LTBP1

protein-coding

latent transforming growth factor beta binding protein 1, the group of Latent transforming growth factor beta binding proteins

Gene summary

The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_206943.4

Inheritance

ClinVar variants

P:8U:323B:50

Top phenotype

Cutis laxa, autosomal recessive, type IIE

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr2:32,946,953-33,399,509

External References & Databases

Ensembl (ENSG00000049323)

Transcript & Mutation Effects

hg38 • Region Span ~452.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cutis laxa, autosomal recessive, type 2ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030337

Submitter: PanelApp Australia

cutis laxa, autosomal recessive, type 2ELIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030337

Submitter: Ambry Genetics

cutis laxa, autosomal recessive, type 2ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030337

Submitter: Labcorp Genetics (formerly Invitae)

cutis laxa, autosomal recessive, type 2ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030337

Submitter: G2P

Clinical Genomic Database (CGD)

Cutis laxa, autosomal recessive, type IIEAR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition may include congenital cardiovascular anomalies, and awareness may allow early identification and management

Refs: 33991472

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LTBP1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 305

not providedTotal: 72

Cutis laxa, autosomal recessive, type 2ETotal: 12

LTBP1-related disorderTotal: 5

Congenital heart diseaseTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_206943.4. 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			2 clinvar	25 clinvar	2 clinvar	29
missense			313 clinvar	17 clinvar	6 clinvar	336
nonsense	2 clinvar	1 clinvar				3
start loss						0
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	7 clinvar			9
Total	5	3	323	42	8	381

Highest pathogenic variant AF is 0.0000020531857

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 122 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_206943.4	RefSeq	NP_996826.3	34	MANE Select
ENST00000404816.7	Ensembl	ENSP00000386043.2	34	MANE Select
NM_000627.4	RefSeq	NP_000618.4	30	Standard
NM_001166264.2	RefSeq	NP_001159736.2	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta signaling pathway - Homo sapiens (human)
Hypothesized Pathways in Pathogenesis of Cardiovascular Disease
TGF-beta Receptor Signaling
Post-translational protein phosphorylation
Post-translational protein modification

Biological Process

ventricular septum development
transmembrane receptor protein serine/threonine kinase signaling pathway
sequestering of TGFbeta in extracellular matrix
aorta development
post-translational protein modification

Molecular Function

transforming growth factor beta-activated receptor activity
extracellular matrix structural constituent
calcium ion binding
protein binding
transforming growth factor beta binding

Cellular Component

microfibril
extracellular region
endoplasmic reticulum lumen
extracellular matrix
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404816
Coding exons: 34
Length: 452538
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.172	909	924	0.984	0.0000506	11251
Missense (PolyPhen)		261	342.52	0.76201		4014
Synonymous	-2.47	416	357	1.17	0.0000215	3271
Loss of Function	5.71	32	90.8	0.353	0.00000468	1077

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000033	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.00030	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (PubMed:2022183, PubMed:8617200, PubMed:8939931). 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 (PubMed:8617200, PubMed:8939931, PubMed:15184403). Outcompeted by LRRC32/GARP for binding to LAP regulatory chain of TGF-beta (PubMed:22278742). {ECO:0000269|PubMed:15184403, ECO:0000269|PubMed:2022183, ECO:0000269|PubMed:22278742, ECO:0000269|PubMed:8617200, ECO:0000269|PubMed:8939931}.;

Recessive Scores

pRec: 0.147

Intolerance Scores

LoFtool: 0.0115
RVIS EVS: -0.44
RVIS percentile EVS: 24.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.494

Gene Damage Prediction

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