Charcot-Marie-Tooth disease type 1F

Summary

Charcot-Marie-Tooth disease type 1F (MONDO:0011902) is a disease caused by NEFL (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: NEFL (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 70
• Phenotypes (HPO): 50
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000762	Decreased nerve conduction velocity	Very frequent (80-99%)
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003474	Somatic sensory dysfunction	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0007220	Demyelinating motor neuropathy	Very frequent (80-99%)
HP:0011402	Demyelinating sensory neuropathy	Very frequent (80-99%)
HP:0001155	Abnormality of the hand	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002346	Head tremor	Frequent (30-79%)
HP:0002378	Hand tremor	Frequent (30-79%)
HP:0002403	Positive Romberg sign	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0003387	Decreased number of large peripheral myelinated nerve fibers	Frequent (30-79%)
HP:0004463	Absent brainstem auditory responses	Frequent (30-79%)
HP:0007149	Distal upper limb amyotrophy	Frequent (30-79%)
HP:0007327	Mixed demyelinating and axonal polyneuropathy	Frequent (30-79%)
HP:0007328	Impaired pain sensation	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0009130	Hand muscle atrophy	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0010873	Cervical spinal cord atrophy	Frequent (30-79%)
HP:0030237	Hand muscle weakness	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000609	Optic nerve hypoplasia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0003691	Scapular winging	Occasional (5-29%)
HP:0008956	Proximal lower limb amyotrophy	Occasional (5-29%)
HP:0008994	Proximal muscle weakness in lower limbs	Occasional (5-29%)
HP:0008997	Proximal muscle weakness in upper limbs	Occasional (5-29%)
HP:0012452	Restless legs	Occasional (5-29%)
HP:0012473	Tongue atrophy	Occasional (5-29%)
HP:0012785	Flexion contracture of finger	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0002540	Inability to walk	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 1F
Mondo ID	MONDO:0011902
MeSH	C537987
OMIM	607734
Orphanet	101085
DOID	DOID:0110149
ICD-11	1160290076
SNOMED CT	719980006
UMLS	C1843164
MedGen	334337
GARD	0009191
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 1F · Charcot-Marie-Tooth disease type 1 caused by mutation in NEFL · Charcot-Marie-Tooth disease, demyelinating, type 1F · Charcot-Marie-Tooth disease, type 1F · CMT 1F · CMT1F · NEFL Charcot-Marie-Tooth disease type 1

Data availability: 70 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 1 › Charcot-Marie-Tooth disease type 1F

Related subtypes (5): Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1E, Charcot-Marie-Tooth disease type 1C, Charcot-Marie-Tooth disease type 1D

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

70 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 16 conflicting classifications of pathogenicity, 9 benign, 6 benign/likely benign, 5 pathogenic, 4 pathogenic/likely pathogenic, 2 not provided, 2 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333320	NM_006158.5(NEFL):c.18C>G (p.Tyr6Ter)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14029	NM_006158.5(NEFL):c.64C>T (p.Pro22Ser)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14030	NM_006158.5(NEFL):c.22_23delinsAG (p.Pro8Arg)	NEFL	Pathogenic	no assertion criteria provided
14034	NM_006158.5(NEFL):c.418G>T (p.Glu140Ter)	NEFL	Pathogenic	no assertion criteria provided
29803	NM_006158.5(NEFL):c.628G>T (p.Glu210Ter)	NEFL	Pathogenic	no assertion criteria provided
3376740	NM_006158.5(NEFL):c.1357G>T (p.Glu453Ter)	NEFL	Pathogenic	criteria provided, single submitter
41236	NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444742	NM_006158.5(NEFL):c.1195C>T (p.Arg399Ter)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66671	NM_006158.5(NEFL):c.1186G>A (p.Glu396Lys)	NEFL	Pathogenic	criteria provided, multiple submitters, no conflicts
1048599	NM_006158.5(NEFL):c.54C>A (p.Tyr18Ter)	NEFL	Likely pathogenic	criteria provided, single submitter
1412326	NM_006158.5(NEFL):c.262A>C (p.Thr88Pro)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219429	NM_006158.5(NEFL):c.65C>A (p.Pro22His)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220209	NM_006158.5(NEFL):c.1610A>G (p.Gln537Arg)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234913	NM_006158.5(NEFL):c.986T>C (p.Leu329Pro)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362647	NM_006158.5(NEFL):c.141G>A (p.Val47=)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447763	NM_006158.5(NEFL):c.793T>G (p.Tyr265Asp)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464926	NM_006158.5(NEFL):c.338_339delinsCC (p.Gln113Pro)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66684	NM_006158.5(NEFL):c.19G>A (p.Glu7Lys)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66686	NM_006158.5(NEFL):c.227T>C (p.Val76Ala)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66693	NM_006158.5(NEFL):c.45G>A (p.Lys15=)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66695	NM_006158.5(NEFL):c.639C>G (p.Ile213Met)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908821	NM_006158.5(NEFL):c.1315T>A (p.Phe439Ile)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909673	NM_006158.5(NEFL):c.564C>G (p.Ala188=)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909677	NM_006158.5(NEFL):c.339G>C (p.Gln113His)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910601	NM_006158.5(NEFL):c.338A>C (p.Gln113Pro)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911788	NM_006158.5(NEFL):c.1408C>T (p.Pro470Ser)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1513738	NM_006158.5(NEFL):c.690G>C (p.Glu230Asp)	NEFL	Uncertain significance	criteria provided, single submitter
2585606	NM_006158.5(NEFL):c.311T>G (p.Phe104Cys)	NEFL	Uncertain significance	criteria provided, single submitter
362616	NM_006158.5(NEFL):c.*1744T>C	NEFL	Uncertain significance	criteria provided, single submitter
362619	NM_006158.5(NEFL):c.*1482C>T	NEFL	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
NEFL	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEFL	Orphanet:101085	Charcot-Marie-Tooth disease type 1F
NEFL	Orphanet:228374	Charcot-Marie-Tooth disease type 2B5
NEFL	Orphanet:99939	Autosomal dominant Charcot-Marie-Tooth disease type 2E

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
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEFL	Neurofilament light 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: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

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
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
NEFL	214	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
NEFL	4,644

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEFL	P07196	73.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Ras activation upon Ca2+ influx through NMDA receptor	1	571.0×	0.003	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.003	NEFL
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.003	NEFL
Long-term potentiation	1	475.8×	0.003	NEFL
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.005	NEFL
RAF/MAP kinase cascade	1	61.1×	0.016	NEFL

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
intermediate filament polymerization or depolymerization	1	16852.0×	0.001	NEFL
response to sodium arsenite	1	8426.0×	0.001	NEFL
response to acrylamide	1	8426.0×	0.001	NEFL
neurofilament bundle assembly	1	5617.3×	0.001	NEFL
regulation of axon diameter	1	3370.4×	0.002	NEFL
peripheral nervous system axon regeneration	1	2106.5×	0.002	NEFL
neurofilament cytoskeleton organization	1	1685.2×	0.002	NEFL
retrograde axonal transport	1	1532.0×	0.002	NEFL
locomotion	1	1532.0×	0.002	NEFL
negative regulation of motor neuron apoptotic process	1	1532.0×	0.002	NEFL
axonal transport of mitochondrion	1	1404.3×	0.002	NEFL
response to corticosterone	1	1123.5×	0.002	NEFL
motor neuron apoptotic process	1	1123.5×	0.002	NEFL
protein polymerization	1	991.3×	0.002	NEFL
regulation of synapse maturation	1	936.2×	0.002	NEFL
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.003	NEFL
anterograde axonal transport	1	581.1×	0.003	NEFL
positive regulation of axonogenesis	1	581.1×	0.003	NEFL
spinal cord development	1	510.7×	0.003	NEFL
response to peptide hormone	1	391.9×	0.003	NEFL
neuromuscular process controlling balance	1	330.4×	0.004	NEFL
intermediate filament organization	1	240.7×	0.005	NEFL
hippocampus development	1	230.8×	0.005	NEFL
response to toxic substance	1	210.7×	0.005	NEFL
cerebral cortex development	1	205.5×	0.005	NEFL
axonogenesis	1	160.5×	0.006	NEFL
microtubule cytoskeleton organization	1	121.2×	0.008	NEFL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEFL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NEFL

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)
NEFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease