GeneBe

LAMA2

protein-coding

laminin subunit alpha 2, the group of Laminin subunits

Gene summary

Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • LAMM

MANE transcript

NM_000426.4

Inheritance

AR, AD

ClinVar variants

P:1090U:1531B:1635

Top phenotype

Schizophrenia; Muscular dystrophy, congenital merosin-deficient, 1A; Muscular dystrophy, limb-girdle, autosomal recessive 23

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr6:128,883,138-129,516,566

External References & Databases

Ensembl (ENSG00000196569)NCBI Gene (3908)OMIM (156225)HGNC:6482GenCCUniProt (P24043)AlphaFoldClinVar (LAMA2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~633.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital merosin-deficient muscular dystrophy 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011925

Submitter: Myriad Women's Health

congenital merosin-deficient muscular dystrophy 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011925

Submitter: G2P

LAMA2-related muscular dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100228

Submitter: PanelApp Australia

congenital merosin-deficient muscular dystrophy 1ASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011925

Submitter: Orphanet

congenital merosin-deficient muscular dystrophy 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011925

Submitter: Labcorp Genetics (formerly Invitae)

muscular dystrophy, limb-girdle, autosomal recessive 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029136

Submitter: Labcorp Genetics (formerly Invitae)

LAMA2-related muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100228

Submitter: ClinGen

*LAMA2* was first reported in relation to ​autosomal recessive congenital muscular dystrophy ​​in ​1994 (Tomé et al., PMID: 8000914)​, with the first *LAMA2* variants associated with muscular dystrophy identified in 1995 (Helbling-Leclerc et al., PMID: 7550355)​. Later publications described additional *LAMA2* variants in relation to a less severe, adult onset form of muscular dystrophy (PMID: 21922472, PMID: 21953594). Well over 100 unique variants (including missense, nonsense, frameshift, and splicing variants) have been reported in humans. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found insufficient evidence of a distinct molecular mechanism and a phenotypic spectrum of disease. Both disease entities in the literature (merosin deficient or partially deficient congenital muscular dystrophy (OMIM: 607855) and limb girdle muscular dystrophy (OMIM: 618138)) are caused by loss of function variants leading to variable degrees of reduction of the alpha chain of the laminin 2 protein in a recessive fashion and, therefore, the disease entities have been lumped into one disease entity (autosomal recessive *LAMA2*-related muscular dystrophy). Evidence ​supporting this gene-disease relationship includes ​case-level data from 9 probands in 7 publications (PMID: 8651294, PMID: 10852549, PMID: 18700894, PMID: 21953594, PMID: 24611677, PMID: 26104111, PMID: 30055037), extending beyond the maximum score for genetic evidence (12 points). Of note, several reported individuals asserted to have a limb girdle muscular dystrophy presentation were evaluated and determined to meet the Limb Girdle Muscular Dystrophy GCEP-specified criteria for a limb girdle muscular dystrophy phenotype (progressive weakness in limb musculature (pelvic and shoulder girdle), independent ambulation by the age 2 years, elevated creatine kinase of >2X the upper limit of normal, muscle biopsy with dystrophic and myopathic features): PMID: 21922472; Patient 5, PMID: 21953594; Patients 6 and 8, PMID: 25663498; PMID: 27932089; Patients 1 and 2, PMID: 32904964. This gene-disease association is also supported by experimental evidence, including expression, protein interactions, functional alteration, and multiple animal models (PMID: 3278318, PMID: 8000914, PMID: 8188645, PMID: 19692349, PMID: 17438294, PMID: 9710454), also extending beyond the maximum score for experimental evidence (6 points). In summary, ​*LAMA2*​​ is definitively associated with ​autosomal recessive muscular dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on 1/25/2021 and by the ClinGen Limb Girdle Muscular Dystrophy Gene Curation Expert Panel on 2/8/2022 (SOP Version 8).

Clinical Genomic Database (CGD)

Schizophrenia; Muscular dystrophy, congenital merosin-deficient, 1A; Muscular dystrophy, limb-girdle, autosomal recessive 23AD/AR

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: In Muscular dystrophy, congenital merosin-deficient, 1A, 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; In Schizophrenia, the evidence or clinical applicability is unclear

Comments: Clinically significant cardiomyopathy has not been described

Refs: 7550355; 8887959; 8729391; 12552556; 16216942; 18700894; 20627570; 21953594; 22166137; 22675738; 23042115; 24611677; 25663498; 30055037Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMA2 variants in ClinVar

32 Conditions Cataloged
LAMA2-related muscular dystrophyTotal: 4443
not providedTotal: 1197
Merosin deficient congenital muscular dystrophyTotal: 623
not specifiedTotal: 470
Inborn genetic diseasesTotal: 445
Muscular dystrophy, limb-girdle, autosomal recessive 23Total: 289
Congenital muscular dystrophy due to partial LAMA2 deficiencyTotal: 244
LAMA2-related disorderTotal: 172

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000426.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
24
clinvar
1369
clinvar
9
clinvar
 1405
missense
4
clinvar
35
clinvar
1488
clinvar
245
clinvar
10
clinvar
 1782
nonsense
169
clinvar
160
clinvar
1
clinvar
 330
start loss
1
clinvar
 1
frameshift
294
clinvar
198
clinvar
3
clinvar
1
clinvar
 496
splice donor/acceptor (+/-2bp)
52
clinvar
174
clinvar
16
clinvar
 242
Total52057015311616194256

Highest pathogenic variant AF is 0.00014498501

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000426.4RefSeqNP_000417.365MANE Select
ENST00000421865.3EnsemblENSP00000400365.265MANE Select
NM_001079823.2RefSeqNP_001073291.264Standard
ENST00000466230.2EnsemblENSP00000509691.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
lama2Danio rerio

Structure: fast muscle cell

Quality: detached from

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)
  • Dilated cardiomyopathy (DCM) - Homo sapiens (human)
  • Viral myocarditis - Homo sapiens (human)

Biological Process

  • cell adhesion
  • axon guidance
  • muscle organ development
  • Schwann cell differentiation
  • regulation of cell adhesion

Molecular Function

  • signaling receptor binding
  • structural molecule activity
  • extracellular matrix structural constituent

Cellular Component

  • extracellular region
  • basement membrane
  • neuromuscular junction
  • sarcolemma
  • synaptic cleft

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000421865
Coding exons
65
Length
633373
Individuals with no LoFs
125331
Homozygous LoFs
0
Heterozygous LoFs
417
Defined
125748
p
0.00166
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.030016981.69e+31.000.000094820542
Missense (PolyPhen)670726.430.922328975
Synonymous-1.446666201.070.00003635955
Loss of Function4.501021640.6210.000009481988

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00120.0012notable
Latino/Admixed American0.00140.0013notable
Ashkenazi Jewish0.00170.0017notable
East Asian0.00400.0040notable
Finnish0.000510.00051rare
European (Non-Finnish)0.00170.0017notable
South Asian0.00160.0016notable
Other0.00160.0016notable

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: Merosin-deficient congenital muscular dystrophy 1A (MDC1A) [MIM:607855]: Characterized by difficulty walking, hypotonia, proximal weakness, hyporeflexia, and white matter hypodensity on MRI. {ECO:0000269|PubMed:11591858, ECO:0000269|PubMed:12552556, ECO:0000269|PubMed:27234031}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.636

Intolerance Scores

LoFtool
0.948
RVIS EVS
0.5
RVIS percentile EVS
79.64

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.513

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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