VSX1

Summary

VSX1 (visual system homeobox 1, HGNC:12723) is a protein-coding gene on chromosome 20p11.21, encoding Visual system homeobox 1 (Q9NZR4). Binds to the 37-bp core of the locus control region (LCR) of the red/green visual pigment gene cluster.

The protein encoded by this gene contains a paired-like homeodomain and binds to the core of the locus control region of the red/green visual pigment gene cluster. The encoded protein may regulate expression of the cone opsin genes early in development. Mutations in this gene can cause posterior polymorphous corneal dystrophy and keratoconus. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 30813 — RefSeq curated summary.

At a glance

• Gene–disease (curated): keratoconus 1 (Moderate, GenCC) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 175 total
• Phenotypes (HPO): 39
• MANE Select transcript: NM_014588

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12723
Approved symbol	VSX1
Name	visual system homeobox 1
Location	20p11.21
Locus type	gene with protein product
Status	Approved
Aliases	PPD, PPCD1
Ensembl gene	ENSG00000100987
Ensembl biotype	protein_coding
OMIM	605020
Entrez	30813

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000376707, ENST00000376709, ENST00000409285, ENST00000409958, ENST00000429762, ENST00000444511, ENST00000557285

RefSeq mRNA: 4 — MANE Select: NM_014588 NM_001256271, NM_001256272, NM_014588, NM_199425

CCDS: CCDS13168, CCDS13169, CCDS58766, CCDS58767

Canonical transcript exons

ENST00000376709 — 5 exons

Exon	Start	End
ENSE00000660987	25079436	25079514
ENSE00001364461	25078829	25078952
ENSE00001471432	25075463	25076550
ENSE00001471437	25081673	25082141
ENSE00001623269	25077685	25077865

Expression profiles

Bgee: expression breadth ubiquitous, 110 present calls, max score 87.58.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1676 / max 28.3969, expressed in 73 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186786	0.0635	40
186785	0.0589	35
186787	0.0452	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	87.58	gold quality
cerebellar cortex	UBERON:0002129	87.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.70	gold quality
cerebellum	UBERON:0002037	85.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.56	gold quality
buccal mucosa cell	CL:0002336	73.30	silver quality
adenohypophysis	UBERON:0002196	72.69	gold quality
parotid gland	UBERON:0001831	71.66	gold quality
amygdala	UBERON:0001876	70.94	gold quality
pituitary gland	UBERON:0000007	70.68	gold quality
hypothalamus	UBERON:0001898	69.73	gold quality
anterior cingulate cortex	UBERON:0009835	68.57	gold quality
substantia nigra	UBERON:0002038	67.37	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	67.33	gold quality
nucleus accumbens	UBERON:0001882	66.99	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.88	gold quality
right frontal lobe	UBERON:0002810	66.78	gold quality
brain	UBERON:0000955	66.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	66.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.38	gold quality
midbrain	UBERON:0001891	66.15	gold quality
spinal cord	UBERON:0002240	65.98	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.87	gold quality
putamen	UBERON:0001874	65.49	gold quality
prefrontal cortex	UBERON:0000451	65.29	gold quality
caudate nucleus	UBERON:0001873	64.90	gold quality
forebrain	UBERON:0001890	64.18	gold quality
biceps brachii	UBERON:0001507	63.99	gold quality
cerebellar vermis	UBERON:0004720	63.82	silver quality
temporal lobe	UBERON:0001871	63.48	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	2045.05
E-GEOD-137537	yes	1907.43
E-MTAB-7316	yes	1415.21
E-ANND-3	no	2.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
HTT
MCL1
NXNL1
RNU1-1
SHH
VSX1

JASPAR motifs

Motif	Name	Family
MA0725.1	VSX1	Paired-related HD factors
MA0725.2	VSX1	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): ISL1, VSX1, VSX2

miRNA regulators (miRDB)

59 targeting VSX1, 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-340-5P	100.00	72.50	4437
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195

Literature-anchored findings (GeneRIF, showing 37)

• Mutations in VSX1 homeobox gene results in impaired DNA binding and is associated with posterior polymorphous dystrophy and keratoconus (PMID:11978762)
• The new mutation in the VSX1 (RINX) gene described in this report results in abnormal craniofacial features, absence of the roof of the sella turcica, and anomalous development of the corneal endothelium. (PMID:15051220)
• Mutational analysis of the VSX1 gene in a series of Italian patients revealed one novel mutation and confirmed an important role played by this gene in a significant proportion of patients affected by keratoconus (PMID:15623752)
• CHX10 and VSX1 may control retinal bipolar cell specification or differentiation by repressing genes required for the development of other cell types (PMID:15647262)
• The human VSX1 is required for cone ON bipolar cell function but not for rod and cone OFF bipolar cells, giving a unique example of such a selective heritable retinal defect in humans. (PMID:16384943)
• The absence of pathogenic mutations in the VSX1 gene in a large number of unrelated KTCN (keratoconus) patients indicates that other genetic factors are involved in the development of this disorder. (PMID:16799019)
• The results show that VSX1 is expressed in vitro and in vivo during human corneal wound healing, a process in which differentiation of corneal keratocytes into myofibroblasts occurs. (PMID:17122109)
• We excluded c.432C>G sequence alteration as cause. Involvement of this gene in pathogenesis of keratoconus is likely to be confined to a small number of pedigrees. (PMID:17960127)
• We cannot confirm the previously reported association of the polymorphism in the VSX1 gene with keratoconus. (PMID:18216574)
• First documentation of VSX1 expression in human neonatal cornea. Full genomic sequence of VSX1 and coding exons of three other candidate genes were excluded from being pathogenic in original posterior polymorphous corneal dystrophy family. (PMID:18253095)
• VSX1 gene mutation is associated with keratoconus (PMID:18484309)
• VSX1 gene variants seem to be significant genetic variants for keratoconus predisposition in unrelated Korean patients. (PMID:18626569)
• The results exclude VSX1 and SOD1 as potential disease-causing genes in these families and localize a novel gene for keratoconus to a 5.6-Mb interval on 13q32. (PMID:19011015)
• The absence of pathogenic mutations in the VSX-1 gene in affected family members of 3 pedigrees indicates that other genetic factors are involved in the development of familial Fuchs endothelial corneal dystrophy. (PMID:19507099)
• VSX1has a minor role in keratoconus pathogenesis. (PMID:19763142)
• This is the first report from the Indian subcontinent exploring the role of VSX1 in the causation of keratoconus. (PMID:19956409)
• The absence of pathogenic mutations in our large number of unrelated patients with KC (keratoconus) indicates that other genetic factors are involved in the development of this disorder. (PMID:20023586)
• The absence of pathogenic mutations in VSX1 gene in our large number of unrelated keratoconus patients indicates that other genetic factors are involved in the development of this disorder (PMID:20664914)
• No pathogenic VSX1 mutation was identified. (PMID:21139977)
• VSX1 may have an important role in the pathogenesis of keratoconus. (PMID:21365019)
• In the keratoconus cohort, no pathogenic VSX1 mutation(s) were identified. (PMID:21403853)
• In mice, Vsx1 mRNA, protein or reporter gene expression is not detected in the normal or damaged cornea. (PMID:21437200)
• A novel mutation p.G239R and previously reported mutations were found in VSX1 in Italian patients with keratoconus. (PMID:21976959)
• A significant association between keratoconus patients and VSX1 genetic alterations, is reported. (PMID:22171159)
• Our results suggest that the VSX1 gene and its mutations with amino acid changes do not play a major role in the pathogenesis of keratoconus. (PMID:22531431)
• Our findings confirmed previous reports that polymorphisms of VSX1 and IL1A genes were associated with risk of keratoconus in the Chinese population (PMID:23289806)
• lack of VSX1 pathogenic variations in a large number of unrelated sporadic keratoconus patients tend to omit its role, and corroborate the involvement of other genetic, environmental or behavioural factors in the development of this complex disorder (PMID:23506487)
• This study reports the presence of pathogenic mutations in VSX1 in posterior polymorphous dystrophy and keratoconus. (PMID:23592923)
• We cannot confirm the previously reported association of the polymorphism in the VSX1 gene with keratoconus (KC). Our results suggest a possible causative role of SOD1 in the pathogenesis of KC. (PMID:24099280)
• Our investigation showed that Keratoconus-related VSX1 mutations were found in a very small proportion of the studied patients from Iran. (PMID:24107477)
• novel missense substitutions in the VSX1 gene: clinical and genetic analysis of families with Keratoconus from India (PMID:25963163)
• The aim of this study was to screen the visual system homeobox 1 (VSX1) gene in Turkish patients with keratoconus (PMID:27819732)
• In this study, we added one novel missense sequence variation (p.Arg131Pro) in the coding region of the VSX1 gene to the range of VSX1 coding region variations observed in patients with sporadic keratoconus from China. (PMID:28950846)
• Sequence variants of the VSX1 gene were identified for the first time in Chinese patients with sporadic keratoconus (PMID:29518881)
• VSX1 is involved in keratoconus and other corneal pathologies (PMID:30574758)
• High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10. (PMID:36463181)
• The association between VSX1 exon3 gene variants and keratoconus in Malaysian patients. (PMID:37322657)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	vsx1	ENSDARG00000056292
mus_musculus	Vsx1	ENSMUSG00000033080
rattus_norvegicus	Vsx1	ENSRNOG00000042220
caenorhabditis_elegans		WBGENE00001096

Protein

Protein identifiers

Visual system homeobox 1 — Q9NZR4 (reviewed: Q9NZR4)

Alternative names: Homeodomain protein RINX, Retinal inner nuclear layer homeobox protein, Transcription factor VSX1

All UniProt accessions (1): Q9NZR4

UniProt curated annotations — full annotation on UniProt →

Function. Binds to the 37-bp core of the locus control region (LCR) of the red/green visual pigment gene cluster. May regulate the activity of the LCR and the cone opsin genes at earlier stages of development. Dispensable in early retinal development.

Subcellular location. Nucleus.

Tissue specificity. In the adult eye, expressed in lens, iris, ciliary body, choroid, optical nerve head and, most strongly, in retina, but not expressed in sclera and cornea. According to PubMed:11978762, expressed in adult retina but not in lens and cornea. Within adult retina, found exclusively in the inner nuclear layer. Isoform 1, isoform 2, isoform 3 and isoform 4 expressed in adult retina, but not in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle. Not expressed in thymus and spleen. Expressed in embryonic craniofacial tissue. Expressed in fetal (week 14) retina. Strongly expressed in neonatal retina, weakly in neonatal lens, choroid and cornea (day 1, 4; month 9).

Disease relevance. Keratoconus 1 (KTCN1) [MIM:148300] Frequent corneal dystrophy with an incidence that varies from 50 to 230 per 100'000. The cornea assumes a conical shape as a result of a progressive non-inflammatory thinning of the corneal stroma. Keratoconus is most often an isolated sporadic condition with cases of autosomal dominant and autosomal recessive transmission. The disease is caused by variants affecting the gene represented in this entry. Craniofacial anomalies and anterior segment dysgenesis syndrome (CAASDS) [MIM:614195] A disorder with extremely variable expressivity. Clinical features include wide interpupillary distance, abnormal corneal endothelium, unusual pinnae, partially to completely empty sella turcica, posterior fossa cyst, anterior encephalocele, and/or hydrocephalus. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Major form. Major form. Minor form. Minor form.

Similarity. Belongs to the paired homeobox family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q9NZR4-1	1, L1	yes
Q9NZR4-2	2, S1, L3
Q9NZR4-3	3, S2
Q9NZR4-4	4, S3
Q9NZR4-5	5
Q9NZR4-6	6
Q9NZR4-7	7
Q9NZR4-8	8

RefSeq proteins (4): NP_001243200, NP_001243201, NP_055403, NP_955457 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR023339	CVC	Domain
IPR051775	Homeobox_domain	Family

Pfam: PF00046

UniProt features (35 total): splice variant 13, sequence variant 11, compositionally biased region 3, region of interest 3, short sequence motif 2, chain 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZR4-F1	61.61	0.16

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 182 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, MYAATNNNNNNNGGC_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEURON_MATURATION, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CELL_MATURATION, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_SENSORY_PERCEPTION, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_SENSORY_ORGAN_MORPHOGENESIS, GOBP_RETINA_DEVELOPMENT_IN_CAMERA_TYPE_EYE, GOBP_CAMERA_TYPE_EYE_MORPHOGENESIS

GO Biological Process (6): regulation of DNA-templated transcription (GO:0006355), visual perception (GO:0007601), neuron maturation (GO:0042551), neuron development (GO:0048666), retinal bipolar neuron differentiation (GO:0060040), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (6): transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
sensory perception of light stimulus	1
cell maturation	1
neuron development	1
neuron differentiation	1
cell development	1
neural retina development	1
retina morphogenesis in camera-type eye	1
glutamatergic neuron differentiation	1
transcription by RNA polymerase II	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1044 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VSX1	COL8A2	P25067	894
VSX1	NXNL1	Q96CM4	841
VSX1	ATOH7	Q8N100	737
VSX1	COL4A3	Q01955	724
VSX1	FOXN4	Q96NZ1	666
VSX1	ZEB1	P37275	658
VSX1	BHLHE23	Q8NDY6	651
VSX1	SP3	Q02447	644
VSX1	DOCK9	Q9BZ29	643
VSX1	ZNF469	Q96JG9	629
VSX1	PDE6B	P35913	619
VSX1	PTF1A	Q7RTS3	598
VSX1	RAB3GAP1	Q15042	575
VSX1	UBE2I	P50550	571
VSX1	POU4F2	Q12837	565

IntAct

12 interactions, top by confidence:

A	B	Type	Score
VSX1	USP12	psi-mi:“MI:0914”(association)	0.730
BAG6	VSX1	psi-mi:“MI:0915”(physical association)	0.560
PPBP	VSX1	psi-mi:“MI:0915”(physical association)	0.370
ARMCX3	MAPK13	psi-mi:“MI:0914”(association)	0.350
VSX1	A2ML1	psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
VSX1	NFIB	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (77): CTBP2 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), USP9Y (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), CSNK2A2 (Affinity Capture-MS), CSNK2A1 (Affinity Capture-MS), CSNK2B (Affinity Capture-MS), MOCS3 (Affinity Capture-MS), WDR20 (Affinity Capture-MS), HIST2H2AC (Affinity Capture-MS), CSNK2A1 (Affinity Capture-MS), CSNK2A2 (Affinity Capture-MS), CSNK2B (Affinity Capture-MS), HIST2H2AC (Affinity Capture-MS), USP12 (Affinity Capture-MS)

ESM2 similar proteins: A0A5F9ZHS7, A1YGK1, A2T7E6, A8MZG2, O08574, O43593, O60393, O75593, O88621, O95231, P0C1T1, P0CG20, P20428, P97609, Q04667, Q17QR5, Q2KIS6, Q2M1V0, Q2T9Q7, Q32LE6, Q497V6, Q5JUK2, Q5M844, Q5RJB0, Q5TGS1, Q61645, Q61657, Q6ZMY3, Q6ZN32, Q6ZNG2, Q7RTU1, Q8BZW2, Q8CGW9, Q8IWN7, Q8IXT2, Q8IZ20, Q8N1L9, Q8N7G0, Q8N944, Q8N9Y4

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	26
Benign	22

Top pathogenic / likely-pathogenic (0)

SpliceAI

796 predictions. Top by Δscore:

Variant	Effect	Δscore
20:25078764:A:AC	donor_gain	1.0000
20:25078765:C:CC	donor_gain	1.0000
20:25079524:C:CT	acceptor_gain	1.0000
20:25079525:A:T	acceptor_gain	1.0000
20:25080298:AT:A	donor_gain	1.0000
20:25076549:CCCT:C	acceptor_gain	0.9900
20:25076550:CCT:C	acceptor_gain	0.9900
20:25076552:T:C	acceptor_gain	0.9900
20:25077678:T:TA	donor_gain	0.9900
20:25078948:CTGTC:C	acceptor_gain	0.9900
20:25079515:C:CC	acceptor_gain	0.9900
20:25079522:C:CT	acceptor_gain	0.9900
20:25080298:ATC:A	donor_gain	0.9900
20:25080299:T:C	donor_gain	0.9900
20:25076552:T:TC	acceptor_gain	0.9800
20:25078953:C:CC	acceptor_gain	0.9800
20:25079431:TATAC:T	donor_loss	0.9800
20:25079432:ATAC:A	donor_loss	0.9800
20:25079433:TA:T	donor_loss	0.9800
20:25079434:ACCT:A	donor_loss	0.9800
20:25079435:CCTG:C	donor_loss	0.9800
20:25079452:T:TA	donor_gain	0.9800
20:25079512:CAT:C	acceptor_gain	0.9800
20:25080294:A:AC	donor_gain	0.9800
20:25080295:C:CC	donor_gain	0.9800
20:25080298:A:AC	donor_gain	0.9800
20:25077866:C:CA	acceptor_loss	0.9700
20:25077870:T:C	acceptor_gain	0.9700
20:25077877:C:CT	acceptor_gain	0.9700
20:25078786:T:A	donor_gain	0.9700

AlphaMissense

2337 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:25077853:T:C	N214D	1.000
20:25077857:A:C	F212L	1.000
20:25077857:A:T	F212L	1.000
20:25077859:A:G	F212L	1.000
20:25077860:C:A	W211C	1.000
20:25077860:C:G	W211C	1.000
20:25077862:A:G	W211R	1.000
20:25077862:A:T	W211R	1.000
20:25078907:G:C	F183L	1.000
20:25078907:G:T	F183L	1.000
20:25078909:A:G	F183L	1.000
20:25078943:G:C	F171L	1.000
20:25078943:G:T	F171L	1.000
20:25078944:A:C	F171C	1.000
20:25078944:A:G	F171S	1.000
20:25078945:A:G	F171L	1.000
20:25077835:G:T	R220S	0.999
20:25077845:C:A	R216S	0.999
20:25077845:C:G	R216S	0.999
20:25077846:C:A	R216M	0.999
20:25077846:C:G	R216T	0.999
20:25077849:C:G	R215P	0.999
20:25077850:G:T	R215S	0.999
20:25077851:G:C	N214K	0.999
20:25077851:G:T	N214K	0.999
20:25077852:T:A	N214I	0.999
20:25077852:T:C	N214S	0.999
20:25077852:T:G	N214T	0.999
20:25077854:T:A	Q213H	0.999
20:25077854:T:G	Q213H	0.999

dbSNP variants (sampled 300 via entrez): RS1000104257 (20:25077345 C>T), RS1000362897 (20:25073618 T>C), RS1000416199 (20:25079088 C>A,G,T), RS1000471831 (20:25079371 G>T), RS1000724307 (20:25078841 T>C), RS1000898617 (20:25084045 C>T), RS1000989556 (20:25074908 A>G), RS1001092977 (20:25079178 A>G), RS1001317002 (20:25074680 T>C), RS1001598681 (20:25073899 A>C,G), RS1001758379 (20:25079933 C>A,T), RS1001920528 (20:25075970 C>G,T), RS1002445113 (20:25081740 C>A,T), RS1002495973 (20:25081906 G>A,C), RS1002606272 (20:25075166 A>G)

Disease associations

OMIM: gene MIM:605020 | disease phenotypes: MIM:122000, MIM:148300, MIM:192500, MIM:614195

GenCC curated gene-disease

Disease	Classification	Inheritance
keratoconus 1	Moderate	Autosomal dominant
posterior polymorphous corneal dystrophy	Supportive	Autosomal dominant
posterior polymorphous corneal dystrophy 1	Limited	Unknown
craniofacial anomalies and anterior segment dysgenesis syndrome	Limited	Unknown

Mondo (6): posterior polymorphous corneal dystrophy (MONDO:0020364), keratoconus 1 (MONDO:0007851), long QT syndrome (MONDO:0002442), familial long QT syndrome (MONDO:0019171), craniofacial anomalies and anterior segment dysgenesis syndrome (MONDO:0013618), posterior polymorphous corneal dystrophy 1 (MONDO:0007378)

Orphanet (3): Posterior polymorphous corneal dystrophy (Orphanet:98973), Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000238	Hydrocephalus
HP:0000316	Hypertelorism
HP:0000377	Abnormal pinna morphology
HP:0000483	Astigmatism
HP:0000501	Glaucoma
HP:0000512	Abnormal electroretinogram
HP:0000533	Chorioretinal atrophy
HP:0000543	Optic disc pallor
HP:0000563	Keratoconus
HP:0000565	Esotropia
HP:0000585	Band keratopathy
HP:0000613	Photophobia
HP:0000622	Blurred vision
HP:0000632	Lacrimation abnormality
HP:0000646	Amblyopia
HP:0002119	Ventriculomegaly
HP:0002315	Headache
HP:0002321	Vertigo
HP:0003577	Congenital onset
HP:0007291	Posterior fossa cyst
HP:0007663	Reduced visual acuity
HP:0007676	Hypoplasia of the iris
HP:0007700	Ocular anterior segment dysgenesis
HP:0007906	Ocular hypertension
HP:0007957	Corneal opacity
HP:0008625	Severe sensorineural hearing impairment
HP:0009918	Ectopia pupillae
HP:0011462	Young adult onset
HP:0011483	Anterior synechiae of the anterior chamber

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007328_73	Alcohol consumption (drinks per week)	5.000000e-09
GCST010002_64	Refractive error	5.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C563649	Keratoconus 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	1
butylbenzyl phthalate	decreases expression	1
tetrachlorodian	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Theophylline	affects cotreatment, decreases expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT00800111	Not specified	COMPLETED	Study of Endothelial Keratoplasty Outcomes
NCT02020044	Not specified	UNKNOWN	Outcome After Descemet Membrane Endothelial Keratoplasty (DMEK) and Ultra-thin Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)
NCT04387331	Not specified	UNKNOWN	The Postoperative Head Position as a Predictor of the Surgical Outcome After DMEK
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies