NEFL
protein-codingneurofilament light chain, the group of Intermediate filaments Type IV|Protein phosphatase 1 regulatory subunits|MicroRNA protein coding host genes
Gene summary
Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the light chain neurofilament protein. Mutations in this gene cause Charcot-Marie-Tooth disease types 1F (CMT1F) and 2E (CMT2E), disorders of the peripheral nervous system that are characterized by distinct neuropathies. A pseudogene has been identified on chromosome Y. [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015626
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0018993
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011902
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018993
Submitter: ClinGen
NEFL was first gene reported in relation to autosomal dominant Charcot-Marie-Tooth disease in 2000 (Mersiyanova et al., PMID: 10841809). Based on the literature we differentiate between autosomal dominant NEFL CMT (MONDO:0015626), autosomal recessive NEFL CMT (MONDO:0018993). The split curation for autosomal dominant and recessive CMT has been curated separately. Three different variants (stop-gained) that have been reported in 3 probands in 3 publications (PMIDs: 20039262, 29191368, 19158810) are included in this curation. The mechanism of pathogenicity appears to be a loss-of-function due to the lack of NF network development as described in the in-vitro studies. Functional experimental evidence supports NEFL in controls, patients, and animal models (PMIDs: 17881652, 9388258, 28654681, 26383514, 35237613, 9398473, 8468353). In-vitro functional studies for all described variants depict failure of development in NF networks and lack of NF distribution. In summary, NEFL is definitively associated with autosomal recessive axonal Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0011902
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011902
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011894
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015626
Submitter: ClinGen
NEFL was first gene reported in relation to autosomal dominant Charcot-Marie-Tooth disease in 2000 (Mersiyanova et al., PMID: 10841809). Based on the literature we differentiate between autosomal dominant NEFL CMT (MONDO:0015626), autosomal recessive NEFL CMT (MONDO:0018993). For autosomal dominant NEFL CMT, five variants (missense) that have been reported in 9 probands in 7 publications (PMIDs: 10841809, 28501821, 11220745, 12566280, 18758688, 14733962, 12477167) are included in this curation. The p.Pro22(Thr/Arg/Ser), p.Pro8(Leu/GlnArg) and the p.Asn98(Ser/Thr) are considered hotspot variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be a gain-of-function due to misdistribution and aggregate formations of NFL. This gene-disease relationship is also supported by functional experimental evidence in controls, patients, and animal models (PMIDs: 25552649, 28654681, 17881652, 9388258, 9398473, 34485306, 31715019). In-vitro functional studies for all described variants depict disruptions in NF network and aggregation of NFL. In summary, NEFL is definitively associated with autosomal dominant axonal Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0016454
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NEFL variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006158.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 9 | 146 | 2 | 157 | ||
| missense | 6 | 24 | 378 | 20 | 1 | 429 |
| nonsense | 15 | 9 | 3 | 27 | ||
| start loss | 0 | |||||
| frameshift | 8 | 3 | 6 | 17 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 29 | 37 | 397 | 166 | 3 | 632 |
Highest pathogenic variant AF is 0.000058948524
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006149.2 | 4 | MANE Select | |
| Ensembl | ENSP00000482169.2 | 4 | MANE Select | |
| Ensembl | ENSP00000586615.1 | 4 | Standard | |
| Ensembl | ENSP00000765041.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
- Amyotrophic lateral sclerosis (ALS)
- Association Between Physico-Chemical Features and Toxicity Associated Pathways
- NO-cGMP-PKG mediated Neuroprotection
- Signal Transduction
Biological Process
- MAPK cascade
- microtubule cytoskeleton organization
- anterograde axonal transport
- retrograde axonal transport
- peripheral nervous system axon regeneration
Molecular Function
- Ras guanyl-nucleotide exchange factor activity
- structural constituent of cytoskeleton
- protein binding
- protein C-terminus binding
- protein domain specific binding
Cellular Component
- cytoplasm
- cytosol
- neurofilament
- axon
- growth cone
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Neurofilaments usually contain three intermediate filament proteins: L, M, and H which are involved in the maintenance of neuronal caliber.;
- Disease
- DISEASE: Charcot-Marie-Tooth disease 1F (CMT1F) [MIM:607734]: A dominant demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. CMT1F is characterized by onset in infancy or childhood (range 1 to 13 years). {ECO:0000269|PubMed:12566280, ECO:0000269|PubMed:14733962, ECO:0000269|PubMed:15241803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2E (CMT2E) [MIM:607684]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:10841809, ECO:0000269|PubMed:11220745, ECO:0000269|PubMed:12481988, ECO:0000269|PubMed:15241803, ECO:0000269|PubMed:22206013}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.658
Essentials
- Indispensability pred.
- E
- Indispensability score
- 0.871