Autosomal recessive nonsyndromic hearing loss 89

Summary

Autosomal recessive nonsyndromic hearing loss 89 (MONDO:0013489) is a disease caused by KARS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KARS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 89
Mondo ID	MONDO:0013489
OMIM	613916
DOID	DOID:0110534
UMLS	C3151351
MedGen	462701
GARD	0022640
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 89 · autosomal recessive nonsyndromic deafness 89 · autosomal recessive nonsyndromic deafness caused by mutation in KARS · autosomal recessive nonsyndromic deafness type 89 · autosomal recessive nonsyndromic hearing loss 89 · deafness, autosomal recessive 89 · deafness, autosomal recessive type 89 · DFNB89 · KARS autosomal recessive nonsyndromic deafness

Data availability: 19 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 89

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 7, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 12, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 39, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 28, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 44, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 1B, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

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

19 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 5 conflicting classifications of pathogenicity, 4 pathogenic, 1 pathogenic/likely pathogenic, 1 benign, 1 likely benign, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1675188	NM_005548.3(KARS1):c.1696-2A>C	KARS1	Pathogenic	criteria provided, single submitter
224983	NM_005548.3(KARS1):c.599C>T (p.Pro200Leu)	KARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236113	NM_005548.3(KARS1):c.336T>G (p.Tyr112Ter)	KARS1	Pathogenic	criteria provided, single submitter
3242246	NM_005548.3(KARS1):c.682C>T (p.Arg228Cys)	KARS1	Pathogenic	criteria provided, single submitter
437931	NM_005548.3(KARS1):c.1430G>A (p.Arg477His)	LOC126862402	Pathogenic	criteria provided, single submitter
4849358	NM_005548.3(KARS1):c.1119C>G (p.Tyr373Ter)	KARS1	Likely pathogenic	criteria provided, single submitter
3112685	NM_005548.3(KARS1):c.944T>C (p.Val315Ala)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
562001	NM_005548.3(KARS1):c.787T>G (p.Phe263Val)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60752	NM_005548.3(KARS1):c.433T>C (p.Tyr145His)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60753	NM_005548.3(KARS1):c.1045G>A (p.Asp349Asn)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
694746	NM_005548.3(KARS1):c.1493C>T (p.Ala498Val)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064651	NM_005548.3(KARS1):c.797T>C (p.Ile266Thr)	KARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1687372	NM_005548.3(KARS1):c.1513C>G (p.Pro505Ala)	KARS1	Uncertain significance	criteria provided, single submitter
228758	NM_005548.3(KARS1):c.274G>C (p.Glu92Gln)	KARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2574034	NM_005548.3(KARS1):c.421A>C (p.Lys141Gln)	KARS1	Uncertain significance	criteria provided, single submitter
1687365	NM_005548.3(KARS1):c.1357G>C (p.Glu453Gln)	LOC126862402	Uncertain significance	criteria provided, single submitter
226682	NM_005548.3(KARS1):c.1784C>G (p.Thr595Ser)	KARS1	Benign	criteria provided, multiple submitters, no conflicts
320626	NM_005548.3(KARS1):c.1695+5G>A	KARS1	Likely benign	criteria provided, single submitter
778613	NM_005548.3(KARS1):c.223-8_223-6del	KARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
KARS1	Strong	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 89	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KARS1	Orphanet:254334	Autosomal recessive intermediate Charcot-Marie-Tooth disease type B
KARS1	Orphanet:3240	Early-onset progressive leukoencephalopathy-central nervous system calcification-deafness-visual impairment syndrome
KARS1	Orphanet:652532	Adult-onset progressive leukoencephalopathy-early-onset deafness
KARS1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KARS1	HGNC:6215	ENSG00000065427	Q15046	Lysine–tRNA ligase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KARS1	Lysine–tRNA ligase	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KARS1	Enzyme (other)	yes	6.1.1.6	Lys-tRNA-ligase_II, Aa-tRNA-synt_II, NA-bd_OB_tRNA

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
gingival epithelium	1
parietal pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KARS1	299	ubiquitous	marker	gingival epithelium, parietal pleura, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KARS1	4,681

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KARS1	Q15046	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 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 1 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	519.1×	0.012	KARS1
Cytosolic tRNA aminoacylation	1	439.2×	0.012	KARS1
tRNA Aminoacylation	1	285.5×	0.012	KARS1
Selenoamino acid metabolism	1	196.9×	0.012	KARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.012	KARS1
MITF-M-regulated melanocyte development	1	114.2×	0.016	KARS1
Metabolism of amino acids and derivatives	1	67.6×	0.022	KARS1
Translation	1	62.1×	0.022	KARS1
Developmental Biology	1	14.5×	0.085	KARS1
Metabolism of proteins	1	12.4×	0.086	KARS1
Metabolism	1	11.6×	0.086	KARS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lysyl-tRNA aminoacylation	1	16852.0×	4e-04	KARS1
basophil activation involved in immune response	1	8426.0×	4e-04	KARS1
positive regulation of inflammatory response to antigenic stimulus	1	5617.3×	4e-04	KARS1
diadenosine tetraphosphate biosynthetic process	1	5617.3×	4e-04	KARS1
response to X-ray	1	887.0×	0.002	KARS1
tRNA processing	1	842.6×	0.002	KARS1
positive regulation of macrophage activation	1	842.6×	0.002	KARS1
ERK1 and ERK2 cascade	1	318.0×	0.004	KARS1
positive regulation of DNA-templated transcription	1	27.9×	0.036	KARS1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KARS1	IMATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KARS1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMATINIB	4	KARS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KARS1	46	Binding:45, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KARS1	6.1.1.6	lysine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
IMATINIB	4	KARS1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KARS1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.