LAMA5

protein-coding

laminin subunit alpha 5, the group of Laminin subunits|MicroRNA protein coding host genes

Gene summary

This gene encodes one of the vertebrate laminin alpha chains. 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. The protein encoded by this gene is the alpha-5 subunit of of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523). [provided by RefSeq, Jun 2013]

MANE transcript

NM_005560.6

Inheritance

AR, AD

ClinVar variants

P:33U:1089B:805

Top phenotype

Bent bone dysplasia syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr20:62,307,955-62,367,312

External References & Databases

Ensembl (ENSG00000130702)

Transcript & Mutation Effects

hg38 • Region Span ~59.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

LAMA5-related multisystemic syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033856

Submitter: ClinGen

*LAMA5* was first reported in relation to autosomal recessive *LAMA5*-related multisystemic syndrome in 2013 (Chatterjee et al., PMID: 24130771). *LAMA5*—related multisystemic syndrome is a complex syndrome with a wide spectrum of symptoms involving renal (exclusive at times) phenotypes. 16 variants (missense and nonsense) that have been reported in 11 probands in 9 publications (PMIDs: 24130771, 28544784, 29534211, 31130284, 31680349, 31937884, 32439764, 33242826, 35584218) are included in this curation. The mechanism of pathogenicity is reported to be LOF. This gene-disease association is also supported by experimental evidence (animal models, expression studies, and biochemical function) (PMIDs: 10625553, 20150535, 35584218). Multiple animal models capitulate a multisystemic phenotype with evidence of renal involvement, supported by expression studies in the glomerular basement membrane (GBM) and *LAMA5*’s importance in GBM integrity. In summary, *LAMA5* is definitively associated with autosomal recessive *LAMA5*-related multisystemic syndrome. 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 Glomerulopathy GCEP on the meeting date April 26th, 2022 (SOP Version 8).

LAMA5-related multisystemic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033856

Submitter: Orphanet

LAMA5-related multisystemic syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033856

Submitter: PanelApp Australia

bent bone dysplasia syndrome 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859573

Submitter: LiferaOmics

Genetic evidence – Published PMID: 33242826 – Reports one nonconsanguineous family with three affected siblings presenting with severe prenatal skeletal dysplasia consistent with Bent Bone Dysplasia Syndrome 2. Case-level (AR model; compound heterozygous; non-LOF variants ; each variant scored independently start at 0.1; scored once per family; nonconsanguineous so no deduction) = 0.2; segregation (two additional affected siblings; conservative) = 0.5; case-control = 0 PMID: 33242826 total = 0.7. Published genetic evidence total = 0.7/12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity unknown so no deduction applied) = 1.5; segregation = 0; case-control = 0 Family 1 total = 1.5. Our cases total = 1.5/12 Total genetic evidence (published + our cases) 0.7 + 1.5 = 2.2/12 Experimental evidence – Published PMID: 33242826 – Demonstrates that LAMA5 variants disrupt laminin α5 function, affecting basement membrane integrity and skeletal development. Expression analyses and functional modeling support a role in skeletal morphogenesis consistent with the dysplasia phenotype. Gene function / biological plausibility = 0.5; Functional alteration evidence (variant impact on protein function as shown in study) = 0.5; Experimental evidence total = 1.0/6 Overall score Genetic evidence = 2.2 Experimental evidence = 1.0 Overall score = 3.2

nephrotic syndrome, IIa 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031061

Submitter: Labcorp Genetics (formerly Invitae)

LAMA5-related multisystemic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033856

Submitter: PanelApp Australia

nephrotic syndrome, IIa 26MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0031061

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Bent bone dysplasia syndrome 2AR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Renal

Intervention: Cardiovascular

Rationale: Among other features, the condition can include atrial septal defects, and awareness may allow early diagnosis and management

Comments: Some individuals with Nephrotic syndrome, type 26 have been reported as being responsive to steroids

Refs: 29534211; 33242826; 35419533

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMA5 variants in ClinVar

24 Conditions Cataloged

not providedTotal: 1428

Inborn genetic diseasesTotal: 809

LAMA5-related disorderTotal: 380

not specifiedTotal: 197

Nephrotic syndrome, IIa 26Total: 53

Bent bone dysplasia syndrome 2Total: 14

Nephrotic syndromeTotal: 14

Short statureTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005560.6. 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			17 clinvar	540 clinvar	40 clinvar	597
missense		12 clinvar	1034 clinvar	183 clinvar	42 clinvar	1271
nonsense	4 clinvar	5 clinvar	5 clinvar			14
start loss						0
frameshift	2 clinvar	8 clinvar	7 clinvar			17
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	26 clinvar			28
Total	7	26	1089	723	82	1927

Highest pathogenic variant AF is 0.00021695982

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005560.6	RefSeq	NP_005551.3	80	MANE Select
ENST00000252999.7	Ensembl	ENSP00000252999.3	80	MANE Select
ENST00000474128.1	Ensembl	ENSP00000420069.1	2	Standard
ENST00000497053.2	Ensembl	ENSP00000481814.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lama5	Danio rerio	Structure: epidermal cell Quality: shape abnormal

Gene / Model

Organism

Observed Phenotype

lama5

Danio rerio

Structure: epidermal cell

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

angiogenesis
branching involved in ureteric bud morphogenesis
morphogenesis of a polarized epithelium
neural crest cell migration
hair follicle development

Molecular Function

integrin binding
extracellular matrix structural constituent

Cellular Component

extracellular region
basement membrane
laminin-5 complex
extracellular space
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252999
Coding exons: 80
Length: 59358
Individuals with no LoFs: 125353
Homozygous LoFs: 0
Heterozygous LoFs: 149
Defined: 125502
p: 0.000594

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.272	2301	2.26e+3	1.02	0.000165	23392
Missense (PolyPhen)		499	570.18	0.87516		5807
Synonymous	-6.45	1240	983	1.26	0.0000750	7679
Loss of Function	9.48	44	182	0.242	0.00000988	1948

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00077	0.00074	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00064	0.00060	rare
East Asian	0.00078	0.00076	rare
Finnish	0.00034	0.00032	rare
European (Non-Finnish)	0.00073	0.00066	rare
South Asian	0.00066	0.00062	rare
Other	0.00070	0.00065	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.;

Intolerance Scores

LoFtool: 0.482
RVIS EVS: 3.13
RVIS percentile EVS: 99.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.959

Gene Damage Prediction

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