TGFBR1

protein-coding

transforming growth factor beta receptor 1, the group of Type 1 receptor serine/threonine kinases

Gene summary

The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

Previous symbols:

MSSE
ESS1

MANE transcript

NM_004612.4

Inheritance

ClinVar variants

P:152U:529B:241

Top phenotype

Loeys-Dietz syndrome, type 1A; Loeys-Dietz syndrome, type 2A

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr9:99,104,038-99,154,192

External References & Databases

Ensembl (ENSG00000106799)

Transcript & Mutation Effects

hg38 • Region Span ~50.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Loeys-Dietz syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012212

Submitter: Genomics England PanelApp

multiple self-healing squamous epitheliomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007566

Submitter: ClinGen

Missense mutations in the intracellular kinase domain of TGFBR1 are known to cause Loeys-Dietz syndrome (OMIM 609192) with unclear molecular mechanism which could include gain of function and dominant negative. Whereas truncating variants or missense variants in the receptor domain of TGFBR1 cause multiple self-healing squamous epithelioma (MSSE; OMIM 132800) with loss of function mechanism. There is abundant evidence published associating the TGFBR1 gene with MSSE, since the gene-disease relationship was first proposed by Goudie et al. (2011). Multiple case level studies have been performed with MSSE patients that have variants in the TGFBR1 gene. At least 11 different mutations in 18 families were reported. A significant amount of case-level data is available, however the maximum points for genetic evidence has been reached (12 points). Nonsense mediated mRNA decay or loss of heterozygosity were detected in patients' samples. Frequent TGFBR1 mutations are identified in human vemurafenib- or Sorafenib-induced skin lesions and in squamous cell carcinomas with loss of TGFb signalling. Deletion of Tgfbr1 coupled with BRAF/KRAS activation or Tp53 mutation/deletion leads to skin tumorigenesis in mice. All of these types of evidence are consistent with a definitive relationship between the TGFBR1 gene and multiple self-healing squamous epithelioma.

familial thoracic aortic aneurysm and aortic dissectionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Orphanet

multiple self-healing squamous epitheliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007566

Submitter: Orphanet

multiple self-healing squamous epitheliomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007566

Submitter: G2P

Loeys-Dietz syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012212

Submitter: Ambry Genetics

Loeys-Dietz syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012212

Submitter: G2P

multiple self-healing squamous epitheliomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007566

Submitter: Labcorp Genetics (formerly Invitae)

multiple self-healing squamous epitheliomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007566

Submitter: Ambry Genetics

Loeys-Dietz syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018954

Submitter: Orphanet

Loeys-Dietz syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012212

Submitter: Labcorp Genetics (formerly Invitae)

Loeys-Dietz syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018954

Submitter: ClinGen

The first report indicating a relationship between the TGFBR1 gene and autosomal dominant Loeys Dietz syndrome was reported by Dietz et al in 2005 (PMID: 15731757). Loeys Dietz syndrome is a multisystemic disorder with craniofacial, skeletal, integumental and ocular involvement (reviewed in Van Laer et al., 2014 PMID: 24443023 ). Loeys Dietz syndrome comprises a broad phenotypic spectrum of severity including seemingly isolated aortic aneurysm and/or dissection to the full syndrome and thus represents a continuum of disease (reviewed in Van Laer et al., 2014 PMID: 24443023; Verstraeten et al., 2016 PMID: 26919284). Aortic aneurysm and tortuosity represent the major morbidity and mortality of Loeys Dietz syndrome. Over 120 variants have been identified in TGBFR1 (Verstraeten et al., 2016 PMID: 26919284) according to the UMD-TGFBR1 database (http://www.umd.be/TGFBR1/), with the majority being missense and more rarely, nonsense, splice site and small deletions. The mechanism for the gene-disease relationship is perturbation of the TGF beta signaling pathway, however the exact molecular mechanism remains unclear and could include gain of function and dominant negative (reviewed in Van Laer et al., 2014 PMID: 24443023; Verstraeten et al., 2016 PMID: 26919284). The majority of the mutations result in aberrant kinase activity of TGFBR1. Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 10 years and a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In summary, TGFBR1 is definitively associated with autosomal dominant Loeys Dietz 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 General GCEP on March 27, 2019 (SOP Version 6).

Clinical Genomic Database (CGD)

Loeys-Dietz syndrome, type 1A; Loeys-Dietz syndrome, type 2AAD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Obstetric

Intervention: Cardiovascular; Obstetric

Rationale: Medical management to decrease risk of vascular events is warranted, including avoidance of certain types of activities such as contact sports; Specific surveillance for surgical considerations related to issues such as aneurysms and cervical spine instability, other issues include subacute bacterial endocarditis prophylaxis with dental work; Precautions during pregnancy may be warranted due to the potential of complications including uterine rupture

Refs: 5173258; 3565476; 15731757; 16928994; 20301312; 19542084; 21358634; 24344637

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TGFBR1 variants in ClinVar

25 Conditions Cataloged

Familial thoracic aortic aneurysm and aortic dissectionTotal: 907

not providedTotal: 246

Loeys-Dietz syndromeTotal: 212

Loeys-Dietz syndrome 1Total: 91

not specifiedTotal: 82

Multiple self-healing squamous epitheliomaTotal: 43

TGFBR1-related disorderTotal: 26

Ehlers-Danlos syndromeTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004612.4. 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		13 clinvar	216 clinvar	5 clinvar	235
missense	16 clinvar	75 clinvar	480 clinvar	18 clinvar	1 clinvar	590
nonsense	10 clinvar	5 clinvar	4 clinvar			19
start loss			2 clinvar			2
frameshift	17 clinvar	7 clinvar	18 clinvar			42
splice donor/acceptor (+/-2bp)	5 clinvar	16 clinvar	12 clinvar	1 clinvar		34
Total	49	103	529	235	6	922

Highest pathogenic variant AF is 0.000013636696

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004612.4	RefSeq	NP_004603.1	9	MANE Select
ENST00000374994.9	Ensembl	ENSP00000364133.4	9	MANE Select
NM_001130916.3	RefSeq	NP_001124388.1	8	Standard
NM_001306210.2	RefSeq	NP_001293139.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Chronic myeloid leukemia - Homo sapiens (human)
Gastric cancer - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Adherens junction - Homo sapiens (human)

Biological Process

activation of MAPKK activity
skeletal system development
in utero embryonic development
kidney development
blastocyst development

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
transforming growth factor beta-activated receptor activity
transforming growth factor beta receptor activity, type I
type II transforming growth factor beta receptor binding

Cellular Component

endosome
plasma membrane
integral component of plasma membrane
bicellular tight junction
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374994
Coding exons: 9
Length: 50155
Individuals with no LoFs: 125707
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125714
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.79	133	260	0.512	0.0000143	3258
Missense (PolyPhen)		61	148.37	0.41113		1742
Synonymous	0.0459	88	88.5	0.994	0.00000483	985
Loss of Function	3.77	4	23.9	0.167	0.00000142	304

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non- canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation. {ECO:0000269|PubMed:15761148, ECO:0000269|PubMed:16754747, ECO:0000269|PubMed:18758450, ECO:0000269|PubMed:7774578, ECO:0000269|PubMed:8752209, ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9346908}.;
Disease: DISEASE: Loeys-Dietz syndrome 1 (LDS1) [MIM:609192]: An aortic aneurysm syndrome with widespread systemic involvement, characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. Some patients have craniosynostosis, exotropy, micrognathia and retrognathia, structural brain abnormalities, and intellectual deficit. {ECO:0000269|PubMed:15731757, ECO:0000269|PubMed:16596670, ECO:0000269|PubMed:16791849, ECO:0000269|PubMed:16928994, ECO:0000269|PubMed:19883511, ECO:0000269|PubMed:22113417}. Note=The disease is caused by mutations affecting the gene represented in this entry. TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS1 by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS1 by the OMIM resource. {ECO:0000269|PubMed:16791849}.; DISEASE: Multiple self-healing squamous epithelioma (MSSE) [MIM:132800]: A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars. {ECO:0000269|PubMed:21358634}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.778

Intolerance Scores

LoFtool: 0.0543
RVIS EVS: -0.27
RVIS percentile EVS: 34.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.674

Gene Damage Prediction

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