LTBP3

Summary

LTBP3 (latent transforming growth factor beta binding protein 3, HGNC:6716) is a protein-coding gene on chromosome 11q13.1, encoding Latent-transforming growth factor beta-binding protein 3 (Q9NS15). Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.

The protein encoded by this gene forms a complex with transforming growth factor beta (TGF-beta) proteins and may be involved in their subcellular localization. Activation of this complex requires removal of the encoded binding protein. This protein also may play a structural role in the extracellular matrix. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4054 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glaucoma 3, primary congenital, D (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 3,286 total — 92 pathogenic, 53 likely-pathogenic
• Phenotypes (HPO): 128
• MANE Select transcript: NM_001130144

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6716
Approved symbol	LTBP3
Name	latent transforming growth factor beta binding protein 3
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000168056
Ensembl biotype	protein_coding
OMIM	602090
Entrez	4054

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 14 retained_intron, 11 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000301873, ENST00000322147, ENST00000524798, ENST00000525443, ENST00000526124, ENST00000526825, ENST00000526927, ENST00000527339, ENST00000527792, ENST00000528516, ENST00000528966, ENST00000529189, ENST00000529371, ENST00000529582, ENST00000529764, ENST00000530785, ENST00000530866, ENST00000530990, ENST00000532661, ENST00000532932, ENST00000685178, ENST00000688764, ENST00000689505, ENST00000971646, ENST00000971647, ENST00000971648, ENST00000971649, ENST00000971650

RefSeq mRNA: 3 — MANE Select: NM_001130144 NM_001130144, NM_001164266, NM_021070

CCDS: CCDS44647, CCDS8103

Canonical transcript exons

ENST00000301873 — 28 exons

Exon	Start	End
ENSE00001603933	65557629	65558359
ENSE00002155004	65538559	65539231
ENSE00003464093	65551972	65552157
ENSE00003474985	65539548	65539628
ENSE00003488759	65547439	65547567
ENSE00003496886	65546442	65546564
ENSE00003503692	65551402	65551474
ENSE00003505078	65553701	65553903
ENSE00003512036	65553425	65553530
ENSE00003524774	65547920	65548045
ENSE00003531404	65547690	65547821
ENSE00003536097	65540245	65540382
ENSE00003542405	65539720	65539881
ENSE00003548184	65551548	65551564
ENSE00003551669	65543105	65543224
ENSE00003564673	65541126	65541293
ENSE00003576430	65546798	65546920
ENSE00003591164	65540013	65540153
ENSE00003610665	65553164	65553256
ENSE00003623025	65552860	65552982
ENSE00003640923	65554051	65554380
ENSE00003641056	65541600	65541728
ENSE00003643330	65551126	65551224
ENSE00003643732	65539328	65539459
ENSE00003648281	65543427	65543549
ENSE00003651949	65552248	65552406
ENSE00003686560	65540486	65540614
ENSE00003690173	65540871	65540954

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.23.

FANTOM5 (CAGE): breadth broad, TPM avg 6.6973 / max 197.4661, expressed in 745 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120634	25.4050	1577
120636	16.6774	1507
144065	6.6973	745
144064	3.2915	708
120620	1.6212	394
120621	1.2796	402
120633	0.8760	524
120635	0.8317	476
120631	0.6838	430
120637	0.5335	320

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	99.23	gold quality
thoracic aorta	UBERON:0001515	99.17	gold quality
ascending aorta	UBERON:0001496	99.16	gold quality
right ovary	UBERON:0002118	99.00	gold quality
right coronary artery	UBERON:0001625	98.96	gold quality
left ovary	UBERON:0002119	98.89	gold quality
aorta	UBERON:0000947	98.87	gold quality
mucosa of stomach	UBERON:0001199	98.86	gold quality
right uterine tube	UBERON:0001302	98.85	gold quality
body of uterus	UBERON:0009853	98.83	gold quality
stromal cell of endometrium	CL:0002255	98.72	gold quality
endocervix	UBERON:0000458	98.72	gold quality
nerve	UBERON:0001021	98.71	gold quality
tibial nerve	UBERON:0001323	98.71	gold quality
popliteal artery	UBERON:0002250	98.68	gold quality
tibial artery	UBERON:0007610	98.67	gold quality
adenohypophysis	UBERON:0002196	98.66	gold quality
left coronary artery	UBERON:0001626	98.64	gold quality
right lobe of thyroid gland	UBERON:0001119	98.61	gold quality
left uterine tube	UBERON:0001303	98.60	gold quality
coronary artery	UBERON:0001621	98.58	gold quality
left lobe of thyroid gland	UBERON:0001120	98.51	gold quality
pituitary gland	UBERON:0000007	98.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.24	gold quality
right atrium auricular region	UBERON:0006631	98.11	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.09	gold quality
thyroid gland	UBERON:0002046	98.06	gold quality
apex of heart	UBERON:0002098	98.05	gold quality
sural nerve	UBERON:0015488	98.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting LTBP3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-217-3P	95.67	68.42	1000
HSA-MIR-10A-3P	93.57	64.43	451
HSA-MIR-5090	93.28	60.86	94
HSA-MIR-6775-5P	92.43	61.00	132
HSA-MIR-615-3P	90.62	68.07	69
HSA-MIR-4508	90.37	59.62	240

Literature-anchored findings (GeneRIF, showing 19)

• These findings indicate that human latent TGF-beta-binding protein-3 (LTBP-3) has an essential role in the secretion and targeting of transforming growth factor-beta1 (TGF-beta1). (PMID:12154076)
• Extracellular matrix is an important site of deposition for LTBP-3 and LTBP-4. (PMID:16157329)
• stimulation of transcriptional activity of promoter is stimulated by TGF-beta 1 (PMID:16223572)
• Data show that LTBP-3 play an important regulatory role in TGF-beta activation and autocrine growth control in mesenchymal stem cells. (PMID:18672106)
• homozygous nonsense mutation, Y774X, in a consanguineous Pakistani family where oligodontia is inherited along with short stature in an autosomal-recessive fashion (PMID:19344874)
• Latent transforming growth factor beta-binding proteins-2 and -3 inhibit the proprotein convertase 5/6A. (PMID:21700711)
• the mechanism of transcriptional activation of LTBP3 promoter depends on MALAT1 initiated from neighboring gene LTBP3 and involves both the direct interaction of the Sp1 and promoter-specific activation (PMID:25187517)
• Phenotype-genotype correlations between LTBP3 mutations and families with brachyolmia with amelogenesis imperfecta. (PMID:25669657)
• New recessive truncating mutation in LTBP3 has been described in a family with oligodontia, short stature, and mitral valve prolapse. (PMID:25899461)
• LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum. (PMID:27068007)
• A specific role for LTBP3 in cancer progression toward metastatic disease. (PMID:29348457)
• homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities. (PMID:29625025)
• Data indicate that latent transforming growth factor beta binding protein 3 (LTBP3) is a disease gene for acromicric dysplasia (ACMICD) and suggest the genotype-phenotype correlation of LTBP3 mutations. (PMID:30887145)
• Bi-allelic loss-of-function novel variants in LTBP3-related skeletal dysplasia: Report of first patient from India. (PMID:32432408)
• Common variants in LTBP3 gene contributed to the risk of hip osteoarthritis in Han Chinese population. (PMID:32452514)
• Latent TGFbeta-binding proteins regulate UCP1 expression and function via TGFbeta2. (PMID:34481123)
• Novel LTBP3 mutations associated with thoracic aortic aneurysms and dissections. (PMID:34906192)
• Expanding genotypic and phenotypic spectrums of LTBP3 variants in dental anomalies and short stature syndrome. (PMID:35352826)
• [IDENTIFICATION OF A NOVEL LTBP3 GENE PATHOGENIC VARIANT IN DRUZE ARAB PATIENTS PRESENTED WITH SYNDROMIC SHORT STATURE WITH BRACHYOLMIA AND AMELOGENESIS IMPERFECTA]. (PMID:37394436)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ltbp3	ENSDARG00000035682
mus_musculus	Ltbp3	ENSMUSG00000024940
rattus_norvegicus	Ltbp3	ENSRNOG00000020813

Paralogs (3): LTBP1 (ENSG00000049323), LTBP4 (ENSG00000090006), LTBP2 (ENSG00000119681)

Protein

Protein identifiers

Latent-transforming growth factor beta-binding protein 3 — Q9NS15 (reviewed: Q9NS15)

All UniProt accessions (7): A0A8I5KYV1, E9PKW1, E9PPT7, E9PRF2, Q9NS15, H0YC99, H0YE75

UniProt curated annotations — full annotation on UniProt →

Function. Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta.

Subunit / interactions. Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex. Interacts with EFEMP2.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Isoform 2: Expressed prominently in heart, skeletal muscle, prostate, testis, small intestine and ovary. Isoform 1: Strongly expressed in pancreas and liver.

Post-translational modifications. Contains hydroxylated asparagine residues. Two intrachain disulfide bonds from the TB3 domain are rearranged upon TGFB1 binding, and form interchain bonds with TGFB1 propeptide, anchoring it to the extracellular matrix.

Disease relevance. Dental anomalies and short stature (DASS) [MIM:601216] A disorder characterized by hypoplastic amelogenesis imperfecta, significant short stature, brachyolmia-like anomalies including platyspondyly with short pedicles, narrow intervertebral and interpedicular distances, rectangular-shaped vertebrae with posterior scalloping and herniation of the nuclei, and broad femoral necks. Dental anomalies include widely spaced, small, yellow teeth, oligodontia, and severely reduced to absent enamel. The disease is caused by variants affecting the gene represented in this entry. Geleophysic dysplasia 3 (GPHYSD3) [MIM:617809] A form of geleophysic dysplasia, a rare skeletal disease characterized by severe short stature, short hands and feet, and joint limitations. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a ‘happy’ face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include skin thickening, progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues. GPHYSD3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the LTBP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NS15-1	1	yes
Q9NS15-2	2

RefSeq proteins (3): NP_001123616, NP_001157738, NP_066548 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013032	EGF-like_CS	Conserved_site
IPR017878	TB_dom	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR026823	cEGF	Domain
IPR036773	TB_dom_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR052080	vWF_C/EGF_Fibrillin	Family

Pfam: PF00683, PF07645, PF12661, PF12662

UniProt features (87 total): disulfide bond 54, domain 17, glycosylation site 5, region of interest 3, compositionally biased region 2, sequence conflict 2, signal peptide 1, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NS15-F1	64.21	0.01

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (54): 113–123, 117–129, 131–140, 279–303, 289–316, 304–319, 359–370, 365–379, 381–394, 405–428, 415–440, 429–443, 430–455, 578–590, 585–599, 601–614, 620–632, 625–641, 664–676, 670–685 …

Glycosylation sites (5): 89, 349, 845, 936, 1275

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2129379	Molecules associated with elastic fibres
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-1474244	Extracellular matrix organization
R-HSA-1566948	Elastic fibre formation
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 735 (showing top): RNGTGGGC_UNKNOWN, MODULE_92, BENPORATH_ES_WITH_H3K27ME3, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, TGACCTY_ERR1_Q2, CHX10_01, chr11q13, HUMMERICH_SKIN_CANCER_PROGRESSION_DN

GO Biological Process (13): chondrocyte differentiation (GO:0002062), transforming growth factor beta receptor signaling pathway (GO:0007179), bone mineralization (GO:0030282), negative regulation of bone mineralization (GO:0030502), negative regulation of chondrocyte differentiation (GO:0032331), positive regulation of bone resorption (GO:0045780), bone remodeling (GO:0046849), bone morphogenesis (GO:0060349), lung saccule development (GO:0060430), positive regulation of mesenchymal stem cell proliferation (GO:1902462), positive regulation of mesenchymal stem cell differentiation (GO:2000741), skeletal system development (GO:0001501), regulation of cell differentiation (GO:0045595)

GO Molecular Function (4): calcium ion binding (GO:0005509), transforming growth factor beta binding (GO:0050431), protein binding (GO:0005515), growth factor binding (GO:0019838)

GO Cellular Component (3): extracellular region (GO:0005576), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Elastic fibre formation	1
Signaling by TGF-beta Receptor Complex	1
Extracellular matrix organization	1
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
cartilage development	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
ossification	1
biomineral tissue development	1
negative regulation of ossification	1
bone mineralization	1
regulation of bone mineralization	1
negative regulation of biomineral tissue development	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
tissue remodeling	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
lung alveolus development	1
anatomical structure development	1
mesenchymal stem cell proliferation	1
regulation of mesenchymal stem cell proliferation	1
positive regulation of stem cell proliferation	1
mesenchymal stem cell differentiation	1
positive regulation of stem cell differentiation	1
regulation of mesenchymal stem cell differentiation	1
system development	1
regulation of developmental process	1
regulation of cellular process	1
metal ion binding	1
growth factor binding	1
cytokine binding	1
binding	1
protein binding	1
cellular anatomical structure	1
external encapsulating structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

2289 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LTBP3	TGFB1	P01137	975
LTBP3	TGFB2	P08112	973
LTBP3	MSTN	O14793	860
LTBP3	TGFB3	P10600	824
LTBP3	LOXL1	Q08397	813
LTBP3	WNT10A	Q9GZT5	752
LTBP3	ADAMTS10	Q9H324	749
LTBP3	PAX9	P55771	710
LTBP3	FBN1	P35555	709
LTBP3	FBLN5	Q9UBX5	697
LTBP3	ELN	P15502	676
LTBP3	ADORA3	P0DMS8	655
LTBP3	ADORA1	P30542	648
LTBP3	MSX1	P28360	647
LTBP3	GDF11	O95390	639

IntAct

21 interactions, top by confidence:

A	B	Type	Score
TGFB1	LAMC1	psi-mi:“MI:0914”(association)	0.530
	LTBP3	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	MBD1	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	NUFIP2	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
CCNG1	LTBP3	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	PIK3R2	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	RAC1	psi-mi:“MI:0915”(physical association)	0.370
GORASP2	LTBP3	psi-mi:“MI:0915”(physical association)	0.370
PELI2	LTBP3	psi-mi:“MI:0915”(physical association)	0.370
LTBP3	PRPF40A	psi-mi:“MI:0915”(physical association)	0.370
MFAP4	CRLF1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
WNT10A	MANBA	psi-mi:“MI:0914”(association)	0.350
EPHA7	PLOD2	psi-mi:“MI:0914”(association)	0.350
IL12RB1	ZNF185	psi-mi:“MI:0914”(association)	0.350
EFEMP1	TGFB1	psi-mi:“MI:0914”(association)	0.350
SLC9A9	PODXL	psi-mi:“MI:0914”(association)	0.350
DYRK1A	LTBP3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-RNA), LTBP3 (Proximity Label-MS), LTBP3 (Two-hybrid), LTBP3 (Two-hybrid), LTBP3 (Two-hybrid), LTBP3 (Two-hybrid), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-MS), LTBP3 (Affinity Capture-RNA)

ESM2 similar proteins: A1A5Y0, A2ASQ1, O00468, O00548, O57409, O89103, O95428, P06579, P07204, P0C5J5, P15306, P20063, P25304, P31696, P97607, P97677, P98160, Q05793, Q08E66, Q14112, Q2PC93, Q501P1, Q53RD9, Q5W7P8, Q61483, Q61810, Q66PY1, Q6NUX0, Q6NZL8, Q6ZRI0, Q71U07, Q75N90, Q7T3Q2, Q8IWY4, Q8IX30, Q8JZM4, Q8NFT8, Q8R0S6, Q8R4Y4, Q8VIK5

Diamond homologs: A0A1U9VX91, O08999, O22925, O35806, O80977, P35555, P35556, P41990, P93484, P98133, Q00918, Q14766, Q14767, Q28019, Q56ZQ3, Q61549, Q61554, Q61555, Q61810, Q6AZ60, Q75N90, Q7TN16, Q8CG19, Q8K4G1, Q8N2S1, Q9NS15, Q9QXT5, Q9TV36, Q9UHF1, A0A6I8RMG7, B5DFC9, O42182, O73775, O77469, O88322, P23142, Q08879, Q09165, Q2KIT5, Q2VWQ2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

3286 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	92
Likely pathogenic	53
Uncertain significance	1496
Likely benign	1299
Benign	134

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032352	NM_000428.3(LTBP2):c.2931del (p.Gly978fs)	Pathogenic
126952	NM_000428.3(LTBP2):c.1642C>T (p.Arg548Ter)	Pathogenic
126959	NM_000428.3(LTBP2):c.5376del (p.Cys1793fs)	Pathogenic
1327506	NM_001130144.3(LTBP3):c.2017G>T (p.Gly673Cys)	Pathogenic
1327507	NM_001130144.3(LTBP3):c.1721-2A>G	Pathogenic
1387276	NM_001130144.3(LTBP3):c.536_537del (p.Val179fs)	Pathogenic
1416583	NM_000428.3(LTBP2):c.972del (p.Asp325fs)	Pathogenic
1417406	NM_001130144.3(LTBP3):c.1735C>T (p.Arg579Ter)	Pathogenic
1418711	NM_000428.3(LTBP2):c.2327del (p.Val776fs)	Pathogenic
1441073	NM_001130144.3(LTBP3):c.932G>A (p.Trp311Ter)	Pathogenic
1445505	NM_001130144.3(LTBP3):c.2542dup (p.Tyr848fs)	Pathogenic
1451121	NM_000428.3(LTBP2):c.304G>T (p.Glu102Ter)	Pathogenic
1451240	NM_000428.3(LTBP2):c.1107_1108del (p.Ala370fs)	Pathogenic
1452054	NM_001130144.3(LTBP3):c.1160_1161insGTGT (p.Gly388fs)	Pathogenic
1452258	NM_000428.3(LTBP2):c.744del (p.Ser249fs)	Pathogenic
1455225	NM_000428.3(LTBP2):c.3856_3857del (p.Val1286fs)	Pathogenic
1722765	NM_001130144.3(LTBP3):c.3629-1G>T	Pathogenic
1909521	NM_000428.3(LTBP2):c.112del (p.Asp38fs)	Pathogenic
1925448	NM_000428.3(LTBP2):c.3776-1G>C	Pathogenic
1950571	NM_001130144.3(LTBP3):c.1854_1860dup (p.Glu621fs)	Pathogenic
1975426	NM_000428.3(LTBP2):c.4869del (p.Cys1624fs)	Pathogenic
1982594	NM_000428.3(LTBP2):c.4667dup (p.Leu1557fs)	Pathogenic
1994635	NM_000428.3(LTBP2):c.3833_3840dup (p.Gly1281fs)	Pathogenic
2005613	NM_001130144.3(LTBP3):c.2821G>T (p.Glu941Ter)	Pathogenic
2009579	NM_001130144.3(LTBP3):c.1483del (p.Glu495fs)	Pathogenic
2015794	NM_000428.3(LTBP2):c.129C>G (p.Tyr43Ter)	Pathogenic
2022494	NM_001130144.3(LTBP3):c.1569del (p.Val524fs)	Pathogenic
2026372	NM_001130144.3(LTBP3):c.2553_2554del (p.Cys852fs)	Pathogenic
2033728	NM_000428.3(LTBP2):c.3509del (p.Asn1170fs)	Pathogenic
2035901	NM_001130144.3(LTBP3):c.3615dup (p.Lys1206fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

8524 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65540337:C:G	C1051S	1.000
11:65540338:A:T	C1051S	1.000
11:65540370:C:G	C1040S	1.000
11:65540371:A:T	C1040S	1.000
11:65540491:C:G	C1034S	1.000
11:65540492:A:G	C1034R	1.000
11:65540492:A:T	C1034S	1.000
11:65540529:G:C	C1021W	1.000
11:65540530:C:G	C1021S	1.000
11:65540530:C:T	C1021Y	1.000
11:65540531:A:T	C1021S	1.000
11:65540536:C:G	C1019S	1.000
11:65540537:A:G	C1019R	1.000
11:65540537:A:T	C1019S	1.000
11:65540562:G:C	C1010W	1.000
11:65540563:C:G	C1010S	1.000
11:65540564:A:G	C1010R	1.000
11:65540564:A:T	C1010S	1.000
11:65540577:G:C	C1005W	1.000
11:65540578:C:G	C1005S	1.000
11:65540578:C:T	C1005Y	1.000
11:65540579:A:G	C1005R	1.000
11:65540579:A:T	C1005S	1.000
11:65540602:C:G	C997S	1.000
11:65540603:A:G	C997R	1.000
11:65540603:A:T	C997S	1.000
11:65540936:C:G	C971S	1.000
11:65540937:A:G	C971R	1.000
11:65540937:A:T	C971S	1.000
11:65541143:C:T	C959Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000094143 (11:65542063 G>A), RS1000353333 (11:65545387 A>G,T), RS1000520445 (11:65542036 A>C), RS1000535755 (11:65538682 G>A), RS1000626384 (11:65539897 G>A,C), RS1000742282 (11:65544152 T>A,C), RS1000863620 (11:65550259 A>C), RS1000869430 (11:65550469 G>A,C), RS1000921418 (11:65550693 G>A), RS1000937510 (11:65550125 C>G,T), RS1001170247 (11:65556990 G>A,C), RS1001727797 (11:65548627 C>A), RS1001745309 (11:65555696 T>A), RS1002150082 (11:65540056 G>A), RS1002297944 (11:65543711 G>A,T)

Disease associations

OMIM: gene MIM:602090 | disease phenotypes: MIM:601216, MIM:617809, MIM:613086, MIM:614819, MIM:154700, MIM:251750, MIM:277600, MIM:137760, MIM:129600, MIM:600975, MIM:231300, MIM:231050, MIM:104500

GenCC curated gene-disease

Disease	Classification	Inheritance
microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	Definitive	Autosomal recessive
brachyolmia-amelogenesis imperfecta syndrome	Definitive	Autosomal recessive
geleophysic dysplasia 3	Strong	Autosomal dominant
glaucoma 3, primary congenital, D	Strong	Autosomal recessive
Weill-Marchesani syndrome 3	Moderate	Autosomal recessive
glaucoma secondary to spherophakia/ectopia lentis and megalocornea	Supportive	Autosomal recessive
Weill-Marchesani syndrome	Supportive	Autosomal dominant
congenital glaucoma	Supportive	Autosomal dominant
geleophysic dysplasia	Supportive	Autosomal dominant
Acromicric dysplasia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
glaucoma 3, primary congenital, D	Definitive	AR

Mondo (22): brachyolmia-amelogenesis imperfecta syndrome (MONDO:0011018), geleophysic dysplasia 3 (MONDO:0054722), glaucoma 3, primary congenital, D (MONDO:0013122), Weill-Marchesani syndrome 3 (MONDO:0013899), Marfan syndrome (MONDO:0007947), exfoliation syndrome (MONDO:0008327), microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma (MONDO:0009633), Weill-Marchesani syndrome (MONDO:0018096), OPTN-related open angle glaucoma (MONDO:0100553), ectopia lentis 1, isolated, autosomal dominant (MONDO:0007514), glaucoma 3, primary infantile, B (MONDO:0010968), glaucoma 3A (MONDO:0009277), geleophysic dysplasia 1 (MONDO:0009269), intellectual disability (MONDO:0001071), amelogenesis imperfecta (MONDO:0019507)

Orphanet (12): Brachyolmia-amelogenesis imperfecta syndrome (Orphanet:2899), Congenital glaucoma (Orphanet:98976), Weill-Marchesani syndrome (Orphanet:3449), Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558), Glaucoma secondary to spherophakia/ectopia lentis and megalocornea (Orphanet:238763), Isolated ectopia lentis (Orphanet:1885), Juvenile glaucoma (Orphanet:98977), Geleophysic dysplasia (Orphanet:2623), Amelogenesis imperfecta (Orphanet:88661), NON RARE IN EUROPE: Exfoliation syndrome (Orphanet:529819), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

128 total (30 of 128 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000293	Full cheeks
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000485	Megalocornea
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000527	Long eyelashes
HP:0000534	Abnormal eyebrow morphology
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000557	Buphthalmos
HP:0000572	Visual loss
HP:0000594	Shallow anterior chamber
HP:0000613	Photophobia
HP:0000643	Blepharospasm

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000817_154	Height	7.000000e-14
GCST002647_107	Height	6.000000e-20
GCST002702_69	Height	2.000000e-12
GCST005237_3	Mood instability	1.000000e-06
GCST005238_3	Mood instability	3.000000e-09
GCST006394_97	Intraocular pressure	1.000000e-08
GCST006412_88	Intraocular pressure	1.000000e-11
GCST006624_51	Systolic blood pressure	3.000000e-13
GCST006944_55	Experiencing mood swings	2.000000e-09
GCST006948_64	Feeling nervous	4.000000e-12
GCST006950_28	Feeling worry	1.000000e-10
GCST007267_108	Systolic blood pressure	2.000000e-11
GCST007269_123	Pulse pressure	6.000000e-11
GCST008163_591	Height	3.000000e-06
GCST008839_574	Height	2.000000e-17
GCST010002_156	Refractive error	7.000000e-25
GCST012226_356	Waist circumference adjusted for body mass index	6.000000e-13
GCST012226_357	Waist circumference adjusted for body mass index	6.000000e-09
GCST012227_280	Hip circumference adjusted for BMI	1.000000e-08
GCST90011770_68	Glaucoma (primary open-angle)	2.000000e-13
GCST90013466_12	Height	5.000000e-27
GCST90013466_30	Height	1.000000e-10
GCST90013468_16	Height	4.000000e-07
GCST90020028_1869	Hip circumference adjusted for BMI	2.000000e-09
GCST90020028_1870	Hip circumference adjusted for BMI	8.000000e-09
GCST90020029_399	Waist circumference adjusted for body mass index	4.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement
EFO:0004695	intraocular pressure measurement
EFO:0006335	systolic blood pressure
EFO:0009597	feeling nervous measurement
EFO:0009589	worry measurement
EFO:0005763	pulse pressure measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
D017889	Exfoliation Syndrome	C11.941.375.285
D006871	Hydrophthalmos	C11.250.480; C11.525.381.407.480; C16.131.384.480; C16.614.438
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D056846	Weill-Marchesani Syndrome	C05.116.099.343.957; C11.270.921; C16.131.077.941; C16.320.290.842; C17.300.899
C535662	Acromicric dysplasia (supp.)
C567765	Glaucoma 3, Primary Congenital, D (supp.)
C536824	Glaucoma 3, primary infantile, B (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, decreases expression	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Phthalic Acids	increases methylation	1
Selenium	increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Thiram	increases expression	1

Clinical trials (associated diseases)

306 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01295047	PHASE4	COMPLETED	Comparison of Medical Therapies in Marfan Syndrome.
NCT00273442	PHASE4	COMPLETED	Assessing Cosopt Switch Patients
NCT07228221	PHASE4	RECRUITING	Standalone iStent Infinite and iDose TR for Management of Moderate to Severe Open Angle Glaucoma
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00429364	PHASE3	COMPLETED	Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome
NCT00485368	PHASE3	COMPLETED	Angiotensin Converting Enzyme Inhibitors in Marfan Syndrome
NCT00683124	PHASE3	UNKNOWN	Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients
NCT00723801	PHASE3	COMPLETED	Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome
NCT00763893	PHASE3	TERMINATED	Study of the Efficacy of Losartan on Aortic Dilatation in Patients With Marfan Syndrome
NCT00782327	PHASE3	COMPLETED	Randomized, Double-blind Study for the Evaluation of the Effect of Losartan Versus Placebo on Aortic Root Dilatation in Patients With Marfan Syndrome Under Treatment With Beta-blockers
NCT01145612	PHASE3	UNKNOWN	Atenolol Versus Losartan in the Prevention of Progressive Dilation of the Aorta in Marfan Syndrome
NCT01361087	PHASE3	WITHDRAWN	Circulating Transforming Growth Factor Beta (TGF-β) in Individuals With Marfan Syndrome
NCT01715207	PHASE3	COMPLETED	Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS
NCT00331240	PHASE3	COMPLETED	24-Hour Intraocular Pressure (IOP) Control With Travoprost/Timolol Fixed Combination
NCT01126203	PHASE3	COMPLETED	Randomized Prospective Study of Selective Laser Trabeculoplasty (SLT) Versus Argon Trabeculoplasty (ALT) in Patients With Pseudoexfoliation Glaucoma and Ocular Hypertension
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04947124	PHASE2	COMPLETED	A Study to Determine the Safety and Tolerability of 2 Concentrations of QLS-101
NCT00593710	PHASE2	COMPLETED	Losartan Versus Atenolol for the Treatment of Marfan Syndrome
NCT00651235	PHASE2	UNKNOWN	A Randomized, Open-label, LOSARTAN Therapy on the Progression of Aortic Root Dilation in Patients With Marfan Syndrome
NCT01949233	PHASE2	UNKNOWN	The Oxford Marfan Trial
NCT01936389	PHASE2	COMPLETED	A Prospective Study to Assess the Hypotensive Efficacy of Rho-Kinase Inhibitor AR-12286 Ophthalmic Solution 0.5% and 0.7% in Patients With Exfoliation Syndrome and Ocular Hypertension or Glaucoma
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01460017	PHASE1	UNKNOWN	Comparison Between Deep Sclerectomy and Traditional Trabeculotomy & Trabeculectomy in Congenital Glaucoma
NCT02121171	PHASE1	UNKNOWN	Combined Trab+Trab Versus Combined Trab+Trab With Subconjunctival Implantation of Ologen for Primary Congenital Glaucoma
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01020721	Not specified	UNKNOWN	The Genetic Characteristics in South Korean Patients With Primary Congenital Glaucoma
NCT01136460	Not specified	UNKNOWN	Genetic Testing in Primary Congenital Glaucoma Patients
NCT02945176	Not specified	COMPLETED	Safety and Performance Study of the ARGOS-IO System in Patients Undergoing Boston Keratoprosthesis Implantation
NCT03077789	Not specified	COMPLETED	Prospective Study of the Diagnostic and Therapeutic Management of Congenital Glaucoma in France
NCT03541551	Not specified	COMPLETED	Ologen® Collagen Matrix in Patients With Primary Congenital Glaucoma Undergoing Trabeculectomy