LTBP2

protein-coding

latent transforming growth factor beta binding protein 2, the group of Latent transforming growth factor beta binding proteins

Gene summary

The protein encoded by this gene belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family possessing unique regions and with most similarity to the fibrillins. It has thus been suggested that it may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and a role in cell adhesion. [provided by RefSeq, Jul 2008]

Previous symbols:

LTBP3
C14orf141

MANE transcript

NM_000428.3

Inheritance

AR, AD

ClinVar variants

P:82U:667B:530

Top phenotype

Glaucoma 3, primary congenital, D; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma; Weill-Marchesani syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr14:74,498,183-74,612,378

External References & Databases

Ensembl (ENSG00000119681)

Transcript & Mutation Effects

hg38 • Region Span ~114.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glaucoma secondary to spherophakia/ectopia lentis and megalocorneaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016559

Submitter: Orphanet

Weill-Marchesani syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018096

Submitter: Orphanet

congenital glaucomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020366

Submitter: Orphanet

glaucoma 3, primary congenital, DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013122

Submitter: Labcorp Genetics (formerly Invitae)

glaucoma 3, primary congenital, DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013122

Submitter: PanelApp Australia

Weill-Marchesani syndrome 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013899

Submitter: Labcorp Genetics (formerly Invitae)

microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucomaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009633

Submitter: Labcorp Genetics (formerly Invitae)

glaucoma 3, primary congenital, DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013122

Submitter: ClinGen

The relationship between *LTBP2* and *LTBP2*-related ocular dysgenesis, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of February 16, 2023. *LTBP2* belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is expressed in elastic tissues and associates with fibrillin-1 containing microfibrils. Pathogenic variants in this gene are known to cause multiple disorders including Primary congenital glaucoma (MIM# 613086), Weill-Marchesani syndrome 3 (MIM# 614819), and Microspherophakia and/or megalocornea, with ectopia lentils and with or without secondary glaucoma (MIM# 251750). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities have been lumped into one disease entity, *LTBP2*-related ocular dysgenesis. *LTBP2* was first reported in relation to autosomal recessive *LTBP2*-related ocular dysgenesis in 2009 (Ali et al, 2009, PMID: 19361779; Narooie-Nejad, 2009, PMID: 19656777). More than 50 nonsense, frameshift, and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 6 probands in 3 publications (PMID: 19361779, 20617341, 33958902). Variants in this gene segregated with disease in 13 additional family members. The mechanism for disease is biallelic loss of function. Summary of experimental data (6 points): This gene-disease association is supported by in vitro functional assays and animal models. *LTBP2* is expressed in tissues relevant to disease within the eye including trabecular meshwork, ciliary processes, lens capsule, Descemet membrane (PMID: 19361779 , 19656777). The LTBP2 protein has a function in promoting the assembly of mature microfibrils in ciliary zonules (PMID: 24908666). *LTBP2* variants expressed in HEK293T cells are shown to be trapped intracellularly due to secretion defects and/or lack fibrillin-1-binding activity (PMID: 24908666). Homozygous knock out of *LTBP2* in animal models recapitulates the human phenotype. An initial report of LTBP2 knock-out in mice showed complete embryonic lethality (PMID: 10848613). A conditional knock-out mouse model, however, survived to adulthood with no systemic abnormalities, but showed ectopia lentils due to defects in the formation of microfibrils (PMID: 24908666). A spontaneous form of primary congenital glaucoma inherited in the autosomal recessive manner in domestic cats was shown to result from a frameshift variant in the feline *LTBP2* gene (PMID: 24908666). In summary, *LTBP2* is definitively associated with autosomal recessive *LTBP2*-related ocular dysgenesis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Weill-Marchesani syndrome 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013899

Submitter: Ambry Genetics

microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucomaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009633

Submitter: Ambry Genetics

microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucomaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009633

Submitter: G2P

Clinical Genomic Database (CGD)

Glaucoma 3, primary congenital, D; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma; Weill-Marchesani syndrome 3AR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Ophthalmologic

Intervention: Cardiovascular; Ophthalmologic; Pharmacogenomic

Rationale: Surveillance, early diagnosis, and treatment of manifestations such as ectopia lentis and glaucoma with surgical interventions (with the use of pre and postoperative agents to control intraocular pressure), or, if surgery is not effective, drainage implants or cyclodestruction, may be effective to decrease morbidity and mortality related to vision loss; Individuals with cardiovascular manifestations including pulmonary and aortic stenosis have been described, and awareness may allow early diagnosis and treatment; Agents that may contribute to glaucoma, as well as alpha-2-agonists, should be avoided

Refs: 18776954; 19361779; 19656777; 20179738; 20301293; 20301314; 20617341; 21081970; 22025892; 22539340; 23401661

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LTBP2 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 1355

Inborn genetic diseasesTotal: 321

Glaucoma 3, primary congenital, DTotal: 180

Weill-Marchesani syndromeTotal: 137

not specifiedTotal: 76

LTBP2-related disorderTotal: 69

Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucomaTotal: 49

Weill-Marchesani syndrome 3Total: 48

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000428.3. 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			9 clinvar	471 clinvar	3 clinvar	483
missense	1 clinvar	3 clinvar	647 clinvar	49 clinvar	7 clinvar	707
nonsense	11 clinvar	5 clinvar	1 clinvar			17
start loss			1 clinvar			1
frameshift	36 clinvar	7 clinvar	1 clinvar			44
splice donor/acceptor (+/-2bp)	2 clinvar	17 clinvar	8 clinvar			27
Total	50	32	667	520	10	1279

Highest pathogenic variant AF is 0.00003097736

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000428.3	RefSeq	NP_000419.1	36	MANE Select
ENST00000261978.9	Ensembl	ENSP00000261978.4	36	MANE Select
ENST00000553939.5	Ensembl	ENSP00000452110.1	35	Standard
ENST00000556206.1	Ensembl	ENSP00000450668.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hypothesized Pathways in Pathogenesis of Cardiovascular Disease
Extracellular matrix organization
Molecules associated with elastic fibres
Elastic fibre formation

Biological Process

protein targeting
transforming growth factor beta receptor signaling pathway
protein secretion
supramolecular fiber organization

Molecular Function

extracellular matrix structural constituent
calcium ion binding
protein binding
heparin binding
growth factor binding

Cellular Component

extracellular region
extracellular space
cell
extracellular matrix
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261978
Coding exons: 36
Length: 114434
Individuals with no LoFs: 125677
Homozygous LoFs: 1
Heterozygous LoFs: 70
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.189	1061	1.08e+3	0.984	0.0000704	11768
Missense (PolyPhen)		383	430.36	0.88994		4834
Synonymous	-1.76	509	461	1.10	0.0000335	3632
Loss of Function	6.33	24	88.1	0.272	0.00000423	1026

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00064	0.00049	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00032	0.00031	rare
South Asian	0.00029	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play an integral structural role in elastic-fiber architectural organization and/or assembly. {ECO:0000303|PubMed:10743502, ECO:0000303|PubMed:11104663}.;
Disease: DISEASE: Glaucoma 3, primary congenital, D (GLC3D) [MIM:613086]: An autosomal recessive form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:19361779}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma (MSPKA) [MIM:251750]: A rare disease characterized by smaller and more spherical lenses than normal bilaterally, an increased anteroposterior thickness of the lens, and highly myopic eyes. Lens dislocation or subluxation may occur, leading to defective accommodation. {ECO:0000269|PubMed:20617341}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Weill-Marchesani syndrome 3 (WMS3) [MIM:614819]: A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma. {ECO:0000269|PubMed:22539340}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0915

Intolerance Scores

LoFtool: 0.0599
RVIS EVS: -1.55
RVIS percentile EVS: 3.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.521

Gene Damage Prediction

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