Muscular dystrophy, limb-girdle, autosomal recessive 23

Summary

Muscular dystrophy, limb-girdle, autosomal recessive 23 (MONDO:0029136) is a disease caused by LAMA2 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: LAMA2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 455

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy, limb-girdle, autosomal recessive 23
Mondo ID	MONDO:0029136
OMIM	618138
Orphanet	565837
DOID	DOID:0061132
UMLS	C4748327
MedGen	1648462
GARD	0022270
Is cancer (heuristic)	no

Also known as: laminin subunit alpha 2-related limb-girdle muscular dystrophy R23 · LGMDR23 · muscular dystrophy, limb-girdle, autosomal recessive 23

Data availability: 455 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive limb-girdle muscular dystrophy › muscular dystrophy, limb-girdle, autosomal recessive 23

Related subtypes (31): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, autosomal recessive limb-girdle muscular dystrophy type 2B, autosomal recessive limb-girdle muscular dystrophy type 2C, autosomal recessive limb-girdle muscular dystrophy type 2H, autosomal recessive limb-girdle muscular dystrophy type 2F, autosomal recessive limb-girdle muscular dystrophy type 2G, autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy type 2I, autosomal recessive limb-girdle muscular dystrophy type 2D, autosomal recessive limb-girdle muscular dystrophy type 2J, autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2L, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2Q, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type R18, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, autosomal recessive limb-girdle muscular dystrophy type 2X, autosomal recessive limb-girdle muscular dystrophy type 2W, autosomal recessive limb-girdle muscular dystrophy type 2Y, autosomal recessive limb-girdle muscular dystrophy type 2R1, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, muscular dystrophy, limb-girdle, autosomal recessive 26, muscular dystrophy, limb-girdle, autosomal recessive 27, muscular dystrophy, limb-girdle, autosomal recessive 28, muscular dystrophy, limb-girdle, autosomal recessive 29

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

455 retrieved; paginated sample, class counts are floors:

204 likely pathogenic, 62 pathogenic/likely pathogenic, 61 conflicting classifications of pathogenicity, 59 uncertain significance, 46 pathogenic, 13 benign, 7 benign/likely benign, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1712295	Single allele	ARHGAP18	Pathogenic	criteria provided, single submitter
1072865	NM_000426.4(LAMA2):c.5602G>T (p.Glu1868Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363194	NM_000426.4(LAMA2):c.872del (p.Gly291fs)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14291	NM_000426.4(LAMA2):c.9253C>T (p.Arg3085Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14296	NM_000426.4(LAMA2):c.7732C>T (p.Arg2578Ter)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
14299	NM_000426.4(LAMA2):c.4645C>T (p.Arg1549Ter)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
14300	NM_000426.4(LAMA2):c.7147C>T (p.Arg2383Ter)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1431679	NM_000426.4(LAMA2):c.437C>A (p.Ser146Tyr)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445696	NM_000426.4(LAMA2):c.6501C>A (p.Tyr2167Ter)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
167242	NM_000426.4(LAMA2):c.3623_3645del (p.Lys1208fs)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686645	NM_000426.4(LAMA2):c.6617del (p.Phe2206fs)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1712294	Single allele	LAMA2	Pathogenic	criteria provided, single submitter
1725656	NM_000426.4(LAMA2):c.1233C>A (p.Cys411Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1726400	NM_000426.4(LAMA2):c.2916del (p.Phe972fs)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803157	NM_000426.4(LAMA2):c.5122G>T (p.Glu1708Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191214	NM_000426.4(LAMA2):c.4348C>T (p.Arg1450Ter)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
196993	NM_000426.4(LAMA2):c.5260del (p.Lys1753_Val1754insTer)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
197024	NM_000426.4(LAMA2):c.5562+5G>C	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197987	NM_000426.4(LAMA2):c.7810C>T (p.Arg2604Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235805	NM_000426.4(LAMA2):c.1303C>T (p.Arg435Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500757	NM_000426.4(LAMA2):c.442del (p.Arg148fs)	LAMA2	Pathogenic	criteria provided, single submitter
2584804	NM_000426.4(LAMA2):c.1823_1824del (p.Ser607_Tyr608insTer)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265425	NM_000426.4(LAMA2):c.5374G>T (p.Glu1792Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265426	NM_000426.4(LAMA2):c.5476C>T (p.Arg1826Ter)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265427	NM_000426.4(LAMA2):c.7991del (p.Gly2664fs)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2676236	NM_000426.4(LAMA2):c.1976C>A (p.Ser659Ter)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
2706272	NM_000426.4(LAMA2):c.6444_6445del (p.Ser2149fs)	LAMA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279978	NM_000426.4(LAMA2):c.3215del (p.Cys1072fs)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
280520	NM_000426.4(LAMA2):c.3799_3821del (p.Phe1267fs)	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts
282977	NM_000426.4(LAMA2):c.396+1G>T	LAMA2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LAMA2	Definitive	Autosomal recessive	congenital merosin-deficient muscular dystrophy 1A	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMA2	Orphanet:258	Laminin subunit alpha 2-related congenital muscular dystrophy
LAMA2	Orphanet:565837	Laminin subunit alpha 2-related limb-girdle muscular dystrophy R23
TRAPPC11	Orphanet:369840	TRAPPC11-related limb-girdle muscular dystrophy R18
TRAPPC11	Orphanet:369847	Intellectual disability-hyperkinetic movement-truncal ataxia syndrome
TRAPPC11	Orphanet:869	Triple A syndrome
L1CAM	Orphanet:1497	X-linked complicated corpus callosum dysgenesis
L1CAM	Orphanet:2182	Hydrocephalus with stenosis of the aqueduct of Sylvius
L1CAM	Orphanet:2466	MASA syndrome
L1CAM	Orphanet:306617	X-linked complicated spastic paraplegia type 1

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LAMA2	HGNC:6482	ENSG00000196569	P24043	Laminin subunit alpha-2	gencc,clinvar
ARHGAP18	HGNC:21035	ENSG00000146376	Q8N392	Rho GTPase-activating protein 18	clinvar
TRAPPC11	HGNC:25751	ENSG00000168538	Q7Z392	Trafficking protein particle complex subunit 11	clinvar
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMA2	Laminin subunit alpha-2	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.
ARHGAP18	Rho GTPase-activating protein 18	Rho GTPase activating protein that suppresses F-actin polymerization by inhibiting Rho.
TRAPPC11	Trafficking protein particle complex subunit 11	Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
L1CAM	Neural cell adhesion molecule L1	Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	7.3×	0.260
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAMA2	Other/Unknown	no		Laminin_IV, EGF, Laminin_G
ARHGAP18	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, RHG40/28/18_ubiquitin
TRAPPC11	Other/Unknown	no		TPC11, TRAPPC11_C
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
mucosa of stomach	1
right ovary	1
bronchial epithelial cell	1
germinal epithelium of ovary	1
oviduct epithelium	1
adrenal tissue	1
primordial germ cell in gonad	1
cerebellar hemisphere	1
cortical plate	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMA2	272	ubiquitous	marker	mucosa of stomach, calcaneal tendon, right ovary
ARHGAP18	254	ubiquitous	marker	germinal epithelium of ovary, oviduct epithelium, bronchial epithelial cell
TRAPPC11	277	ubiquitous	marker	calcaneal tendon, adrenal tissue, primordial germ cell in gonad
L1CAM	239	ubiquitous	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
L1CAM	2,937
LAMA2	2,688
TRAPPC11	1,442
ARHGAP18	1,113

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LAMA2	P24043	2
L1CAM	P32004	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRAPPC11	Q7Z392	87.76
ARHGAP18	Q8N392	75.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET promotes cell motility	1	150.3×	0.030	LAMA2
Signal transduction by L1	1	129.8×	0.030	L1CAM
Attachment of bacteria to epithelial cells	1	124.1×	0.030	LAMA2
Basigin interactions	1	109.8×	0.030	L1CAM
Laminin interactions	1	95.2×	0.030	LAMA2
MET activates PTK2 signaling	1	95.2×	0.030	LAMA2
Interaction between L1 and Ankyrins	1	92.1×	0.030	L1CAM
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	92.1×	0.030	LAMA2
Signaling by MET	1	79.3×	0.030	LAMA2
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.030	LAMA2
Nervous system development	2	21.5×	0.030	LAMA2, L1CAM
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.035	LAMA2
Recycling pathway of L1	1	56.0×	0.035	L1CAM
Non-integrin membrane-ECM interactions	1	38.6×	0.041	LAMA2
ECM proteoglycans	1	37.6×	0.041	LAMA2
RHOC GTPase cycle	1	36.6×	0.041	ARHGAP18
Developmental Biology	2	7.2×	0.041	LAMA2, L1CAM
RAB GEFs exchange GTP for GDP on RABs	1	31.0×	0.045	TRAPPC11
L1CAM interactions	1	30.1×	0.045	L1CAM
Cell surface interactions at the vascular wall	1	23.8×	0.054	L1CAM
RHOA GTPase cycle	1	18.7×	0.065	ARHGAP18
Extracellular matrix organization	1	15.8×	0.073	LAMA2
Signaling by Receptor Tyrosine Kinases	1	12.9×	0.085	LAMA2
Axon guidance	1	11.3×	0.093	L1CAM
Hemostasis	1	9.0×	0.111	L1CAM
Signal Transduction	1	2.5×	0.339	LAMA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of synaptic transmission, cholinergic	1	842.6×	0.011	LAMA2
constitutive secretory pathway	1	702.2×	0.011	TRAPPC11
regulation of basement membrane organization	1	702.2×	0.011	LAMA2
Schwann cell differentiation	1	601.9×	0.011	LAMA2
axon guidance	2	45.3×	0.011	LAMA2, L1CAM
positive regulation of integrin-mediated signaling pathway	1	324.1×	0.012	LAMA2
positive regulation of muscle cell differentiation	1	280.9×	0.012	LAMA2
regulation of protein complex stability	1	263.3×	0.012	TRAPPC11
obsolete vesicle tethering	1	247.8×	0.012	TRAPPC11
regulation of cell motility	1	247.8×	0.012	ARHGAP18
cell adhesion	2	18.7×	0.012	LAMA2, L1CAM
COPII vesicle coat assembly	1	175.5×	0.016	TRAPPC11
regulation of actin filament polymerization	1	145.3×	0.017	ARHGAP18
positive regulation of axon extension	1	127.7×	0.018	L1CAM
maintenance of blood-brain barrier	1	120.4×	0.018	LAMA2
axon development	1	113.9×	0.018	L1CAM
regulation of embryonic development	1	82.6×	0.023	LAMA2
synapse organization	1	70.2×	0.025	L1CAM
positive regulation of cell adhesion	1	68.0×	0.025	LAMA2
small GTPase-mediated signal transduction	1	45.8×	0.034	ARHGAP18
muscle organ development	1	41.7×	0.034	LAMA2
cell-matrix adhesion	1	40.9×	0.034	L1CAM
regulation of cell migration	1	39.4×	0.034	LAMA2
regulation of actin cytoskeleton organization	1	39.4×	0.034	ARHGAP18
regulation of small GTPase mediated signal transduction	1	36.0×	0.034	ARHGAP18
homophilic cell-cell adhesion	1	35.1×	0.034	L1CAM
endoplasmic reticulum to Golgi vesicle-mediated transport	1	34.0×	0.034	TRAPPC11
chemotaxis	1	34.0×	0.034	L1CAM
Golgi organization	1	33.4×	0.034	TRAPPC11
regulation of cell shape	1	30.8×	0.034	ARHGAP18

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LAMA2	0	0
ARHGAP18	0	0
TRAPPC11	0	0
L1CAM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
L1CAM	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	L1CAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	LAMA2, ARHGAP18, TRAPPC11

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LAMA2	0	—
ARHGAP18	0	—
TRAPPC11	0	—
L1CAM	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.