USH1C

protein-coding

USH1 protein network component harmonin, the group of PDZ domain containing

Gene summary

This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

Previous symbols:

DFNB18

MANE transcript

NM_153676.4

Inheritance

AR, AD

ClinVar variants

P:194U:406B:362

Top phenotype

Usher syndrome, type IC; Deafness, autosomal recessive 18A

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr11:17,493,895-17,544,416

External References & Databases

Ensembl (ENSG00000006611)

Transcript & Mutation Effects

hg38 • Region Span ~50.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Usher syndrome type 1CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010171

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010171

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive nonsyndromic hearing loss 18ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011192

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 18AMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011192

Submitter: Ambry Genetics

Usher syndrome type 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010171

Submitter: G2P

Usher syndrome type 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010171

Submitter: Ambry Genetics

Usher syndrome type 1CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010171

Submitter: PanelApp Australia

Usher syndrome type 1CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010171

Submitter: Natera

autosomal recessive nonsyndromic hearing loss 18ALIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011192

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 18ALIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011192

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The USH1C gene has been associated with ARNSHL in at least 5 probands in 5 publications. 5 unique variants (missense, frameshift, large deletion) have been reported in humans, and variants in this gene segregated with disease in 5 additional family members (PMID: 12107438, 9653658). However, several variants were not scored due to lack of evidence for pathogenicity (PMID: 12136232). USH1C was first associated with this disease in humans in 1998 (Jain et al.). This gene-disease association is supported by 2 mouse models with deletions in the USH1C gene who were deaf but lacked the retinal phenotype of Usher Syndrome I as well as 1 expression study which showed that the longer transcript including the PDZ domain (which is thought to be the region affected to cause NSHL) was only expressed in the ear and not the retina. However, the mouse model from Williams 2009 was not scored because Johnson 2003 found that the mice displayed retinal degeneration at 9 months in addition to circling behavior (PMID: 19324851, 14519688). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association.

Usher syndrome type 1DEFINITIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0010168

Submitter: ClinGen

Usher syndrome type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: Orphanet

Clinical Genomic Database (CGD)

Usher syndrome, type IC; Deafness, autosomal recessive 18AAR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Hearing loss has been described as late-onset in some individuals

Refs: 5937908; 9653658; 10973248; 10973247; 12107438; 2136232; 23251578

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USH1C variants in ClinVar

17 Conditions Cataloged

not providedTotal: 1169

Usher syndrome type 1CTotal: 364

Autosomal recessive nonsyndromic hearing loss 18ATotal: 207

not specifiedTotal: 145

Inborn genetic diseasesTotal: 105

USH1C-related disorderTotal: 36

Usher syndrome type 1Total: 34

Retinal dystrophyTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153676.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	14 clinvar	287 clinvar	7 clinvar	310
missense	1 clinvar	9 clinvar	358 clinvar	59 clinvar	2 clinvar	429
nonsense	13 clinvar	19 clinvar	11 clinvar	3 clinvar		46
start loss		1 clinvar				1
frameshift	27 clinvar	46 clinvar	13 clinvar	1 clinvar		87
splice donor/acceptor (+/-2bp)	19 clinvar	57 clinvar	10 clinvar	3 clinvar		89
Total	61	133	406	353	9	962

Highest pathogenic variant AF is 0.0003104574

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153676.4	RefSeq	NP_710142.1	27	MANE Select
ENST00000005226.12	Ensembl	ENSP00000005226.7	27	MANE Select
NM_001297764.2	RefSeq	NP_001284693.1	20	Standard
NM_001440679.1	RefSeq	NP_001427608.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ush1c	Danio rerio	Structure: retinal cone cell Quality: detached from abnormal

Gene / Model

Organism

Observed Phenotype

ush1c

Danio rerio

Structure: retinal cone cell

Quality: detached from

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

G2/M transition of mitotic cell cycle
sensory perception of sound
parallel actin filament bundle assembly
regulation of microvillus length
cellular protein-containing complex assembly

Molecular Function

protein binding
spectrin binding
actin filament binding

Cellular Component

photoreceptor outer segment
photoreceptor inner segment
stereocilia ankle link
stereocilia ankle link complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000005226
Coding exons: 27
Length: 50522
Individuals with no LoFs: 125446
Homozygous LoFs: 1
Heterozygous LoFs: 301
Defined: 125748
p: 0.00120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.874	583	527	1.11	0.0000343	5784
Missense (PolyPhen)		219	186.65	1.1733		2010
Synonymous	-1.92	241	206	1.17	0.0000129	1785
Loss of Function	2.22	36	53.5	0.672	0.00000297	606

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0092	0.0091	notable
Latino/Admixed American	0.00072	0.00072	rare
Ashkenazi Jewish	0.0020	0.0020	notable
East Asian	0.0011	0.0011	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00066	0.00065	rare
South Asian	0.00030	0.00029	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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 (By similarity). As part of the intermicrovillar adhesion complex/IMAC plays a role in brush border differentiation, controlling microvilli organization and length. Probably plays a central regulatory role in the assembly of the complex, recruiting CDHR2, CDHR5 and MYO7B to the microvilli tips (PubMed:24725409, PubMed:26812018). {ECO:0000250|UniProtKB:Q9ES64, ECO:0000269|PubMed:24725409, ECO:0000269|PubMed:26812018}.;
Disease: DISEASE: Usher syndrome 1C (USH1C) [MIM:276904]: 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. {ECO:0000269|PubMed:10973247}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 18A (DFNB18A) [MIM:602092]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:12107438}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.169

Intolerance Scores

LoFtool: 0.926
RVIS EVS: -0.41
RVIS percentile EVS: 25.87

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.666

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	Medium	High