USH1C

Chr 11AR

USH1 protein network component harmonin

Also known as: AIE-75, DFNB18, DFNB18A, NY-CO-37, NY-CO-38, PDZ-45, PDZ-73, PDZ-73/NY-CO-38

NCBI Gene: 10083ENSG00000006611UniProt: Q9Y6N9

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]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 18AMIM #602092
AR
Usher syndrome, type 1CMIM #276904
AR
Usher syndrome, type 1CMIM #276904
AR
UniProtUsher syndrome 1C
491
ClinVar variants
74
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— USH1C
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
74 Pathogenic / Likely Pathogenic· 199 VUS of 491 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.89LOEUF
pLI 0.000
Z-score 2.22
OE 0.67 (0.51–0.89)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.87Z-score
OE missense 1.11 (1.03–1.19)
583 obs / 526.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.67 (0.51–0.89)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (1.03–1.19)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.17
0≤1.21.6
LoF obs/exp: 36 / 53.5Missense obs/exp: 583 / 526.6Syn Z: -1.92

ClinVar Variant Classifications

491 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic44
VUS199
Likely Benign215
Benign2
Conflicting1
30
Pathogenic
44
Likely Pathogenic
199
VUS
215
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
20
1
9
0
30
Likely Pathogenic
32
2
10
0
44
VUS
5
157
25
12
199
Likely Benign
0
1
147
67
215
Benign
0
0
2
0
2
Conflicting
—1
Total5716119379491

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

USH1C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

USH1C-related Usher syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
EyeEar
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Deafness, autosomal recessive 18A

MIM #602092

Molecular basis of disorder known

Autosomal recessive

Usher syndrome, type 1C

MIM #276904

Molecular basis of disorder known

Autosomal recessive

Usher syndrome, type 1C

MIM #276904

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — USH1C
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.
Sun T et al.·Invest Ophthalmol Vis Sci
2018Cohort
Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.
Le Quesne Stabej P et al.·J Med Genet
2012
The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification.
Delmaghani S et al.·Hum Genet
2022Review
HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes.
Ng NHJ et al.·Nat Commun
2024
The usher syndromes.
Keats BJ et al.·Am J Med Genet
1999Review
Expression and subcellular localization of USH1C/harmonin in human retina provides insights into pathomechanisms and therapy.
Nagel-Wolfrum K et al.·Hum Mol Genet
2023Functional
Harmonin in the murine retina and the retinal phenotypes of Ush1c-mutant mice and human USH1C.
Williams DS et al.·Invest Ophthalmol Vis Sci
2009
Clinical Findings and Molecular Genetics of USH1C-Associated Usher Syndrome.
Aychoua N et al.·JAMA Ophthalmol
2026
Usher syndrome: from genetics to pathogenesis.
Petit C·Annu Rev Genomics Hum Genet
2001Review
Bardet-Biedl syndrome and Usher syndrome.
Koenig R·Dev Ophthalmol
2003Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools