LAMA2

Chr 6AR

laminin subunit alpha 2

Also known as: LAMM, MDC1A

NCBI Gene: 3908 ENSG00000196569 UniProt: P24043 OMIM: 156225

The LAMA2 gene encodes the alpha-2 chain of laminin, an extracellular matrix protein that forms a major component of basement membranes and mediates cell attachment and organization during development. Mutations cause congenital merosin-deficient muscular dystrophy and limb-girdle muscular dystrophy type 23, both inherited in an autosomal recessive pattern. The pathogenic mechanism involves loss of function of the laminin protein, disrupting the structural integrity of muscle basement membranes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Muscular dystrophy, congenital, merosin deficient or partially deficientMIM #607855

Muscular dystrophy, limb-girdle, autosomal recessive 23MIM #618138

UniProtMerosin-deficient congenital muscular dystrophy 1A

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · LAMA2-related muscular dystrophy · AR · ClinGen 2022
Definitive · congenital merosin-deficient muscular dystrophy 1A · AR · Myriad Women's Health
Strong · muscular dystrophy, limb-girdle, autosomal recessive 23 · AR · Labcorp Genetics (formerly Invitae)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.73

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — LAMA2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.000

Z-score 4.50

OE 0.62 (0.53–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.03Z-score

OE missense 1.00 (0.96–1.04)

1698 obs / 1694.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.62 (0.53–0.73)

0≤0.351.4

Missense OE?1.00 (0.96–1.04)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 102 / 164.3Missense obs/exp: 1698 / 1694.5Syn Z: -1.44

Background carrier burden — how many people carry a rare variant somewhere in LAMA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 14

4,168 rare PASS variants

Rare truncating (LoF)

1 in 250

572 rare PASS variants

Rare synonymous (reference)

1 in 26

1,519 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LAMA2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 19	1 in 260
South Asian	~43k	1 in 14	1 in 230
Remaining (unassigned)	~30k	1 in 12	1 in 240
European (Finnish)	~27k	1 in 78	1 in 620
Admixed American	~22k	1 in 13	1 in 360
African / African American	~21k	1 in 12	1 in 250
East Asian	~20k	1 in 15	1 in 250
Ashkenazi Jewish	~13k	1 in 39	1 in 210
Middle Eastern	~2,884	1 in 13	1 in 300

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 44 of 65 coding exons well covered in gnomAD exomes; exons 3, 6, 7, 9, 13 and 16 more marginal. Genomes: 64 of 65 (exon 53 below).? see exons ↓