GeneBe

L1CAM

protein-coding

L1 cell adhesion molecule, the group of CD molecules|Ig-like cell adhesion molecule family|Fibronectin type III domain containing|I-set domain containing

Gene summary

The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]

Previous symbols:
  • HSAS1
  • SPG1
  • HSAS
  • MASA
  • MIC5
  • S10

MANE transcript

NM_001278116.2

Inheritance

XL

ClinVar variants

P:221U:398B:588

Top phenotype

Hydrocephalus due to congenital stenosis of aqueduct of Sylvius; MASA syndrome; CRASH syndrome; Corpus callosum, partial agenesis of; Spastic paraplegia-1

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chrX:153,861,514-153,886,173

External References & Databases

Ensembl (ENSG00000198910)NCBI Gene (3897)OMIM (308840)HGNC:6470GenCCUniProt (P32004)AlphaFoldClinVar (L1CAM)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~24.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked complicated corpus callosum dysgenesisSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010569

Submitter: Genomics England PanelApp

X-linked complicated corpus callosum dysgenesisSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010569

Submitter: Orphanet

L1 syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017140

Submitter: ClinGen

*L1CAM* encodes the L1 cell adhesion molecule, a cell surface glycoprotein primarily expressed in neurons that is implicated in axon outgrowth, neuronal migration, and synapse formation and function. *L1CAM* was first reported in relation to the constellation of phenotypic features related to X-linked recessive L1 syndrome in 1992 (Rosenthal et al., PMID: 1303258) and 1994 (Jouet et al., PMID: 7920659). L1 syndrome involves a spectrum of overlapping phenotypes including X‐linked hydrocephalus, MASA syndrome (intellectual disability, aphasia, spastic paraplegia, and adducted thumbs), and X‐linked complicated corpus callosum agenesis. The clinical findings can range from mild to severe, even within the same family. L1 syndrome is seen almost exclusively in males, although a few affected females have been reported (e.g., PMIDs: 8062435, 38480026). Over 200 *L1CAM* variants have been reported, including nonsense, frameshift, splice, and missense variants, as well as large deletions (PMIDs: 9268105, 10797421, 19846429). Twenty variants (nonsense, frameshift, splice, and missense) that have been reported in 20 probands in two publications (PMIDs: 7562969, 19846429) are included in this curation. Variants in this gene segregated with disease in at least 40 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is hemizygous loss of function. This gene-disease relationship is also supported by a mouse model (PMID: 19565280). In summary, there is definitive evidence supporting the relationship between *L1CAM* and X-linked recessive L1 syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 2, 2019. It was reevaluated on July 29, 2026 (SOP Version 12). Although additional genetic evidence was scored, the classification did not change.

X-linked hydrocephalus with stenosis of the aqueduct of SylviusSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010611

Submitter: Orphanet

MASA syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010559

Submitter: Orphanet

X-linked complicated corpus callosum dysgenesisSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010569

Submitter: Labcorp Genetics (formerly Invitae)

X-linked complicated spastic paraplegia type 1SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0017630

Submitter: Orphanet

L1 syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0017140

Submitter: PanelApp Australia

X-linked hydrocephalus with stenosis of the aqueduct of SylviusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010611

Submitter: Genomics England PanelApp

X-linked hydrocephalus with stenosis of the aqueduct of SylviusDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010611

Submitter: G2P

MASA syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010559

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Hydrocephalus due to congenital stenosis of aqueduct of Sylvius; MASA syndrome; CRASH syndrome; Corpus callosum, partial agenesis of; Spastic paraplegia-1XL

Manifestation: Gastrointestinal; Musculoskeletal; 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

Comments: Individuals may be at risk for findings including Hirschsprung disease as well as hydrocephalus

Refs: 4855169; 7070456; 6702900; 2737668; 2277384; 1870106; 1303258; 7920659; 8062435; 7920660; 8556302; 7562969; 9279760; 15368500; 16650080; 21271669; 21644943; 21839187; 21961551; 22222883; 22344793; 22354677Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to L1CAM variants in ClinVar

26 Conditions Cataloged
Spastic paraplegiaTotal: 1061
not providedTotal: 394
not specifiedTotal: 153
Inborn genetic diseasesTotal: 139
X-linked hydrocephalus syndromeTotal: 103
L1CAM-related disorderTotal: 86
MASA syndromeTotal: 68
X-linked complicated corpus callosum dysgenesisTotal: 49

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278116.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
23
clinvar
311
clinvar
56
clinvar
 391
missense
11
clinvar
31
clinvar
353
clinvar
170
clinvar
50
clinvar
 615
nonsense
46
clinvar
12
clinvar
6
clinvar
 64
start loss
3
clinvar
 3
frameshift
43
clinvar
24
clinvar
2
clinvar
 69
splice donor/acceptor (+/-2bp)
19
clinvar
31
clinvar
14
clinvar
1
clinvar
 65
Total1191023984821061207

Highest pathogenic variant AF is 0.000008941424

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001278116.2RefSeqNP_001265045.128MANE Select
ENST00000370060.7EnsemblENSP00000359077.128MANE Select
NM_000425.5RefSeqNP_000416.128Standard
NM_001143963.2RefSeqNP_001137435.126Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
l1camaDanio rerio

Structure: medial longitudinal fasciculus

Quality: defasciculated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell adhesion molecules (CAMs) - Homo sapiens (human)
  • Axon guidance - Homo sapiens (human)
  • Developmental Biology
  • Recycling pathway of L1
  • Beta3 integrin cell surface interactions

Biological Process

  • chemotaxis
  • cell adhesion
  • homophilic cell adhesion via plasma membrane adhesion molecules
  • cell-matrix adhesion
  • nervous system development

Molecular Function

  • protein binding
  • axon guidance receptor activity
  • protein domain specific binding

Cellular Component

  • plasma membrane
  • focal adhesion
  • cell surface
  • integral component of membrane
  • axon

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000370060
Coding exons
28
Length
47709
Individuals with no LoFs
125737
Homozygous LoFs
1
Heterozygous LoFs
1
Defined
125739
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.843735620.6630.00005008251
Missense (PolyPhen)106240.90.440023609
Synonymous-0.6592572441.050.00002292479
Loss of Function6.22249.00.04080.00000372734

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000240.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors. During brain development, critical in multiple processes, including neuronal migration, axonal growth and fasciculation, and synaptogenesis. In the mature brain, plays a role in the dynamics of neuronal structure and function, including synaptic plasticity. {ECO:0000269|PubMed:20621658, ECO:0000305}.;
Disease
DISEASE: Hydrocephalus due to stenosis of the aqueduct of Sylvius (HSAS) [MIM:307000]: Hydrocephalus is a condition in which abnormal accumulation of cerebrospinal fluid in the brain causes increased intracranial pressure inside the skull. This is usually due to blockage of cerebrospinal fluid outflow in the brain ventricles or in the subarachnoid space at the base of the brain. In children is typically characterized by enlargement of the head, prominence of the forehead, brain atrophy, mental deterioration, and convulsions. In adults the syndrome includes incontinence, imbalance, and dementia. HSAS is characterized by mental retardation and enlarged brain ventricles. {ECO:0000269|PubMed:10797421, ECO:0000269|PubMed:11857550, ECO:0000269|PubMed:12435569, ECO:0000269|PubMed:12514225, ECO:0000269|PubMed:19846429, ECO:0000269|PubMed:20621658, ECO:0000269|PubMed:22344793, ECO:0000269|PubMed:22973895, ECO:0000269|PubMed:24155914, ECO:0000269|PubMed:7562969, ECO:0000269|PubMed:7762552, ECO:0000269|PubMed:7881431, ECO:0000269|PubMed:7920659, ECO:0000269|PubMed:8401576, ECO:0000269|PubMed:8556302, ECO:0000269|PubMed:8929944, ECO:0000269|PubMed:9118141, ECO:0000269|PubMed:9195224, ECO:0000269|PubMed:9268105, ECO:0000269|PubMed:9521424, ECO:0000269|PubMed:9744477, ECO:0000269|PubMed:9832035}. Note=The disease is caused by mutations affecting the gene represented in this entry. L1CAM mutations have also been found in few patients affected by hydrocephalus with Hirschsprung disease, suggesting a role of this gene acting either in a direct or indirect way in the pathogenesis of Hirschsprung disease (PubMed:22344793). {ECO:0000269|PubMed:22344793}.; DISEASE: Mental retardation, aphasia, shuffling gait, and adducted thumbs syndrome (MASA) [MIM:303350]: An X-linked recessive syndrome with a highly variable clinical spectrum. Main clinical features include spasticity and hyperreflexia of lower limbs, shuffling gait, mental retardation, aphasia and adducted thumbs. The features of spasticity have been referred to as complicated spastic paraplegia type 1 (SPG1). Some patients manifest corpus callosum hypoplasia and hydrocephalus. Inter- and intrafamilial variability is very wide, such that patients with hydrocephalus, MASA, SPG1, and agenesis of corpus callosum can be present within the same family. {ECO:0000269|PubMed:10797421, ECO:0000269|PubMed:10805190, ECO:0000269|PubMed:11857550, ECO:0000269|PubMed:16816908, ECO:0000269|PubMed:19846429, ECO:0000269|PubMed:22344793, ECO:0000269|PubMed:22973895, ECO:0000269|PubMed:24155914, ECO:0000269|PubMed:26891472, ECO:0000269|PubMed:7562969, ECO:0000269|PubMed:7762552, ECO:0000269|PubMed:7881431, ECO:0000269|PubMed:7920659, ECO:0000269|PubMed:7920660, ECO:0000269|PubMed:8556302, ECO:0000269|PubMed:9268105, ECO:0000269|PubMed:9300653, ECO:0000269|PubMed:9452110, ECO:0000269|PubMed:9521424, ECO:0000269|PubMed:9744477, ECO:0000269|PubMed:9832035}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in L1CAM may contribute to Hirschsprung disease by modifying the effects of Hirschsprung disease- associated genes to cause intestinal aganglionosis. {ECO:0000269|PubMed:11857550}.; DISEASE: Agenesis of the corpus callosum, X-linked, partial (ACCPX) [MIM:304100]: A syndrome characterized by partial corpus callosum agenesis, hypoplasia of inferior vermis and cerebellum, mental retardation, seizures and spasticity. Other features include microcephaly, unusual facies, and Hirschsprung disease in some patients. {ECO:0000269|PubMed:16650080}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in L1CAM are associated with a wide phenotypic spectrum which varies from severe hydrocephalus and prenatal death (HSAS) to a milder phenotype (MASA). These variations may even occur within the same family. Due to the overlap of phenotypes between HSAS and MASA, many authors use the general concept of L1 syndrome which covers both ends of the spectrum. {ECO:0000269|PubMed:19846429, ECO:0000269|PubMed:22222883, ECO:0000269|PubMed:26891472}.;

Intolerance Scores

LoFtool
0.0181
RVIS EVS
-1.3
RVIS percentile EVS
4.92

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.843

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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