Usher syndrome type 3B
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Also known as HARS Usher syndromeUSH3BUsher syndrome caused by mutation in HARSUSHER syndrome, type IIIB
Summary
Usher syndrome type 3B (MONDO:0013788) is a disease caused by HARS1 (GenCC Strong), with 2 cohort genes.
At a glance
- Causal gene: HARS1 (GenCC Strong)
- Cohort genes: 2
- ClinVar variants: 586
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Usher syndrome type 3B |
| Mondo ID | MONDO:0013788 |
| OMIM | 614504 |
| DOID | DOID:0110842 |
| UMLS | C3281066 |
| MedGen | 482696 |
| GARD | 0015813 |
| Is cancer (heuristic) | no |
Also known as: HARS Usher syndrome · USH3B · Usher syndrome caused by mutation in HARS · USHER syndrome, type IIIB
Data availability: 586 ClinVar variants · 3 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome type 3 › Usher syndrome type 3B
Related subtypes (1): Usher syndrome type 3A
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
586 retrieved; paginated sample, class counts are floors:
337 uncertain significance, 198 likely benign, 35 conflicting classifications of pathogenicity, 11 benign, 5 benign/likely benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1039735 | NM_002109.6(HARS1):c.1484T>C (p.Val495Ala) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1091017 | NM_002109.6(HARS1):c.1445C>G (p.Thr482Arg) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1097974 | NM_002109.6(HARS1):c.653A>G (p.Asp218Gly) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1112786 | NM_002109.6(HARS1):c.615C>T (p.Gly205=) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1680306 | NM_002109.6(HARS1):c.1105A>G (p.Met369Val) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1680315 | NM_002109.6(HARS1):c.951+5G>T | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1680345 | NM_002109.6(HARS1):c.437_439dup (p.Asn146dup) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1680349 | NM_002109.6(HARS1):c.397-11T>G | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1704893 | NM_002109.6(HARS1):c.192_198delinsACTG (p.Asp64_Ser66delinsGluLeu) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1705704 | NM_002109.6(HARS1):c.345T>A (p.Tyr115Ter) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1981675 | NM_002109.6(HARS1):c.58G>A (p.Gly20Ser) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 198477 | NM_002109.6(HARS1):c.694C>T (p.Arg232Cys) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2528628 | NM_002109.6(HARS1):c.210G>A (p.Met70Ile) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2655742 | NM_002109.6(HARS1):c.1163G>A (p.Arg388Gln) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 29756 | NM_002109.6(HARS1):c.1361A>C (p.Tyr454Ser) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 351240 | NM_002109.6(HARS1):c.382C>T (p.Arg128Cys) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 351242 | NM_002109.6(HARS1):c.103G>A (p.Val35Met) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 446299 | NM_002109.6(HARS1):c.464T>G (p.Val155Gly) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 472990 | NM_002109.6(HARS1):c.1445C>T (p.Thr482Met) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 472991 | NM_002109.6(HARS1):c.14C>A (p.Ala5Glu) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 540202 | NM_002109.6(HARS1):c.1402G>A (p.Glu468Lys) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 546982 | NM_002109.6(HARS1):c.90+1G>C | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 565367 | NM_002109.6(HARS1):c.203G>A (p.Arg68Gln) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 576600 | NM_002109.6(HARS1):c.679T>G (p.Ser227Ala) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 578537 | NM_002109.6(HARS1):c.1372G>A (p.Ala458Thr) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 666839 | NM_002109.6(HARS1):c.1177G>A (p.Val393Met) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 774566 | NM_002109.6(HARS1):c.155A>C (p.Gln52Pro) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 800209 | NM_002109.6(HARS1):c.1124G>A (p.Arg375His) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 804288 | NM_002109.6(HARS1):c.1393A>C (p.Ile465Leu) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 846422 | NM_002109.6(HARS1):c.1329GAA[1] (p.Lys444del) | HARS1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 8 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| HARS1 | Strong | Autosomal recessive | Usher syndrome type 3B | 8 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| HARS1 | Orphanet:231183 | Usher syndrome type 3 |
| HARS1 | Orphanet:488333 | Autosomal dominant Charcot-Marie-Tooth disease type 2W |
| HARS2 | Orphanet:642945 | Perrault syndrome type 1 |
| HARS2 | Orphanet:642976 | Perrault syndrome type 2 |
Cohort genes → proteins
2 cohort genes, 2 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 2 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| HARS1 | HGNC:4816 | ENSG00000170445 | P12081 | Histidine–tRNA ligase, cytoplasmic | gencc,clinvar |
| HARS2 | HGNC:4817 | ENSG00000112855 | P49590 | Histidine–tRNA ligase, mitochondrial | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| HARS1 | Histidine–tRNA ligase, cytoplasmic | Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP). |
| HARS2 | Histidine–tRNA ligase, mitochondrial | Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP). |
Protein-family classification
Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Enzyme (other) | 2 | 12.0× | 0.007 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| HARS1 | Enzyme (other) | yes | 6.1.1.21 | WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ |
| HARS2 | Enzyme (other) | yes | 6.1.1.21 | Anticodon-bd, HisRS/HisZ, aa-tRNA-synth_II |
Expression context
Cohort genes with no expression data: 0.
2 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 2 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| adenohypophysis | 1 |
| lateral nuclear group of thalamus | 1 |
| right frontal lobe | 1 |
| cerebellar cortex | 1 |
| cerebellar hemisphere | 1 |
| right hemisphere of cerebellum | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| HARS1 | 291 | ubiquitous | marker | lateral nuclear group of thalamus, right frontal lobe, adenohypophysis |
| HARS2 | 272 | ubiquitous | marker | cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex |
Protein interactions among cohort
Intra-cohort edges: 1.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| HARS2 | 2,703 |
| HARS1 | 2,480 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| HARS1 | HARS2 | intact |
Structural data
PDB: 1 · AlphaFold-only: 1 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| HARS1 | P12081 | 10 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| HARS2 | P49590 | 88.44 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Mitochondrial tRNA aminoacylation | 1 | 259.6× | 0.011 | HARS2 |
| Cytosolic tRNA aminoacylation | 1 | 219.6× | 0.011 | HARS1 |
| tRNA Aminoacylation | 1 | 142.8× | 0.012 | HARS2 |
| Translation | 1 | 31.0× | 0.040 | HARS2 |
| Metabolism of proteins | 1 | 6.2× | 0.155 | HARS2 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| histidyl-tRNA aminoacylation | 2 | 8426.0× | 3e-08 | HARS1, HARS2 |
| tRNA aminoacylation for protein translation | 2 | 842.6× | 3e-06 | HARS1, HARS2 |
| translation | 2 | 102.8× | 1e-04 | HARS1, HARS2 |
| mitochondrial translation | 1 | 86.9× | 0.011 | HARS2 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2
Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| HARS1 | 0 | 0 |
| HARS2 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 2.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| HARS1 | 5 | Binding:5 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| HARS1 | 6.1.1.21 | histidine-tRNA ligase |
| HARS2 | 6.1.1.21 | histidine-tRNA ligase |
Pharmacogenomics
Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 0 | |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 1 | HARS1 |
| D | Druggable family + AlphaFold only, no drug | 1 | HARS2 |
| E | Difficult family or no structure, no drug | 0 |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| HARS1 | 5 | — |
| HARS2 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.