENST00000370615, ENST00000370621, ENST00000393380, ENST00000398580, ENST00000447127, ENST00000471279, ENST00000486069, ENST00000489873, ENST00000503581

RefSeq mRNA: 4 — MANE Select: NM_001142800 NM_001142800, NM_001142801, NM_001292009, NM_198283

CCDS: CCDS47445, CCDS47446, CCDS4967, CCDS78156

Canonical transcript exons

ENST00000503581 — 43 exons

Exon	Start	End
ENSE00000798529	64886697	64886842
ENSE00001320118	64902404	64902500
ENSE00001364832	65402478	65402605
ENSE00001367595	65344038	65344177
ENSE00001368601	65495859	65495993
ENSE00001374135	65384386	65384500
ENSE00001376348	65353458	65353617
ENSE00001383234	65490594	65490707
ENSE00001391635	65405174	65405367
ENSE00001453165	64997582	64997703
ENSE00001453166	64912484	64912743
ENSE00001453168	64813378	64813577
ENSE00001453170	64821645	64821723
ENSE00001515080	65334980	65335146
ENSE00001515104	65639778	65639892
ENSE00001533737	63762461	63762633
ENSE00001533739	63778006	63778180
ENSE00001533744	63806190	63806372
ENSE00001533745	63864186	63864358
ENSE00001614643	64822651	64822822
ENSE00001616620	64439162	64439352
ENSE00001668994	63726519	63726680
ENSE00001698002	64945793	64945914
ENSE00001722114	65295863	65296119
ENSE00001737817	64388690	64388840
ENSE00001741812	64066338	64066491
ENSE00001742499	64306970	64307082
ENSE00001754122	64590223	64591989
ENSE00001763466	63999075	63999183
ENSE00001764216	64230592	64230824
ENSE00001774255	64436174	64436265
ENSE00001774849	64593117	64593309
ENSE00001776042	64902113	64902220
ENSE00001776248	64081856	64082002
ENSE00001801545	63984383	63984603
ENSE00001944389	65057614	65057727
ENSE00002026430	63719980	63721797
ENSE00003507832	63789058	63789224
ENSE00003515400	64617418	64617533
ENSE00003519686	63788105	63788249
ENSE00003593910	65494663	65495607
ENSE00003632823	64626121	64626245
ENSE00003890635	65707135	65707226

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 80.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0926 / max 332.2312, expressed in 57 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74222	0.7571	35
74224	0.2622	19
74213	0.0476	16
74223	0.0257	11

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.44	gold quality
islet of Langerhans	UBERON:0000006	69.96	gold quality
calcaneal tendon	UBERON:0003701	68.95	gold quality
right testis	UBERON:0004534	66.58	gold quality
left testis	UBERON:0004533	66.22	gold quality
testis	UBERON:0000473	65.40	gold quality
adrenal tissue	UBERON:0018303	62.44	gold quality
rectum	UBERON:0001052	60.26	gold quality
pancreas	UBERON:0001264	59.09	gold quality
tendon	UBERON:0000043	58.09	gold quality
leukocyte	CL:0000738	57.48	gold quality
monocyte	CL:0000576	57.30	gold quality
ganglionic eminence	UBERON:0004023	57.07	gold quality
right adrenal gland cortex	UBERON:0035827	56.49	gold quality
bone marrow cell	CL:0002092	56.46	gold quality
right lobe of liver	UBERON:0001114	55.74	gold quality
colonic epithelium	UBERON:0000397	55.66	gold quality
ventricular zone	UBERON:0003053	55.54	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	55.51	gold quality
mucosa of stomach	UBERON:0001199	55.27	gold quality
granulocyte	CL:0000094	55.01	gold quality
body of pancreas	UBERON:0001150	54.75	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
liver	UBERON:0002107	53.98	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
subcutaneous adipose tissue	UBERON:0002190	53.86	gold quality
blood	UBERON:0000178	53.75	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	2807.41
E-MTAB-5061	yes	11.02
E-ANND-3	yes	7.78
E-GEOD-81547	yes	5.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting EYS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-138-2-3P	98.91	68.33	1643

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• To study if copy number variation exists within RP25, comparative genomic hybridization analysis on a consanguineous family revealed a clone, chr6tp-19C7, spanning 100-Kb was deleted in all affected members of the family. (PMID:18510646)
• In order to validate the original linkage of RP25, study undertook a total genome scan using the 10K GeneChip mapping array on 3 of the previously linked families; data obtained supported the initial findings of linkage. (PMID:18510647)
• EYS, at the RP25 locus on chromosome 6q12 commonly mutated in autosomal recessive retinitis pigmentosa, is identified. (PMID:18836446)
• EYS is identified as a human ortholog of Drosopbhila eys, which is mutated in patients with retinitis pigmentosa. (PMID:18976725)
• EYS is a major causative gene for recessive retinitis pigmentosa and emphasize the role of different types of mutations in disrupting the function of EYS. (PMID:20237254)
• Data identified novel mutations in EYS in a total of 29 patients: Fifteen of the mutations were predicted to create premature stop codons and two represent exonic deletions. Twenty missense, silent or splice-site mutations were detected. (PMID:20333770)
• EYS is currently the most commonly mutated autosomal recessive retinitis pigmentosa gene in the Israeli population, mainly due to founder mutations (PMID:20375346)
• Mutations in EYS account for approximately 5% of autosomal recessive RP (retinitis pigmetosa) patients. (PMID:20537394)
• a single nucleotide substitution of G to T at nucleotide 5506 was identified in a Chinese arRP family, causing a substitution of a glutamic acid residue at codon 1,836 by a stop codon TAA (p.E1836X), resulting in a truncated protein with 1,835 amino acids (PMID:20696082)
• Report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. (PMID:21069908)
• The mutations p.D2767Y and p.D3028Y described in this study affect highly conserved residues at homologous positions in laminin A G-like domains and support the notion that missense mutations in EYS can cause autosomal recessive retinitis pigmentosa. (PMID:21179430)
• Results suggest that midsized genomic rearrangements in EYS gene would be a common event in the appearance of retinitis pigmentosa phenotype (PMID:21519034)
• The results of this GWAS, replication, and fine mapping study provide the first reported evidence that genetic variants mutation within the EYS gene, may be associated with severe statin myopathy. (PMID:21826682)
• One-third of Japanese patients with nonsyndromic autosomal recessive retinitis pigmentosa carried probable pathogenic mutations in the EYS gene, including two founder mutations (PMID:22302105)
• This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese autosomal recessive retinitis pigmentosa patients. (PMID:22363543)
• PTP4A1-PHF3-EYS variants were associated with alcohol dependence. (PMID:23324950)
• It appears that patients share a relatively uniform phenotype with near-normal central visual function up to their twenties. The patients homozygous for the c.4957_4958insA mutation showed a uniform course of visual acuity changes. (PMID:23421333)
• Our results demonstrated that EYS mutations can be the cause of not only autosomal recessive retinitis pigmentosa but also autoisomal recessive cone-rod dystrophy. (PMID:24652164)
• We confirmed with our previous findings that PTP4A1-PHF3-EYS variants were significantly associated with alcohol dependence. (PMID:24961364)
• New variants were found to be located on the USH2A, RPGR, EYS, and RHO genes (PMID:25366773)
• Advanced retinal degenerative changes with near-total absence of rods and preservation of some perifoveal cones are observed in arRP donor retinas with EYS mutations. (PMID:25491159)
• our study expands the genotypic spectrums for EYS mutations, and may provide novel insights into the relevant pathogenesis for RP. We also demonstrate targeted next-generation sequencing approach as a valuable tool for genetic diagnosis. (PMID:25753737)
• Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of retinitis pigmentosa. (PMID:27375351)
• Bietti crystalline dystrophy patients with CYP4V2 mutations showed more severe macular choroid atrophy as compared to EYS-related RP patients. These different damage patterns suggest differences in choroidal expression between CYP4V2 and EYS. (PMID:27658286)
• The results obtained in this study lead us to speculate that, in photoreceptor cells, EYS could be a protein involved in maintaining the stability of the ciliary axoneme in both rods and cones. The variability of its isoform structure suggests that other roles are also possible and yet to be established (PMID:27846257)
• A novel single base pair insertion mutation has been found in the EYS gene in a six generations family with retinitis pigmentosa. (PMID:28419563)
• Of the 297 unique EYS variants identified, almost half (n = 130) are predicted to result in premature truncation of the EYS protein. (PMID:29159838)
• EYS-RP is a heterogeneous manifestation. Variants occurring in positions closer to the C-terminus of EYS are more common in patients presenting with hyperautofluorescent (hyperAF) rings on fundus autofluorescence imaging. (PMID:29550188)
• EYS mutation is associated with retinitis pigmentosa. (PMID:30153090)
• The manner of decay of genetically defective EYS gene transcripts in photoreceptor-directed fibroblasts derived from retinitis pigmentosa patients depends on the type of mutation. (PMID:30359287)
• The study identified eight novel EYS variants and expanded the spectrum of EYS mutations in Chinese retinitis pigmentosa patients. (PMID:30804660)
• Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases (PMID:31074760)
• These results suggest that EYS polymorphism may be associated with lumbar disc herniation among Han Chinese population. It also opens up a new exploration direction for the etiology of lumbar disc herniation. (PMID:31359629)
• This is the first report showing the pathogenicity of three missense variants (p.(Gly843Glu), p.(Gly2186Glu), and p.(Ile2188Thr)) and the presence of copy number variations in the EYS gene. (PMID:31814702)
• Genetic and clinical analysis in Chinese patients with retinitis pigmentosa caused by EYS mutations. (PMID:31944634)
• Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency. (PMID:32218477)
• Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree. (PMID:32436957)
• ““Genetic and clinical findings in an ethnically diverse retinitis pigmentosa cohort associated with pathogenic variants in EYS””. (PMID:32728228)
• Identification of Novel EYS Mutations by Targeted Sequencing Analysis. (PMID:33058741)
• EYS is a major gene involved in retinitis pigmentosa in Japan: genetic landscapes revealed by stepwise genetic screening. (PMID:33247286)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	frac	FBGN0035798

Paralogs (6): FBLN1 (ENSG00000077942), EFEMP1 (ENSG00000115380), FBLN5 (ENSG00000140092), VWDE (ENSG00000146530), FBLN2 (ENSG00000163520), EFEMP2 (ENSG00000172638)

Protein

Protein identifiers

Protein eyes shut homolog — Q5T1H1 (reviewed: Q5T1H1)

Alternative names: Epidermal growth factor-like protein 10, Epidermal growth factor-like protein 11, Protein spacemaker homolog

All UniProt accessions (3): F8WDD3, Q5T1H1, H0Y3Q4

UniProt curated annotations — full annotation on UniProt →

Function. Required to maintain the integrity of photoreceptor cells. Specifically required for normal morphology of the photoreceptor ciliary pocket, and might thus facilitate protein trafficking between the photoreceptor inner and outer segments via the transition zone.

Subcellular location. Cell projection. Cilium. Photoreceptor outer segment. Cytoplasm. Cytoskeleton. Cilium axoneme. Microtubule organizing center. Centrosome. Secreted. Extracellular space. Extracellular matrix. Interphotoreceptor matrix.

Tissue specificity. Expressed in retina (at protein level). Isoform 1: Detected in retina. Isoform 2: Detected in retina. Isoform 3: Strongly expressed in retina and testis. Isoform 4: Strongly expressed in testis, and weakly expressed in retina.

Disease relevance. Retinitis pigmentosa 25 (RP25) [MIM:602772] 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. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Although the protein is conserved in Drosophila, the gene encoding the orthologous protein is inactive in rodents.

Similarity. Belongs to the EYS family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5T1H1-3	4	yes
Q5T1H1-1	1
Q5T1H1-2	3
Q5T1H1-4	2

RefSeq proteins (4): NP_001136272, NP_001136273, NP_001278938, NP_938024 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013032	EGF-like_CS	Conserved_site
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site

Pfam: PF00008, PF02210, PF12661

UniProt features (189 total): disulfide bond 78, sequence variant 59, domain 32, glycosylation site 8, sequence conflict 6, splice variant 4, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q5T1H1 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (78): 2130–2139, 2339–2350, 2344–2359, 2375–2386, 2380–2396, 2398–2407, 2576–2609, 2614–2625, 2619–2634, 2636–2645, 2652–2668, 2662–2677, 2679–2688, 2868–2895, 2900–2911, 2905–2920, 2922–2931, 2937–2948, 2942–2958, 2960–2969 …

Glycosylation sites (8): 166, 269, 272, 311, 343, 506, 566, 2170

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, chr6q12, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_GROWTH, GOBP_REGENERATION, GOCC_MICROTUBULE_ORGANIZING_CENTER, SNIJDERS_AMPLIFIED_IN_HEAD_AND_NECK_TUMORS, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOCC_CENTROSOME, GOBP_RESPONSE_TO_RADIATION, GOBP_TISSUE_REGENERATION, GOBP_DETECTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_ABIOTIC_STIMULUS

GO Biological Process (5): skeletal muscle tissue regeneration (GO:0043403), detection of light stimulus involved in visual perception (GO:0050908), visual perception (GO:0007601), developmental growth (GO:0048589), nervous system process (GO:0050877)

GO Molecular Function (1): calcium ion binding (GO:0005509)

GO Cellular Component (12): photoreceptor outer segment (GO:0001750), centrosome (GO:0005813), axoneme (GO:0005930), interphotoreceptor matrix (GO:0033165), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), cell surface (GO:0009986), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
tissue regeneration	1
visual perception	1
detection of light stimulus involved in sensory perception	1
sensory perception of light stimulus	1
developmental process	1
growth	1
system process	1
metal ion binding	1
photoreceptor cell cilium	1
centriole	1
microtubule organizing center	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
specialized extracellular matrix	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1871 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EYS	CERKL	Q49MI3	857
EYS	IMPG2	Q9BZV3	853
EYS	PRPF31	Q8WWY3	841
EYS	PCARE	A6NGG8	841
EYS	RPGR	Q92834	832
EYS	ABCA4	P78363	829
EYS	CNGB1	Q14028	806
EYS	TULP1	O00294	801
EYS	RDH12	Q96NR8	801
EYS	PRCD	Q00LT1	800
EYS	CNGA1	P29973	792
EYS	PDE6A	P16499	790
EYS	PRPH2	P23942	786
EYS	RPE65	Q16518	771
EYS	ZNF513	Q8N8E2	761

IntAct

2 interactions, top by confidence:

A	B	Type	Score
	VPS37C	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): EYS (Affinity Capture-MS), EYS (Affinity Capture-MS), EYS (Affinity Capture-RNA), EYS (Affinity Capture-RNA)

ESM2 similar proteins: A0A2K5V015, A1YIY0, A8MUZ8, A8MWA4, B8JI71, O08569, P01133, P0DJ43, P14370, P14585, P17630, P19070, P48357, P82279, P97435, Q07444, Q0D2K5, Q28066, Q28660, Q29RU2, Q4KUS1, Q5G872, Q5R6R1, Q5RCW9, Q5T1H1, Q5UKY4, Q5Z5Q3, Q60736, Q63515, Q63722, Q6DFV8, Q6GMZ9, Q6V0K7, Q6ZN79, Q7TSY4, Q811Q4, Q8N2E2, Q8VHS2, Q90Y54, Q95MI4

Diamond homologs: A0A2K5V015, A8X481, B8JI71, P13508, P21956, P70490, P78504, Q5R6R1, Q5T1H1, Q8JZM4, Q8NFT8, Q90Y54, Q9NL29, Q9QXX0, Q9Y219, A4FV93, B2LW77, D3ZHH1, O35474, O43854, O60494, O88516, O88671, P00740, P10040, P16293, P79385, P82279, P97607, Q04756, Q20911, Q5E9Z2, Q5GFL6, Q5IJ48, Q5R7K9, Q5ZQU0, Q63722, Q6QNF4, Q6R8J2, Q6UY11

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

5427 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	654
Likely pathogenic	411
Uncertain significance	1853
Likely benign	1867
Benign	164

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013294	NM_001142800.2(EYS):c.3885del (p.Lys1295fs)	Pathogenic
1065702	NM_001142800.2(EYS):c.2461G>T (p.Gly821Ter)	Pathogenic
1065997	NM_001142800.2(EYS):c.2641+2T>C	Pathogenic
1068046	NC_000006.11:g.(?65622367)(65767630_?)del	Pathogenic
1068047	NC_000006.11:g.(?65523251)(65622656_?)del	Pathogenic
1068376	NM_001142800.2(EYS):c.6725+1G>A	Pathogenic
1068538	NM_001142800.2(EYS):c.5661_5662insAA (p.Tyr1888fs)	Pathogenic
1068597	NC_000006.11:g.(?65655676)(65707606_?)del	Pathogenic
1068599	NC_000006.11:g.(?65622377)(65655807_?)del	Pathogenic
1068675	NM_001142800.2(EYS):c.8670T>A (p.Cys2890Ter)	Pathogenic
1068722	NC_000006.11:g.(?66005746)(66115270_?)del	Pathogenic
1068724	NC_000006.11:g.(?65707475)(65707596_?)dup	Pathogenic
1068815	NM_001142800.2(EYS):c.533dup (p.Ser179fs)	Pathogenic
1068977	NM_001142800.2(EYS):c.8189dup (p.Asp2730fs)	Pathogenic
1069227	NM_001142800.2(EYS):c.1387_1388insA (p.Val463fs)	Pathogenic
1069772	NM_001142800.2(EYS):c.3443+1G>A	Pathogenic
1069800	NM_001142800.2(EYS):c.8858del (p.Ser2953fs)	Pathogenic
1070119	NM_001142800.2(EYS):c.9019_9307delinsTTTTTTTAAAATTTTTTTTAAAATTGGT (p.Asp3007_Ile3103delinsPhePheTer)	Pathogenic
1070198	NM_001142800.2(EYS):c.3562C>T (p.Gln1188Ter)	Pathogenic
1070726	NC_000006.11:g.(?65531528)(65622646_?)del	Pathogenic
1070727	NC_000006.11:g.(?65149045)(65336148_?)del	Pathogenic
1070728	NC_000006.11:g.(?64940485)(65336138_?)del	Pathogenic
1070910	NM_001142800.2(EYS):c.1641_1644del (p.Ser547fs)	Pathogenic
1071148	NM_001142800.2(EYS):c.3676G>T (p.Gly1226Ter)	Pathogenic
1071465	NM_001142800.2(EYS):c.6073dup (p.Ile2025fs)	Pathogenic
1071588	NM_001142800.2(EYS):c.4452G>A (p.Trp1484Ter)	Pathogenic
1071665	NM_001142800.2(EYS):c.8596A>T (p.Lys2866Ter)	Pathogenic
1071792	NM_001142800.2(EYS):c.5296del (p.His1766fs)	Pathogenic
1071945	NM_001142800.2(EYS):c.6381_6393del (p.Gln2127fs)	Pathogenic
1072184	NM_001142800.2(EYS):c.8828G>A (p.Trp2943Ter)	Pathogenic

SpliceAI

4384 predictions. Top by Δscore:

Variant	Effect	Δscore
6:63762634:C:CC	acceptor_gain	1.0000
6:63788099:CCTTA:C	donor_loss	1.0000
6:63788100:CTTAC:C	donor_loss	1.0000
6:63788101:TTA:T	donor_loss	1.0000
6:63788102:TA:T	donor_loss	1.0000
6:63788103:A:T	donor_loss	1.0000
6:63788104:CCT:C	donor_loss	1.0000
6:63864354:TATCA:T	acceptor_gain	1.0000
6:63864356:TCA:T	acceptor_gain	1.0000
6:63864357:CA:C	acceptor_gain	1.0000
6:63864357:CAC:C	acceptor_gain	1.0000
6:63864359:C:CC	acceptor_gain	1.0000
6:63964151:A:AC	donor_gain	1.0000
6:63999073:A:AC	donor_gain	1.0000
6:63999073:A:C	donor_loss	1.0000
6:63999074:C:CA	donor_loss	1.0000
6:63999074:C:CC	donor_gain	1.0000
6:63999179:TGTAG:T	acceptor_gain	1.0000
6:63999180:GTAG:G	acceptor_gain	1.0000
6:63999181:TAG:T	acceptor_gain	1.0000
6:63999184:C:CC	acceptor_gain	1.0000
6:63999189:C:CT	acceptor_gain	1.0000
6:63999190:G:C	acceptor_gain	1.0000
6:64081854:A:AC	donor_gain	1.0000
6:64081855:C:CG	donor_gain	1.0000
6:64081855:CT:C	donor_gain	1.0000
6:64081855:CTGT:C	donor_gain	1.0000
6:64081855:CTGTA:C	donor_gain	1.0000
6:64082003:C:CC	acceptor_gain	1.0000
6:64230587:ATTAC:A	donor_loss	1.0000

AlphaMissense

20875 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:64230600:C:G	C2139S	0.993
6:64230601:A:T	C2139S	0.993
6:64230600:C:T	C2139Y	0.990
6:63721155:A:G	F2980S	0.989
6:63721755:A:G	L2780P	0.988
6:63864305:C:G	C2370S	0.988
6:63864306:A:T	C2370S	0.988
6:63721485:C:G	R2870P	0.986
6:63721251:C:G	C2948S	0.985
6:63721252:A:T	C2948S	0.985
6:63721641:A:G	L2818P	0.985
6:63721752:C:G	R2781P	0.985
6:64230600:C:A	C2139F	0.985
6:63721188:C:G	C2969S	0.984
6:63721189:A:T	C2969S	0.984
6:63721269:C:G	C2942S	0.984
6:63721270:A:T	C2942S	0.984
6:63721362:C:G	C2911S	0.984
6:63721363:A:T	C2911S	0.984
6:64230599:A:C	C2139W	0.984
6:64230633:C:G	C2128S	0.984
6:64230634:A:T	C2128S	0.984
6:63721302:C:G	C2931S	0.982
6:63721303:A:T	C2931S	0.982
6:63789062:A:G	L2525P	0.982
6:65495284:A:G	W43R	0.982
6:65495284:A:T	W43R	0.982
6:63721188:C:T	C2969Y	0.981
6:63721380:C:G	C2905S	0.981
6:63721381:A:T	C2905S	0.981

dbSNP variants (sampled 300 via entrez): RS1000002534 (6:64655848 A>G), RS1000003043 (6:64321897 A>G), RS1000003130 (6:64950965 T>C), RS1000006553 (6:64127539 C>T), RS1000008591 (6:65702048 C>T), RS1000013671 (6:65707691 C>G), RS1000014249 (6:63850258 A>T), RS1000018028 (6:65028192 C>T), RS1000018350 (6:64401344 T>C), RS1000021156 (6:64050811 A>G), RS1000022317 (6:65332493 C>A,G,T), RS1000022780 (6:64508679 C>T), RS1000023017 (6:64733349 C>G), RS1000023729 (6:63755112 T>G), RS1000023747 (6:65586395 C>T)

Disease associations

OMIM: gene MIM:612424 | disease phenotypes: MIM:602772, MIM:268000, MIM:120970, MIM:180050, MIM:312530, MIM:153880, MIM:603047, MIM:248200, MIM:215500

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 25	Definitive	Autosomal recessive
retinitis pigmentosa	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
EYS-related retinopathy	Definitive	AR

Mondo (13): retinitis pigmentosa 25 (MONDO:0011272), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), cone-rod dystrophy (MONDO:0015993), optic atrophy (MONDO:0003608), retinal disorder (MONDO:0005283), EYS-related retinopathy (MONDO:0800391), retinal detachment (MONDO:0008375), cystoid macular edema (MONDO:0007935), astigmatism (MONDO:0011284), Stargardt disease (MONDO:0019353), retinitis punctata albescens (MONDO:0018877), central areolar choroidal dystrophy (MONDO:0008982)

Orphanet (7): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cone rod dystrophy (Orphanet:1872), Cystoid macular dystrophy (Orphanet:75381), Stargardt disease (Orphanet:827), Retinitis punctata albescens (Orphanet:52427), Central areolar choroidal dystrophy (Orphanet:75377)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000533	Chorioretinal atrophy
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000550	Undetectable electroretinogram
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001133	Constriction of peripheral visual field
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007843	Attenuation of retinal blood vessels
HP:0007994	Peripheral visual field loss
HP:0008046	Abnormal retinal vascular morphology

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST002041_6	Blood trace element (Cu levels)	4.000000e-06
GCST002514_4	Melanoma	2.000000e-06
GCST003439_1	Response to paclitaxel in ovarian cancer (Caspase 3/7 EC50)	2.000000e-06
GCST004059_2	Exhaled nitric oxide levels	2.000000e-06
GCST004060_5	Exhaled nitric oxide output	7.000000e-07
GCST004136_2	Methadone dose in opioid dependence	7.000000e-07
GCST004904_55	Body mass index	1.000000e-09
GCST004946_57	Schizophrenia	3.000000e-08
GCST005093_6	Iris color (a* coordinate)	3.000000e-06
GCST006248_9	Response to lurasidone in schizophrenia	2.000000e-06
GCST006434_3	Systolic blood pressure x alcohol consumption interaction (2df test)	7.000000e-09
GCST006944_2	Experiencing mood swings	1.000000e-08
GCST006944_41	Experiencing mood swings	9.000000e-09
GCST007201_61	Schizophrenia	2.000000e-08
GCST007362_8	Acute anterior uveitis (with or without ankylosing spondylitis)	5.000000e-06
GCST008175_2	Gamma glutamyl transferase levels	8.000000e-06
GCST008508_2	Stress sensitivity (neuroticism score x major depressive disorder status interaction)	5.000000e-07
GCST008526_73	Coffee consumption	7.000000e-06
GCST008660_8	Lung function in never smokers (high FEV1 vs average FEV1)	1.000000e-07
GCST009849_7	Hallux valgus	2.000000e-06
GCST010122_3	Ceramide levels (C22:0)	9.000000e-06
GCST010145_2	Cerebrospinal fluid immune biomarker levels	3.000000e-08
GCST011382_15	Systemic mastocytosis	9.000000e-08
GCST011741_35	LDL cholesterol levels in HIV infection	6.000000e-06
GCST011773_30	Type 1 diabetes (age at diagnosis)	9.000000e-06
GCST012132_2	hemolysis of donated blood (osmotic)	3.000000e-09
GCST012490_170	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST90011892_4	Retinitis pigmentosa	9.000000e-10
GCST90011893_2	Retinitis pigmentosa	2.000000e-07
GCST90011894_6	Retinitis pigmentosa	1.000000e-13

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0005267	serum copper measurement
EFO:0006952	cytotoxicity measurement
EFO:0005536	nitric oxide exhalation measurement
EFO:0007907	methadone dose measurement
EFO:0004340	body mass index
EFO:0003949	eye color
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0008475	mood instability measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0007660	neuroticism measurement
EFO:0006781	coffee consumption measurement
EFO:0004314	forced expiratory volume
EFO:0004869	YKL40 measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004918	age at diagnosis
EFO:0009473	hemolysis
EFO:0004531	urate measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D001251	Astigmatism	C11.744.212
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012163	Retinal Detachment	C11.768.648
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
C566425	Retinitis Pigmentosa 25 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1337512	Toxicity	3	HMG-CoA reductase inhibitors	Rhabdomyolysis
rs3857532	Toxicity	3	HMG-CoA reductase inhibitors	Rhabdomyolysis
rs9342288	Toxicity	3	HMG CoA reductase inhibitors;other combinations	Cardiovascular Disease;Rhabdomyolysis

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3857532	EYS	3	1.00	1	HMG-CoA reductase inhibitors
rs9342288	EYS	3	1.00	1	HMG CoA reductase inhibitors;other combinations
rs1337512	EYS	3	1.00	1	HMG-CoA reductase inhibitors

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, affects methylation	2
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
pentanal	decreases expression	1
licochalcone B	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Oxygen	decreases expression	1
Polystyrenes	decreases expression	1
Aflatoxin B1	increases methylation	1
Asbestos, Serpentine	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Nanotubes, Carbon	increases expression	1

Cellosaurus cell lines

5 cell lines: 5 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E4E2	MUi038-A	Induced pluripotent stem cell	Male
CVCL_E7T6	VHIRi001-A	Induced pluripotent stem cell	Female
CVCL_E7T7	VHIRi002-A	Induced pluripotent stem cell	Female
CVCL_E7T8	VHIRi003-A	Induced pluripotent stem cell	Female
CVCL_UJ72	CABi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

263 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa