LAMA3

protein-coding

laminin subunit alpha 3, the group of Laminin subunits

Gene summary

The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

Previous symbols:

LAMNA

MANE transcript

NM_198129.4

Inheritance

ClinVar variants

P:269U:649B:835

Top phenotype

Epidermolysis bullosa, junctional 2A, intermediate; Epidermolysis bullosa, junctional 2B, severe; Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr18:23,689,453-23,956,222

External References & Databases

Ensembl (ENSG00000053747)

Transcript & Mutation Effects

hg38 • Region Span ~266.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

junctional epidermolysis bullosaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017612

Submitter: Myriad Women's Health

laryngo-onycho-cutaneous syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009513

Submitter: Labcorp Genetics (formerly Invitae)

junctional epidermolysis bullosa Herlitz typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009182

Submitter: Orphanet

junctional epidermolysis bullosa, non-Herlitz typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009180

Submitter: Genomics England PanelApp

junctional epidermolysis bullosa Herlitz typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009182

Submitter: Genomics England PanelApp

epidermolysis bullosa, junctional 2B, severeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030747

Submitter: PanelApp Australia

laryngo-onycho-cutaneous syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009513

Submitter: PanelApp Australia

epidermolysis bullosa, junctional 2A, intermediateSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030746

Submitter: PanelApp Australia

generalized junctional epidermolysis bullosa non-Herlitz typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019307

Submitter: Orphanet

laryngo-onycho-cutaneous syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009513

Submitter: G2P

junctional epidermolysis bullosa Herlitz typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009182

Submitter: Labcorp Genetics (formerly Invitae)

laryngo-onycho-cutaneous syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009513

Submitter: Genomics England PanelApp

laryngo-onycho-cutaneous syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009513

Submitter: Orphanet

Clinical Genomic Database (CGD)

Epidermolysis bullosa, junctional 2A, intermediate; Epidermolysis bullosa, junctional 2B, severe; Epidermolysis bullosa, junctional 2C, laryngoonychocutaneousAR

Manifestation: Audiologic/Otolaryngologic; Dental; Dermatologic

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

Comments: The condition can include life-threatening respiratory obstruction

Refs: 1342856; 8185366; 7633458; 8530087; 8618022; 8586427; 11810295; 12915477; 20301304; 20881434; 22434185; 22963541

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LAMA3 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1489

Inborn genetic diseasesTotal: 535

Junctional epidermolysis bullosa gravis of HerlitzTotal: 267

Laryngo-onycho-cutaneous syndromeTotal: 177

LAMA3-related disorderTotal: 128

not specifiedTotal: 92

Epidermolysis bullosa, junctional 2B, severeTotal: 82

Epidermolysis bullosa, junctional 2A, intermediateTotal: 68

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198129.4. 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		1 clinvar	14 clinvar	708 clinvar	15 clinvar	738
missense	1 clinvar	6 clinvar	567 clinvar	104 clinvar	7 clinvar	685
nonsense	52 clinvar	24 clinvar	18 clinvar	1 clinvar		95
start loss						0
frameshift	57 clinvar	46 clinvar	16 clinvar			119
splice donor/acceptor (+/-2bp)	8 clinvar	74 clinvar	34 clinvar			116
Total	118	151	649	813	22	1753

Highest pathogenic variant AF is 0.0005489762

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198129.4	RefSeq	NP_937762.2	75	MANE Select
ENST00000313654.14	Ensembl	ENSP00000324532.8	75	MANE Select
NM_000227.6	RefSeq	NP_000218.3	38	MANE Plus Clinical
NM_001127717.4	RefSeq	NP_001121189.2	74	Standard

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 adhesion
epidermis development
regulation of cell adhesion
extracellular matrix organization
regulation of cell migration

Molecular Function

signaling receptor binding
structural molecule activity
extracellular matrix structural constituent

Cellular Component

extracellular region
basement membrane
laminin-5 complex
endoplasmic reticulum
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313654
Coding exons: 75
Length: 265624
Individuals with no LoFs: 125397
Homozygous LoFs: 0
Heterozygous LoFs: 351
Defined: 125748
p: 0.00140

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.487	1752	1.81e+3	0.968	0.000108	21794
Missense (PolyPhen)		531	588.73	0.90194		7306
Synonymous	0.368	680	692	0.982	0.0000425	6494
Loss of Function	5.05	102	174	0.586	0.00000946	2130

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0012	notable
Latino/Admixed American	0.0014	0.0013	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0055	0.0054	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0012	0.0012	notable
South Asian	0.0015	0.0015	notable
Other	0.00066	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.;
Disease: DISEASE: Epidermolysis bullosa, junctional, Herlitz type (H-JEB) [MIM:226700]: An infantile and lethal form of junctional epidermolysis bullosa, a group of blistering skin diseases characterized by tissue separation which occurs within the dermo- epidermal basement In the Herlitz type, death occurs usually within the first six months of life. Occasionally, children survive to teens. It is marked by bullous lesions at birth and extensive denudation of skin and mucous membranes that may be hemorrhagic. {ECO:0000269|PubMed:7633458, ECO:0000269|PubMed:8530087}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Laryngoonychocutaneous syndrome (LOCS) [MIM:245660]: Autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx. {ECO:0000269|PubMed:12915477}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.403

Intolerance Scores

LoFtool: 0.948
RVIS EVS: -2.06
RVIS percentile EVS: 1.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.698

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium