USH1G

Summary

USH1G (USH1 protein network component sans, HGNC:16356) is a protein-coding gene on chromosome 17q25.1, encoding pre-mRNA splicing regulator USH1G (Q495M9). Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assembly of the pre-catalytic spliceosome on t….

This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 124590 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Usher syndrome type 1 (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 481 total — 40 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 18
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_173477

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16356
Approved symbol	USH1G
Name	USH1 protein network component sans
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	Sans, FLJ33924, ANKS4A
Ensembl gene	ENSG00000182040
Ensembl biotype	protein_coding
OMIM	607696
Entrez	124590

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 nonsense_mediated_decay, 1 protein_coding

ENST00000579243, ENST00000614341

RefSeq mRNA: 2 — MANE Select: NM_173477 NM_001282489, NM_173477

CCDS: CCDS32725

Canonical transcript exons

ENST00000614341 — 3 exons

Exon	Start	End
ENSE00003730451	74919454	74920671
ENSE00003733648	74916083	74918076
ENSE00003849187	74922910	74923255

Expression profiles

Bgee: expression breadth broad, 69 present calls, max score 79.40.

FANTOM5 (CAGE): breadth broad, TPM avg 0.4590 / max 27.6376, expressed in 194 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168022	0.4590	194

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	79.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.30	silver quality
esophagus squamous epithelium	UBERON:0006920	75.52	silver quality
esophagus mucosa	UBERON:0002469	74.79	gold quality
endothelial cell	CL:0000115	70.30	gold quality
gingival epithelium	UBERON:0001949	66.30	gold quality
pigmented layer of retina	UBERON:0001782	66.02	gold quality
buccal mucosa cell	CL:0002336	65.56	gold quality
gingiva	UBERON:0001828	65.47	gold quality
upper leg skin	UBERON:0004262	65.01	silver quality
skin of hip	UBERON:0001554	63.70	silver quality
skin of leg	UBERON:0001511	63.40	gold quality
oral cavity	UBERON:0000167	62.63	gold quality
amniotic fluid	UBERON:0000173	62.28	gold quality
right adrenal gland cortex	UBERON:0035827	60.96	gold quality
secondary oocyte	CL:0000655	60.55	gold quality
palpebral conjunctiva	UBERON:0001812	60.28	gold quality
seminal vesicle	UBERON:0000998	60.11	gold quality
jejunal mucosa	UBERON:0000399	60.10	gold quality
zone of skin	UBERON:0000014	59.95	gold quality
adrenal tissue	UBERON:0018303	58.88	gold quality
oocyte	CL:0000023	58.73	gold quality
epithelium of nasopharynx	UBERON:0001951	58.69	gold quality
right adrenal gland	UBERON:0001233	58.49	gold quality
sperm	CL:0000019	58.27	gold quality
left adrenal gland cortex	UBERON:0035825	58.20	gold quality
germinal epithelium of ovary	UBERON:0001304	58.12	gold quality
trabecular bone tissue	UBERON:0002483	58.10	gold quality
left adrenal gland	UBERON:0001234	58.08	gold quality
mammalian vulva	UBERON:0000997	57.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting USH1G, 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-8485	100.00	77.57	4731
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-3688-5P	99.12	69.67	1091

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• A novel D458V mutation in the USH1G PDZ binding motif causes atypical Usher syndrome. (PMID:16283141)
• USH1G has a minor involvement in Usher syndrome pathogenesis. Only eight different changes without a clear pathogenic effect have been detected. (PMID:17896313)
• Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins (PMID:20142502)
• A frameshift mutation in SANS results in atypical Usher syndrome (PMID:21044053)
• crystal structure of MYO7A MyTH4-FERM domains in complex with the central domain (CEN) of Sans at 2.8 angstrom resolution; MyTH4-FERM/CEN complex structure provides mechanistic explanations for known deafness-causing mutations in MYO7A MyTH4-FERM (PMID:21311020)
• A role of the SANS-myomegalin complex in microtubule-dependent inner segment cargo transport towards the ciliary base of photoreceptor cells. (PMID:21767579)
• Pathogenic mutations in MYO7A, USH1C, and USH1G have been found in four consanguineous Israeli Arab families with Usher syndrome type 1. (PMID:22219650)
• A novel p.S243X truncating mutation in USH1G that segregated with the disease phenotype has been identified in consanguineous Saudi Arabia siblings. (PMID:22876113)
• In USH1G patients, mutations in SANS eliminate Magi2 binding and thereby deregulate endocytosis, lead to defective ciliary transport modules and ultimately disrupt photoreceptor cell function inducing retinal degeneration. (PMID:24608321)
• USH1G caused a non-syndromic hearing loss in a Dutch family. Compound heterozygous mutations in USH1G were found to segregate with the hearing loss, a missense (c.310A>G, p.Met104Val) and a frameshift mutation (c.780insGCAC, p.Tyr261Alafs*96). (PMID:25255398)
• Protein-protein interaction assays and co-expression of complex partners reveal that pathogenic mutations in USH1G severely affect formation of the SANS/ush2a/whirlin complex. Translational read-through drug treatment, targeting the c.728C > A (p.S243X) nonsense mutation, restored SANS scaffold function. We conclude that USH1 and USH2 proteins function together in higher order protein complexes. (PMID:28137943)
• Crystall structure shows the interactions between SANS protein domains and its partner Myo7a. (PMID:28660889)
• The protein products of PCDH15 and USH1G function together at the stereocilia tips in the hair cells. (PMID:30029624)
• Novel USH1G homozygous variant underlying USH2-like phenotype of Usher syndrome. (PMID:31566003)
• Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condensed Molecular Assembly via Liquid-Liquid Phase Separation. (PMID:31644917)
• SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes. (PMID:34023904)
• Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome. (PMID:38139438)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ush1ga	ENSDARG00000004322
danio_rerio	ush1gb	ENSDARG00000076079
mus_musculus	Ush1g	ENSMUSG00000045288
rattus_norvegicus	Ush1g	ENSRNOG00000028456
drosophila_melanogaster	Sans	FBGN0033785

Paralogs (1): ANKS4B (ENSG00000175311)

Protein

Protein identifiers

pre-mRNA splicing regulator USH1G — Q495M9 (reviewed: Q495M9)

Alternative names: Scaffold protein containing ankyrin repeats and SAM domain, Usher syndrome type-1G protein

All UniProt accessions (2): Q495M9, J3KSN5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in pre-mRNA splicing by regulating the release and transfer of U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complexes from their assembly site in Cajal bodies to nuclear speckles, thereby contributing to the assembly of the pre-catalytic spliceosome on target pre-mRNAs. May also participate in recycling of snRNPs back to Cajal bodies during splicing. Plays a role in regulating MAGI2-mediated endocytosis. Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal development and maintenance of cochlear hair cell bundles. Required for normal hearing.

Subunit / interactions. Part of a complex composed of USH1C, USH1G and MYO7A. Interacts with USH1C (via the first PDZ domain). Interacts with PDZD7. Interacts with CDH23 and PCDH15; these interactions may recruit USH1G to the plasma membrane. Interacts with intraflagellar transport proteins IFT20, IFT52 and IFT57. Interacts with splicing factors SF3B1, PRPF6, PRPF31 and SON. Interacts with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complex in the presence of pre-mRNAs. Interacts (via SAM domain) with MAGI2 (via PDZ 6 domain); the interaction is triggered by phosphorylation of USH1G by CK2 and negatively regulates MAGI2-mediated endocytosis.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Cell membrane. Cell projection. Cilium. Nucleus speckle. Nucleus. Cajal body. Microtubule organizing center. Centrosome. Photoreceptor inner segment.

Tissue specificity. Expressed in vestibule of the inner ear, eye and small intestine.

Disease relevance. Usher syndrome 1G (USH1G) [MIM:606943] USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. The disease is caused by variants affecting the gene represented in this entry. The first cases with non-syndromic sensorineural hearing loss based on mutations in USH1G. The hearing loss has an onset during early childhood, is progressive, and has a downsloping audiogram configuration. Ophthalmic and vestibular abnormalities are absent.

RefSeq proteins (2): NP_001269418, NP_775748* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037602	USH1G_SAM	Domain

Pfam: PF00536, PF12796

UniProt features (31 total): helix 6, mutagenesis site 5, strand 4, repeat 3, sequence variant 3, sequence conflict 2, turn 2, region of interest 2, chain 1, domain 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3K1R	X-RAY DIFFRACTION	2.3
3PVL	X-RAY DIFFRACTION	2.8
2L7T	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q495M9-F1	68.84	0.34

Functional residue map

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

Post-translational modifications (1): 422

Mutagenesis-validated functional residues (5):

Position	Phenotype
307	reduced affinity for myo7a.
317	reduced affinity for myo7a.
374	strongly reduced affinity for myo7a.
422	abolishes interaction with magi2.
422	phosphomimetic mutant; does not affect interaction with magi2.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 154 (showing top): RNGTGGGC_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, LFA1_Q6, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, CCANNAGRKGGC_UNKNOWN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GATA3_01, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS

GO Biological Process (8): sensory perception of sound (GO:0007605), inner ear morphogenesis (GO:0042472), photoreceptor cell maintenance (GO:0045494), sensory perception of light stimulus (GO:0050953), equilibrioception (GO:0050957), inner ear receptor cell stereocilium organization (GO:0060122), regulation of clathrin-dependent endocytosis (GO:2000369), inner ear receptor cell differentiation (GO:0060113)

GO Molecular Function (3): spectrin binding (GO:0030507), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (18): photoreceptor inner segment (GO:0001917), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), Cajal body (GO:0015030), actin cytoskeleton (GO:0015629), nuclear speck (GO:0016607), photoreceptor connecting cilium (GO:0032391), ciliary basal body (GO:0036064), ciliary base (GO:0097546), photoreceptor cell cilium (GO:0097733), nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), membrane (GO:0016020), cell projection (GO:0042995), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
inner ear development	2
sensory perception	2
microtubule organizing center	2
nuclear ribonucleoprotein granule	2
ciliary transition zone	2
cilium	2
sensory perception of mechanical stimulus	1
ear morphogenesis	1
embryonic morphogenesis	1
retina homeostasis	1
multicellular organismal process	1
neuromuscular process controlling balance	1
neuron projection development	1
inner ear receptor cell development	1
regulation of receptor-mediated endocytosis	1
clathrin-dependent endocytosis	1
mechanoreceptor differentiation	1
cytoskeletal protein binding	1
protein-containing complex binding	1
protein binding	1
binding	1
centriole	1
cytoplasm	1
membrane	1
cell periphery	1
cytoskeleton	1
photoreceptor cell cilium	1
ciliary transition fiber	1
neuron projection	1
9+0 non-motile cilium	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cell projection	1
plasma membrane region	1

Protein interactions and networks

STRING

1226 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USH1G	E9PNW1	E9PNW1	998
USH1G	CDH23	Q9H251	992
USH1G	WHRN	Q9P202	992
USH1G	MYO7A	P78427	989
USH1G	PCDH15	Q96QU1	985
USH1G	PDZD7	Q9H5P4	966
USH1G	ADGRV1	Q8WXG9	964
USH1G	USH2A	O75445	924
USH1G	CLRN1	P58418	893
USH1G	MYO15A	Q9UKN7	827
USH1G	CIB2	O75838	823
USH1G	TMC1	Q8TDI8	760
USH1G	LRRC4C	Q9HCJ2	649
USH1G	TMC2	Q8TDI7	606
USH1G	STRC	Q7RTU9	603

IntAct

95 interactions, top by confidence:

A	B	Type	Score
USH1G	USH1C	psi-mi:“MI:0915”(physical association)	0.960
USH1C	USH1G	psi-mi:“MI:0407”(direct interaction)	0.960
USH1G	USH1C	psi-mi:“MI:2364”(proximity)	0.960
USH1C	USH1G	psi-mi:“MI:0915”(physical association)	0.960
USH1C	USH1G	psi-mi:“MI:0403”(colocalization)	0.960
USH1G	FAM161B	psi-mi:“MI:0915”(physical association)	0.600
FAM161B	USH1G	psi-mi:“MI:0915”(physical association)	0.600
USH1G	USH1G	psi-mi:“MI:0407”(direct interaction)	0.560
PRKAA2	USH1G	psi-mi:“MI:0915”(physical association)	0.560
USH1G	INO80B	psi-mi:“MI:0915”(physical association)	0.560
BYSL	USH1G	psi-mi:“MI:0915”(physical association)	0.560
USH1G	DAXX	psi-mi:“MI:0915”(physical association)	0.560
USH1G	ANKRD11	psi-mi:“MI:0915”(physical association)	0.560
GEM	USH1G	psi-mi:“MI:0915”(physical association)	0.560
USH1G	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
DDX6	USH1G	psi-mi:“MI:0915”(physical association)	0.560
USH1G	TCEANC	psi-mi:“MI:0915”(physical association)	0.560
HOXB5	USH1G	psi-mi:“MI:0915”(physical association)	0.560
USH1G	PRPF31	psi-mi:“MI:0915”(physical association)	0.560
USH1G	AIRIM	psi-mi:“MI:0915”(physical association)	0.560
LMO2	USH1G	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (33): USH1C (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), POTEF (Affinity Capture-MS), USH1G (Affinity Capture-MS), USH1C (FRET), USH1G (Affinity Capture-Luminescence), USH1G (FRET), USH1C (Affinity Capture-Luminescence), USH1G (Two-hybrid), USH1G (Two-hybrid), USH1G (Two-hybrid), USH1G (Two-hybrid), USH1G (Two-hybrid), USH1G (Two-hybrid), USH1G (Two-hybrid)

ESM2 similar proteins: A0A8P0N4K0, A2AB59, B4F7F3, D3YZU1, D3ZD05, O35681, O75427, O95382, P22455, P22607, P40748, P55144, P70218, Q06418, Q14160, Q1LZH7, Q2PS20, Q32P44, Q495M9, Q4ACU6, Q4H4B6, Q505F5, Q5F488, Q61851, Q63ZY3, Q6P9K8, Q6TLK4, Q6ZUM4, Q7KRY7, Q80T11, Q80U72, Q8BH60, Q8BX02, Q8N1G4, Q8TE68, Q8VC03, Q8VHK1, Q8VHK2, Q8WXD9, Q8WXE0

Diamond homologs: B4E2M5, O14593, Q09701, Q18297, Q2KI79, Q495M9, Q4R7L8, Q5RD76, Q6RI86, Q80T11, Q99PE2, Q9BQG2, Q9DCN1, Q9H9E1, Q9Z205, Q9Z2X2, Q9Z2X3, O94830, Q6NZC7, Q80Y98, Q80YA3, Q8K3X6, Q8N8V4, Q9Y6Y8, Q3KP44, Q8BLD6, O00562, O35954, P43125, Q12204, Q3UHE1, Q5U2N3, Q6ZPQ6, Q9BZ71, Q9BZ72

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
USH1G	“form complex”	“TIP-LINK complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	11
Uncertain significance	249
Likely benign	140
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074704	NM_173477.5(USH1G):c.742C>T (p.Gln248Ter)	Pathogenic
1216382	NM_173477.5(USH1G):c.1016dup (p.Ala341fs)	Pathogenic
1323744	NM_173477.5(USH1G):c.387dup (p.Lys130fs)	Pathogenic
1323745	NM_173477.5(USH1G):c.711del (p.Arg238fs)	Pathogenic
1353703	NM_173477.5(USH1G):c.255_256del (p.Ser86fs)	Pathogenic
1367728	NM_173477.5(USH1G):c.1039C>T (p.Gln347Ter)	Pathogenic
1400757	NM_173477.5(USH1G):c.728C>A (p.Ser243Ter)	Pathogenic
1452359	NM_173477.5(USH1G):c.783del (p.Thr260_Tyr261insTer)	Pathogenic
1457749	NM_173477.5(USH1G):c.248_249delinsAA (p.Phe83Ter)	Pathogenic
1459236	NM_173477.5(USH1G):c.666del (p.Arg223fs)	Pathogenic
2138104	NM_173477.5(USH1G):c.805C>T (p.Arg269Ter)	Pathogenic
2427500	NC_000017.10:g.(?72914168)(72919168_?)del	Pathogenic
2445661	NM_173477.5(USH1G):c.1324del (p.Ala442fs)	Pathogenic
2445662	NM_173477.5(USH1G):c.85dup (p.Asp29fs)	Pathogenic
2503097	NM_173477.5(USH1G):c.956_960delinsA (p.Arg319fs)	Pathogenic
2695082	NM_173477.5(USH1G):c.1352_1353del (p.Glu451fs)	Pathogenic
2709087	NM_173477.5(USH1G):c.1004del (p.Gly335fs)	Pathogenic
2736643	NM_173477.5(USH1G):c.1195_1196del (p.Leu399fs)	Pathogenic
2736644	NM_173477.5(USH1G):c.84dup (p.Asp29fs)	Pathogenic
2741442	NM_173477.5(USH1G):c.275G>A (p.Trp92Ter)	Pathogenic
2800855	NM_173477.5(USH1G):c.916_917del (p.Leu306fs)	Pathogenic
2914	NM_173477.5(USH1G):c.143T>C (p.Leu48Pro)	Pathogenic
2915	NM_173477.5(USH1G):c.186_187del (p.Ile63fs)	Pathogenic
2916	NM_173477.5(USH1G):c.832_851del (p.Ser278fs)	Pathogenic
2917	NM_173477.5(USH1G):c.394dup (p.Val132fs)	Pathogenic
2918	NM_173477.5(USH1G):c.113G>A (p.Trp38Ter)	Pathogenic
3026510	NM_173477.5(USH1G):c.175del (p.Asp59fs)	Pathogenic
31577	NM_173477.5(USH1G):c.163_164+13del	Pathogenic
3342863	NM_173477.5(USH1G):c.1162G>T (p.Glu388Ter)	Pathogenic
3601022	NM_173477.5(USH1G):c.104_107dup (p.Leu37fs)	Pathogenic

SpliceAI

235 predictions. Top by Δscore:

Variant	Effect	Δscore
17:74919452:A:AC	donor_gain	1.0000
17:74919452:ACAG:A	donor_gain	1.0000
17:74919453:C:CA	donor_gain	1.0000
17:74919453:CA:C	donor_gain	1.0000
17:74919453:CAG:C	donor_gain	1.0000
17:74919453:CAGC:C	donor_gain	1.0000
17:74919453:CAGCT:C	donor_gain	1.0000
17:74922906:TCA:T	donor_loss	1.0000
17:74922907:CA:C	donor_loss	1.0000
17:74922908:A:AC	donor_gain	1.0000
17:74922908:AC:A	donor_gain	1.0000
17:74922908:ACC:A	donor_gain	1.0000
17:74922908:ACCC:A	donor_loss	1.0000
17:74922909:C:CC	donor_gain	1.0000
17:74922909:CC:C	donor_gain	1.0000
17:74922909:CCC:C	donor_gain	1.0000
17:74922909:CCCG:C	donor_gain	1.0000
17:74919151:T:TA	donor_gain	0.9900
17:74919447:CACT:C	donor_loss	0.9900
17:74919448:ACTC:A	donor_loss	0.9900
17:74919449:CTCA:C	donor_loss	0.9900
17:74919450:TCA:T	donor_loss	0.9900
17:74919452:A:AG	donor_loss	0.9900
17:74920667:CACCC:C	acceptor_gain	0.9900
17:74920668:ACCC:A	acceptor_gain	0.9900
17:74920669:CCC:C	acceptor_gain	0.9900
17:74920669:CCCC:C	acceptor_gain	0.9900
17:74920670:CC:C	acceptor_gain	0.9900
17:74920670:CCC:C	acceptor_gain	0.9900
17:74920671:CC:C	acceptor_gain	0.9900

AlphaMissense

3004 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:74920486:A:G	L117P	0.999
17:74920552:T:A	D95V	0.999
17:74920642:C:A	G65V	0.999
17:74920643:C:G	G65R	0.999
17:74920651:T:A	D62V	0.999
17:74920534:G:C	P101R	0.998
17:74920534:G:T	P101Q	0.998
17:74920552:T:G	D95A	0.998
17:74920553:C:A	D95Y	0.998
17:74920553:C:G	D95H	0.998
17:74920624:A:G	L71P	0.998
17:74920633:G:C	P68R	0.998
17:74920642:C:T	G65D	0.998
17:74920651:T:G	D62A	0.998
17:74920652:C:A	D62Y	0.998
17:74920652:C:G	D62H	0.998
17:74922955:G:T	A40D	0.998
17:74922976:A:G	M33T	0.998
17:74923048:G:T	A9D	0.998
17:74919885:G:C	F317L	0.997
17:74919885:G:T	F317L	0.997
17:74919886:A:G	F317S	0.997
17:74919887:A:G	F317L	0.997
17:74920522:G:T	A105D	0.997
17:74920523:C:G	A105P	0.997
17:74920618:G:T	A73D	0.997
17:74920621:G:T	A72E	0.997
17:74920633:G:T	P68H	0.997
17:74920643:C:A	G65C	0.997
17:74920650:G:C	D62E	0.997

dbSNP variants (sampled 300 via entrez): RS1000011247 (17:74924109 A>G), RS1000158969 (17:74921653 G>A), RS1000275206 (17:74921952 C>T), RS1000517704 (17:74916358 C>A), RS1000565359 (17:74923095 G>A), RS1000596602 (17:74923310 G>A,C), RS1001015730 (17:74917007 C>A), RS1001162406 (17:74917558 G>A), RS1001873828 (17:74922397 C>T), RS1001895630 (17:74921325 A>C), RS1002409521 (17:74915854 T>C), RS1002469858 (17:74921460 C>T), RS1003052325 (17:74920171 C>A,G,T), RS1003386408 (17:74921342 A>C), RS1004192113 (17:74919432 C>A)

Disease associations

OMIM: gene MIM:607696 | disease phenotypes: MIM:606943, MIM:276900, MIM:220290, MIM:607197, MIM:602092

GenCC curated gene-disease

Disease	Classification	Inheritance
Usher syndrome type 1G	Definitive	Autosomal recessive
Usher syndrome type 1	Definitive	Unknown
nonsyndromic genetic hearing loss	Disputed Evidence	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Disputed	AR
Usher syndrome type 1	Definitive	AR

Mondo (9): Usher syndrome type 1G (MONDO:0011748), Usher syndrome (MONDO:0019501), hearing loss disorder (MONDO:0005365), optic atrophy (MONDO:0003608), inherited retinal dystrophy (MONDO:0019118), Usher syndrome type 1 (MONDO:0010168), hearing loss, autosomal recessive (MONDO:0019588), autosomal recessive nonsyndromic hearing loss 18A (MONDO:0011192), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (6): Usher syndrome type 1 (Orphanet:231169), Usher syndrome (Orphanet:886), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare genetic deafness (Orphanet:96210), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

18 total (19 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000375	Abnormal cochlea morphology
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001270	Motor delay
HP:0001751	Abnormal vestibular function
HP:0002141	Gait imbalance
HP:0004646	Hypoplasia of the nasal bone
HP:0007663	Reduced visual acuity
HP:0007994	Peripheral visual field loss
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886
C564609	Deafness, Autosomal Recessive (supp.)
C566580	Deafness, Autosomal Recessive 18 (supp.)
C580334	Nonsyndromic Deafness (supp.)
C564643	Usher Syndrome, Type IG (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Benzo(a)pyrene	increases expression, increases mutagenesis	2
sotorasib	affects cotreatment, decreases expression	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
pentanal	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression	1
Atrazine	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	decreases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT02065011	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Determine the Long-Term Safety, Tolerability and Biological Activity of SAR421869 in Patients With Usher Syndrome Type 1B
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT01505062	PHASE1/PHASE2	TERMINATED	Study of SAR421869 in Participants With Retinitis Pigmentosa Associated With Usher Syndrome Type 1B
NCT04355689	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of NPI-001 Tablets for RP Associated With Usher Syndrome
NCT06789445	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Safety of OpCT-001 in Adults Who Have Primary Photoreceptor Disease (CLARICO)
NCT00004345	Not specified	TERMINATED	Study of Dietary N-3 Fatty Acids in Patients With Retinitis Pigmentosa and Usher Syndrome
NCT00016471	Not specified	COMPLETED	A Genetic Analysis of Usher Syndrome in Ashkenazi Jews
NCT00106743	Not specified	COMPLETED	Natural History and Genetic Studies of Usher Syndrome