L1CAM

Chr XXLR

L1 cell adhesion molecule

Also known as: CAML1, CD171, HSAS, HSAS1, HYCX, MASA, MIC5, N-CAM-L1

NCBI Gene: 3897 ENSG00000198910 UniProt: P32004 OMIM: 308840

L1CAM encodes a neural cell adhesion molecule that mediates cell-cell adhesion and generates transmembrane signals, playing critical roles in neuronal migration, axonal growth and fasciculation, and synaptogenesis during brain development. Loss-of-function mutations cause X-linked recessive neurological syndromes including CRASH syndrome (corpus callosum hypoplasia, intellectual disability, aphasia, spastic paraplegia, and hydrocephalus), MASA syndrome, and X-linked congenital hydrocephalus. The pathogenic mechanism involves loss of protein function leading to disrupted neural development and connectivity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.133 OMIM phenotypes

Clinical Summary— L1CAM

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Gene-Disease Validity (ClinGen)

L1 syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 6.22

OE 0.04 (0.02–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.84Z-score

OE missense 0.66 (0.61–0.72)

373 obs / 562.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.13)

0≤0.351.4

Missense OE?0.66 (0.61–0.72)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 2 / 49.0Missense obs/exp: 373 / 562.2Syn Z: -0.66

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveL1CAM-related hydrocephalus due to stenosis of the aqueduct of sylviusLOFXLR

This gene — mechanism propensity

0.4190th %ile

GOF

0.4974th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.