autosomal dominant Charcot-Marie-Tooth disease type 2W

Summary

autosomal dominant Charcot-Marie-Tooth disease type 2W (MONDO:0014711) is a disease caused by HARS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HARS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0002166	Impaired vibration sensation in the lower limbs	Very frequent (80-99%)
HP:0003474	Somatic sensory dysfunction	Very frequent (80-99%)
HP:0007108	Demyelinating peripheral neuropathy	Very frequent (80-99%)
HP:0008959	Distal upper limb muscle weakness	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0001760	Abnormal foot morphology	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0007002	Motor axonal neuropathy	Frequent (30-79%)
HP:0001765	Hammertoe	Occasional (5-29%)
HP:0003100	Slender long bone	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0006937	Impaired distal tactile sensation	Occasional (5-29%)
HP:0007328	Impaired pain sensation	Occasional (5-29%)
HP:0008954	Intrinsic hand muscle atrophy	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0030237	Hand muscle weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant Charcot-Marie-Tooth disease type 2W
Mondo ID	MONDO:0014711
OMIM	616625
Orphanet	488333
DOID	DOID:0110162
UMLS	C5567486
MedGen	1798909
GARD	0017891
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2 due to HARS mutation · Charcot-Marie-Tooth disease type 2 caused by mutation in HARS · Charcot-Marie-Tooth disease, axonal, type 2w · CMT2W · HARS Charcot-Marie-Tooth disease type 2

Data availability: 16 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease type 2 › autosomal dominant Charcot-Marie-Tooth disease type 2W

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2P, Charcot-Marie-Tooth disease axonal type 2Q, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2U, Charcot-Marie-Tooth disease axonal type 2V, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

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

16 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 conflicting classifications of pathogenicity, 3 pathogenic, 2 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
217506	NM_002109.6(HARS1):c.395C>T (p.Thr132Ile)	HARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217507	NM_002109.6(HARS1):c.401C>A (p.Pro134His)	HARS1	Pathogenic	no assertion criteria provided
217508	NM_002109.6(HARS1):c.525T>G (p.Asp175Glu)	HARS1	Pathogenic	no assertion criteria provided
217509	NM_002109.6(HARS1):c.1090G>T (p.Asp364Tyr)	HARS1	Pathogenic	no assertion criteria provided
1683585	NM_002109.6(HARS1):c.168del (p.Thr58fs)	HARS1	Likely pathogenic	criteria provided, single submitter
548118	NM_002109.6(HARS1):c.397G>T (p.Val133Phe)	HARS1	Likely pathogenic	criteria provided, single submitter
1705704	NM_002109.6(HARS1):c.345T>A (p.Tyr115Ter)	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
546982	NM_002109.6(HARS1):c.90+1G>C	HARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333881	NM_002109.6(HARS1):c.335A>G (p.Lys112Arg)	HARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1678556	NM_002109.6(HARS1):c.256C>T (p.Arg86Cys)	HARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
40062	NM_002109.6(HARS1):c.410G>A (p.Arg137Gln)	HARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
446300	NM_002109.6(HARS1):c.989A>G (p.Tyr330Cys)	HARS1	Uncertain significance	criteria provided, single submitter
446301	NM_002109.6(HARS1):c.1067G>A (p.Ser356Asn)	HARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
472986	NM_002109.6(HARS1):c.1123C>T (p.Arg375Cys)	HARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1167176	NM_002109.6(HARS1):c.951+19G>A	HARS1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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 dominant	autosomal dominant Charcot-Marie-Tooth disease type 2W	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

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
HARS1	HGNC:4816	ENSG00000170445	P12081	Histidine–tRNA ligase, cytoplasmic	gencc,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).

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)
HARS1	Enzyme (other)	yes	6.1.1.21	WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ

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
adenohypophysis	1
lateral nuclear group of thalamus	1
right frontal lobe	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HARS1	2,480

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HARS1	P12081	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Cytosolic tRNA aminoacylation	1	439.2×	0.002	HARS1

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
histidyl-tRNA aminoacylation	1	8426.0×	4e-04	HARS1
tRNA aminoacylation for protein translation	1	842.6×	0.002	HARS1
translation	1	102.8×	0.010	HARS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

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

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	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HARS1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.