Charcot-Marie-Tooth disease axonal type 2C

Summary

Charcot-Marie-Tooth disease axonal type 2C (MONDO:0011633) is a disease caused by TRPV4 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TRPV4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,057

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2C
Mondo ID	MONDO:0011633
OMIM	606071
Orphanet	99937
DOID	DOID:0110182
SNOMED CT	717010007
UMLS	C1853710
MedGen	342947
GARD	0001250
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2C · Charcot Marie Tooth disease type 2C · Charcot-Marie-Tooth disease type 2 caused by mutation in TRPV4 · Charcot-Marie-Tooth disease type 2C · Charcot-Marie-Tooth disease, axonal, type 2C · CMT 2C · CMT2C · hereditary motor and sensory neuropathy 2 C · hereditary motor and sensory neuropathy, type IIC · HMSN 2 C · HMSN2C · TRPV4 Charcot-Marie-Tooth disease type 2

Data availability: 1,057 ClinVar variants · 2 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 › motor peripheral neuropathy › Charcot-Marie-Tooth disease axonal type 2C

Related subtypes (8): motor nerve neuritis, glossopharyngeal motor neuropathy, Charcot-Marie-Tooth disease type 5, neuropathy, hereditary motor and sensory, type 6A, hereditary motor and sensory neuropathy, Okinawa type, Charcot-Marie-Tooth disease type 4G, neuropathy, hereditary motor and sensory, type 6B, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

600 retrieved; paginated sample, class counts are floors:

284 uncertain significance, 204 likely benign, 37 conflicting classifications of pathogenicity, 37 benign/likely benign, 16 benign, 10 pathogenic, 8 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1045051	NM_021625.5(TRPV4):c.838G>A (p.Gly280Ser)	TRPV4	Pathogenic	criteria provided, single submitter
1073853	NM_021625.5(TRPV4):c.709C>G (p.Arg237Gly)	TRPV4	Pathogenic	criteria provided, single submitter
126463	NM_021625.5(TRPV4):c.1219A>G (p.Lys407Glu)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
126464	NM_021625.5(TRPV4):c.1412_1414del (p.Phe471del)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126472	NM_021625.5(TRPV4):c.1851C>A (p.Phe617Leu)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453327	NM_021625.5(TRPV4):c.1849T>C (p.Phe617Leu)	TRPV4	Pathogenic	criteria provided, single submitter
1458308	NM_021625.5(TRPV4):c.1799G>A (p.Gly600Glu)	TRPV4	Pathogenic	criteria provided, single submitter
1489986	NM_021625.5(TRPV4):c.2480C>A (p.Pro827His)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18434	NM_021625.5(TRPV4):c.832G>A (p.Glu278Lys)	TRPV4	Pathogenic	criteria provided, single submitter
18435	NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
2780255	NM_021625.5(TRPV4):c.1058G>A (p.Cys353Tyr)	TRPV4	Pathogenic	criteria provided, single submitter
30469	NM_021625.5(TRPV4):c.1625C>A (p.Ser542Tyr)	TRPV4	Pathogenic	criteria provided, single submitter
30472	NM_021625.5(TRPV4):c.694C>T (p.Arg232Cys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
30473	NM_021625.5(TRPV4):c.947G>A (p.Arg316His)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1014727	NM_021625.5(TRPV4):c.2386_2388del (p.Asn796del)	TRPV4	Likely pathogenic	criteria provided, single submitter
1484191	NM_021625.5(TRPV4):c.1780C>T (p.Arg594Cys)	TRPV4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1493962	NM_021625.5(TRPV4):c.695G>C (p.Arg232Pro)	TRPV4	Likely pathogenic	criteria provided, single submitter
1522581	NM_021625.5(TRPV4):c.947G>T (p.Arg316Leu)	TRPV4	Likely pathogenic	criteria provided, single submitter
18432	NM_021625.5(TRPV4):c.2396C>G (p.Pro799Arg)	TRPV4	Likely pathogenic	criteria provided, single submitter
18437	NM_021625.5(TRPV4):c.547G>A (p.Glu183Lys)	TRPV4	Likely pathogenic	criteria provided, single submitter
2054917	NM_021625.5(TRPV4):c.1624T>C (p.Ser542Pro)	TRPV4	Likely pathogenic	criteria provided, single submitter
3068144	NM_021625.5(TRPV4):c.2199G>A (p.Trp733Ter)	TRPV4	Likely pathogenic	criteria provided, single submitter
1008532	NM_021625.5(TRPV4):c.1379G>A (p.Arg460Gln)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1120272	NM_021625.5(TRPV4):c.2349G>A (p.Val783=)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1224354	NM_021625.5(TRPV4):c.1780C>A (p.Arg594Ser)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256301	NM_021625.5(TRPV4):c.1064G>A (p.Arg355His)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318860	NM_021625.5(TRPV4):c.1171C>T (p.Arg391Trp)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446570	NM_021625.5(TRPV4):c.1675_1698del (p.Leu559_Leu566del)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1525659	NM_021625.5(TRPV4):c.1625C>G (p.Ser542Cys)	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1636571	NM_021625.5(TRPV4):c.1333-5C>T	TRPV4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 10 · 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
TRPV4	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2C	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
NEFH	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	gencc,clinvar
MIR4497	HGNC:41737	ENSG00000263510		microRNA 4497	clinvar
NEFH	HGNC:7737	ENSG00000100285	P12036	Neurofilament heavy polypeptide	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
NEFH	Neurofilament heavy polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
MIR4497	Other/Unknown	no
NEFH	Other/Unknown	no		DUF1388, IF_conserved, IF_rod_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
lower esophagus mucosa	1
olfactory segment of nasal mucosa	1
blood	1
monocyte	1
myometrium	1
dorsal root ganglion	1
lateral nuclear group of thalamus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
MIR4497	29		yes	myometrium, monocyte, blood
NEFH	222	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEFH	2,649
TRPV4	1,948
MIR4497	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV4	Q9HBA0	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEFH	P12036	54.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
TRP channels	1	407.9×	0.005	TRPV4
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.006	TRPV4

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
hyperosmotic salinity response	1	8426.0×	0.002	TRPV4
blood vessel endothelial cell delamination	1	8426.0×	0.002	TRPV4
vasopressin secretion	1	4213.0×	0.002	TRPV4
positive regulation of striated muscle contraction	1	4213.0×	0.002	TRPV4
regulation of response to osmotic stress	1	4213.0×	0.002	TRPV4
calcium ion import into cytosol	1	4213.0×	0.002	TRPV4
neurofilament bundle assembly	1	2808.7×	0.002	NEFH
cellular hypotonic salinity response	1	2808.7×	0.002	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	2808.7×	0.002	TRPV4
peripheral nervous system neuron axonogenesis	1	2106.5×	0.002	NEFH
regulation of organelle transport along microtubule	1	2106.5×	0.002	NEFH
positive regulation of microtubule depolymerization	1	1685.2×	0.002	TRPV4
intermediate filament bundle assembly	1	1404.3×	0.002	NEFH
positive regulation of chemokine (C-C motif) ligand 5 production	1	1404.3×	0.002	TRPV4
negative regulation of brown fat cell differentiation	1	1404.3×	0.002	TRPV4
positive regulation of chemokine (C-X-C motif) ligand 1 production	1	1404.3×	0.002	TRPV4
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.003	TRPV4
regulation of aerobic respiration	1	1053.2×	0.003	TRPV4
cortical microtubule organization	1	936.2×	0.003	TRPV4
multicellular organismal-level water homeostasis	1	842.6×	0.003	TRPV4
neurofilament cytoskeleton organization	1	842.6×	0.003	NEFH
osmosensory signaling pathway	1	766.0×	0.003	TRPV4
diet induced thermogenesis	1	702.2×	0.003	TRPV4
cellular hypotonic response	1	702.2×	0.003	TRPV4
positive regulation of vascular permeability	1	648.1×	0.003	TRPV4
cellular response to osmotic stress	1	601.9×	0.003	TRPV4
positive regulation of monocyte chemotactic protein-1 production	1	601.9×	0.003	TRPV4
cell projection assembly	1	468.1×	0.004	NEFH
microtubule polymerization	1	443.5×	0.004	TRPV4
positive regulation of macrophage chemotaxis	1	401.2×	0.004	TRPV4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV4	6	3
MIR4497	0	0
NEFH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5

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

6 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)
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

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	1	TRPV4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MIR4497, NEFH

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)
MIR4497	0	—
NEFH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.