LAMC3

protein-coding

laminin subunit gamma 3, the group of Laminin subunits

Gene summary

Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 3. The gamma 3 chain is most similar to the gamma 1 chain, and contains all the 6 domains expected of the gamma chain. It is a component of laminin 12. The gamma 3 chain is broadly expressed in skin, heart, lung, and the reproductive tracts. In skin, it is seen within the basement membrane of the dermal-epidermal junction at points of nerve penetration. Gamma 3 is also a prominent element of the apical surface of ciliated epithelial cells of lung, oviduct, epididymis, ductus deferens, and seminiferous tubules. The distribution of gamma 3-containing laminins along ciliated epithelial surfaces suggests that the apical laminins are important in the morphogenesis and structural stability of the ciliated processes of these cells. [provided by RefSeq, Aug 2011]

MANE transcript

NM_006059.4

Inheritance

AR, AD

ClinVar variants

P:112U:742B:513

Top phenotype

Cortical malformations, occipital

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr9:131,009,174-131,094,473

External References & Databases

Ensembl (ENSG00000050555)

Transcript & Mutation Effects

hg38 • Region Span ~85.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

occipital pachygyria and polymicrogyriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*LAMC3* encodes the laminin subunit gamma 3. Laminins are extracellular matrix glycoproteins required for cell adhesion, differentiation and migration. *LAMC3* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2011 (O'Roak et al., PMID: 21572417). Over 25 unique heterozygous truncating and missense variants have been reported in sequencing studies in neurodevelopmental disorders. Autism spectrum disorder was the primary ascertainment for the largest number of individuals, but variants have also been reported in probands with intellectual disability and/or developmental delay. The variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340). These heterozygous variants are unlikely to be deleterious because they also occur in healthy individuals (PMIDs: 23160955, 31981491) and are often inherited from unaffected parents (PMIDs: 23160955, 28191889, 30564305, 31398340). Additionally, many of these variants are present at high frequency in gnomAD (v2.1.1). In agreement with these findings, *LAMC3* is not constrained for either protein truncating variants (pLI = 0, LOEUF = 0.84, gnomAD v2.1.1) or missense variation (Z score = –0.43). Thus, all the reported variants were scored 0 points. A potential mechanism of disease has not been delineated for *LAMC3* heterozygous variants, and no experimental data were identified that provided specific support for this gene-disease relationship. Of note, biallelic variants in *LAMC3* have been implicated in cortical malformations. The relationship between *LAMC3* and autosomal recessive cortical malformations will be curated separately. In summary, the evidence supporting the relationship between *LAMC3* and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *LAMC3* plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 1, 2020 (SOP Version 7). As of July 2026, this record underwent administrative updates to update scoring to be consistent with SOP Version 12. No new evidence has been reviewed or added.

occipital pachygyria and polymicrogyriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: G2P

occipital pachygyria and polymicrogyriaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: Ambry Genetics

occipital pachygyria and polymicrogyriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: Illumina

occipital pachygyria and polymicrogyriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: PanelApp Australia

occipital pachygyria and polymicrogyriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013583

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cortical malformations, occipitalAR

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

Refs: 21572413

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMC3 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 1546

Inborn genetic diseasesTotal: 333

not specifiedTotal: 131

Occipital pachygyria and polymicrogyriaTotal: 83

LAMC3-related disorderTotal: 70

Intellectual disabilityTotal: 13

Left ventricular noncompactionTotal: 3

Neonatal deathTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006059.4. 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			11 clinvar	427 clinvar	3 clinvar	441
missense			725 clinvar	76 clinvar	7 clinvar	808
nonsense	29 clinvar	6 clinvar	1 clinvar			36
start loss						0
frameshift	31 clinvar	15 clinvar	3 clinvar			49
splice donor/acceptor (+/-2bp)	5 clinvar	26 clinvar	2 clinvar			33
Total	65	47	742	503	10	1367

Highest pathogenic variant AF is 0.00025600623

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006059.4	RefSeq	NP_006050.3	28	MANE Select
ENST00000361069.9	Ensembl	ENSP00000354360.4	28	MANE Select
ENST00000355452.5	Ensembl	ENSP00000347627.5	6	Standard
ENST00000678758.1	Ensembl	ENSP00000503612.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lamc3	Danio rerio	Structure: primary motor neuron Quality: shape abnormal

Gene / Model

Organism

Observed Phenotype

lamc3

Danio rerio

Structure: primary motor neuron

Quality: shape

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Small cell lung cancer - Homo sapiens (human)
Amoebiasis - Homo sapiens (human)

Biological Process

cell morphogenesis involved in differentiation
cell adhesion
visual perception
astrocyte development
extracellular matrix organization

Molecular Function

structural molecule activity

Cellular Component

extracellular region
basement membrane
membrane
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361069
Coding exons: 28
Length: 85392
Individuals with no LoFs: 125446
Homozygous LoFs: 0
Heterozygous LoFs: 302
Defined: 125748
p: 0.00120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.430	965	928	1.04	0.0000639	10124
Missense (PolyPhen)		307	324.64	0.94567		3694
Synonymous	-0.126	414	411	1.01	0.0000312	3163
Loss of Function	2.67	48	72.6	0.661	0.00000357	814

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00040	0.00040	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00071	0.00071	rare
Finnish	0.0065	0.0065	notable
European (Non-Finnish)	0.00083	0.00082	rare
South Asian	0.00089	0.00088	rare
Other	0.00099	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.;
Disease: DISEASE: Cortical malformations occipital (OCCM) [MIM:614115]: A disease in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes. {ECO:0000269|PubMed:21572413}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.837
RVIS EVS: 0.64
RVIS percentile EVS: 83.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High