Charcot-Marie-Tooth disease recessive intermediate B

Summary

Charcot-Marie-Tooth disease recessive intermediate B (MONDO:0013338) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		1	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease recessive intermediate B
Mondo ID	MONDO:0013338
OMIM	613641
Orphanet	254334
DOID	DOID:0110204
UMLS	C3150897
MedGen	462247
GARD	0012454
Is cancer (heuristic)	no

Also known as: autosomal recessive intermediate Charcot-Marie-Tooth disease type B · Charcot-Marie-Tooth disease caused by mutation in KARS · Charcot-Marie-Tooth disease recessive intermediate type B · Charcot-Marie-Tooth disease, recessive intermediate B · Charcot-Marie-Tooth disease, recessive Intermediate type B · Charcot-Marie-Tooth disease, recessive intermediate, B · CMTRIB · KARS Charcot-Marie-Tooth disease · RI-CMT type B · RI-CMTB

Data availability: 12 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 › autosomal recessive intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease recessive intermediate B

Related subtypes (3): Charcot-Marie-Tooth disease recessive intermediate A, Charcot-Marie-Tooth disease recessive intermediate C, Charcot-Marie-Tooth disease recessive intermediate D

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

12 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 benign, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
224983	NM_005548.3(KARS1):c.599C>T (p.Pro200Leu)	KARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8169	NM_005548.3(KARS1):c.314T>A (p.Leu105His)	KARS1	Pathogenic	no assertion criteria provided
8170	NM_005548.3(KARS1):c.430_431dup (p.Tyr145fs)	KARS1	Pathogenic	no assertion criteria provided
4849358	NM_005548.3(KARS1):c.1119C>G (p.Tyr373Ter)	KARS1	Likely pathogenic	criteria provided, single submitter
439842	NM_005548.3(KARS1):c.1178G>A (p.Arg393Gln)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299692	NM_005548.3(KARS1):c.1520G>A (p.Arg507Gln)	KARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1682445	NM_005548.3(KARS1):c.382G>A (p.Val128Met)	KARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
228758	NM_005548.3(KARS1):c.274G>C (p.Glu92Gln)	KARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
666840	NM_005548.3(KARS1):c.1256C>T (p.Thr419Ile)	KARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
218513	NM_005548.3(KARS1):c.223-6del	KARS1	Benign	criteria provided, multiple submitters, no conflicts
522243	NM_005548.3(KARS1):c.223-7_223-6del	KARS1	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	Moderate	Autosomal recessive	Charcot-Marie-Tooth disease recessive intermediate B	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.