TGFBR1

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

Basic information

Region (hg38): 9:99104037-99154192

Previous symbols: [ "MSSE", "ESS1" ]

Links

ENSG00000106799 ∙ NCBI:7046 ∙ OMIM:190181 ∙ HGNC:11772 ∙ Uniprot:P36897 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Loeys-Dietz syndrome 1 (Definitive), mode of inheritance: AD
• Loeys-Dietz syndrome 1 (Strong), mode of inheritance: AD
• Loeys-Dietz syndrome 1 (Strong), mode of inheritance: AD
• Loeys-Dietz syndrome (Supportive), mode of inheritance: AD
• multiple self-healing squamous epithelioma (Supportive), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Supportive), mode of inheritance: AD
• Loeys-Dietz syndrome 1 (Strong), mode of inheritance: AD
• multiple self-healing squamous epithelioma (Moderate), mode of inheritance: AD
• Loeys-Dietz syndrome 1 (Strong), mode of inheritance: AD
• multiple self-healing squamous epithelioma (Strong), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Definitive), mode of inheritance: AD
• multiple self-healing squamous epithelioma (Definitive), mode of inheritance: AD
• Loeys-Dietz syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Loeys-Dietz syndrome, type 1A; Loeys-Dietz syndrome, type 2A	AD	Cardiovascular; Obstetric	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	Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Obstetric	5173258; 3565476; 15731757; 16928994; 20301312; 19542084; 21358634; 24344637

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TGFBR1 gene.

• Familial thoracic aortic aneurysm and aortic dissection (681 variants)
• not provided (226 variants)
• Loeys-Dietz syndrome 1 (184 variants)
• Loeys-Dietz syndrome (115 variants)
• not specified (76 variants)
• Ehlers-Danlos syndrome (19 variants)
• Multiple self-healing squamous epithelioma;Loeys-Dietz syndrome 1 (14 variants)
• Multiple self-healing squamous epithelioma (13 variants)
• Loeys-Dietz syndrome 1;Multiple self-healing squamous epithelioma (9 variants)
• TGFBR1-related condition (7 variants)
• Inborn genetic diseases (6 variants)
• Marfan syndrome (3 variants)
• Cardiovascular phenotype (3 variants)
• Familial aortopathy (2 variants)
• See cases (2 variants)
• Familial thoracic aortic aneurysm and aortic dissection;Loeys-Dietz syndrome (2 variants)
• Isolated thoracic aortic aneurysm (2 variants)
• Aortic aneurysm, familial thoracic 6 (1 variants)
• Thoracic aortic aneurysm (1 variants)
• Connective tissue disorder (1 variants)
• Ehlers-Danlos syndrome, classic type (1 variants)
• Marfan syndrome;Loeys-Dietz syndrome 1 (1 variants)
• Craniosynostosis syndrome (1 variants)
• Familial thoracic aortic aneurysm and aortic dissection;Disproportionate tall stature (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TGFBR1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	4	127	3	135
missense	6	32	300	7	1	346
nonsense	7		3			10
start loss			1			1
frameshift	8	2	11			21
inframe indel	3	2	13	3	1	22
splice donor/acceptor (+/-2bp)	1	4	4		1	10
splice region			15	17		32
non coding			100	81	30	211
Total	25	41	436	218	36

Highest pathogenic variant AF is 0.00000658

Variants in TGFBR1

This is a list of pathogenic ClinVar variants found in the TGFBR1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-99105115-C-T		not specified	Benign (Apr 03, 2023)
9-99105137-C-A		not specified	Uncertain significance (May 16, 2023)
9-99105150-G-A		Loeys-Dietz syndrome 1	Uncertain significance (Jan 12, 2018)
9-99105155-GGC-G		not specified	Benign (Jun 30, 2015)
9-99105157-C-G			Likely benign (Apr 06, 2018)
9-99105163-C-A		Loeys-Dietz syndrome 1 • Loeys-Dietz syndrome • Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jun 14, 2016)
9-99105165-C-CGGCCG			Benign (Apr 15, 2016)
9-99105173-C-T			Benign (Nov 28, 2016)
9-99105175-G-A		Loeys-Dietz syndrome 1	Uncertain significance (Jan 13, 2018)
9-99105187-AGGCGGTGGCGGCGGGACCATGGAGGC-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jan 11, 2024)
9-99105193-T-C		Loeys-Dietz syndrome 1 • Familial thoracic aortic aneurysm and aortic dissection • Loeys-Dietz syndrome • Loeys-Dietz syndrome 1;Multiple self-healing squamous epithelioma	Uncertain significance (Oct 19, 2021)
9-99105196-C-G		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Oct 23, 2017)
9-99105201-G-A		Ehlers-Danlos syndrome	Uncertain significance (Jul 25, 2022)
9-99105202-G-A		Familial thoracic aortic aneurysm and aortic dissection	Conflicting classifications of pathogenicity (Mar 15, 2023)
9-99105203-A-G		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Mar 02, 2020)
9-99105204-C-T		not specified • Familial thoracic aortic aneurysm and aortic dissection	Benign/Likely benign (Dec 03, 2020)
9-99105207-T-C		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Nov 23, 2022)
9-99105206-A-ATGGAGGCGGCGGTCGCTGCTCCGCG		Familial thoracic aortic aneurysm and aortic dissection	Pathogenic (Aug 08, 2023)
9-99105212-G-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (May 17, 2022)
9-99105213-C-T		Marfan syndrome	Likely benign (Mar 14, 2019)
9-99105215-G-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Oct 30, 2023)
9-99105216-C-T		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Oct 23, 2022)
9-99105217-G-A		not specified • Familial thoracic aortic aneurysm and aortic dissection	Likely benign (Jun 04, 2023)
9-99105217-G-C		Familial thoracic aortic aneurysm and aortic dissection	Likely benign (Jan 06, 2023)
9-99105218-G-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Nov 12, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TGFBR1	protein_coding	protein_coding	ENST00000374994	9	50155

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.854	0.146	125707	0	7	125714	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.79	133	260	0.512	0.0000143	3258
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Endocytosis - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);EGF-Core;IGF-Core;TGF-Core;Cardiac Hypertrophic Response;Extracellular vesicle-mediated signaling in recipient cells;Hepatitis C and Hepatocellular Carcinoma;TGF-beta Signaling Pathway;Hypothesized Pathways in Pathogenesis of Cardiovascular Disease;MAPK Signaling Pathway;Canonical and Non-Canonical TGF-B signaling;TYROBP Causal Network;p38 MAPK Signaling Pathway;Chromosomal and microsatellite instability in colorectal cancer;EMT transition in Colorectal Cancer;TGF-beta Receptor Signaling;Disease;Signal Transduction;alk in cardiac myocytes;nfkb activation by nontypeable hemophilus influenzae;ctcf: first multivalent nuclear factor;Post-translational protein modification;Metabolism of proteins;TGF-beta super family signaling pathway canonical;IL-7 signaling;UCH proteinases;TGF_beta_Receptor;tgf beta signaling pathway;Ub-specific processing proteases;JAK STAT pathway and regulation;Deubiquitination;EPO signaling;TGFBR2 Kinase Domain Mutants in Cancer;TGF-beta signaling TAK1;SMAD2/3 Phosphorylation Motif Mutants in Cancer;SMAD2/3 MH2 Domain Mutants in Cancer;Loss of Function of SMAD2/3 in Cancer;Loss of Function of TGFBR2 in Cancer;TGFBR1 KD Mutants in Cancer;Loss of Function of TGFBR1 in Cancer;Signaling by TGF-beta Receptor Complex in Cancer;Signaling by TGF-beta Receptor Complex;BMP2 signaling TGF-beta MV;VEGF;Signaling by TGF-beta family members;Downregulation of TGF-beta receptor signaling;TGF-beta receptor signaling activates SMADs;ALK1 signaling events;Diseases of signal transduction;Glypican 1 network;Beta5 beta6 beta7 and beta8 integrin cell surface interactions;TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition);TGF-beta receptor signaling (Consensus)

Recessive Scores

• pRec: 0.778

Intolerance Scores

• loftool: 0.0543
• rvis_EVS: -0.27
• rvis_percentile_EVS: 34.32

Haploinsufficiency Scores

• pHI: 0.999
• hipred: Y
• hipred_score: 0.825
• ghis: 0.612

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.674

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tgfbr1
• Phenotype: neoplasm; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; respiratory system phenotype; embryo phenotype; skeleton phenotype; immune system phenotype; digestive/alimentary phenotype; muscle phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: activation of MAPKK activity;skeletal system development;in utero embryonic development;kidney development;blastocyst development;epithelial to mesenchymal transition;negative regulation of endothelial cell proliferation;positive regulation of endothelial cell proliferation;lens development in camera-type eye;ventricular trabecula myocardium morphogenesis;ventricular compact myocardium morphogenesis;proepicardium development;regulation of transcription, DNA-templated;protein phosphorylation;apoptotic process;cell cycle arrest;signal transduction;transforming growth factor beta receptor signaling pathway;pattern specification process;heart development;positive regulation of cell population proliferation;germ cell migration;male gonad development;post-embryonic development;anterior/posterior pattern specification;positive regulation of gene expression;regulation of epithelial to mesenchymal transition;positive regulation of epithelial to mesenchymal transition;positive regulation of pathway-restricted SMAD protein phosphorylation;protein deubiquitination;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;collagen fibril organization;positive regulation of cell growth;positive regulation of cell migration;negative regulation of transforming growth factor beta receptor signaling pathway;regulation of protein ubiquitination;negative regulation of chondrocyte differentiation;activin receptor signaling pathway;intracellular signal transduction;wound healing;endothelial cell activation;extracellular structure organization;regulation of protein binding;endothelial cell migration;positive regulation of transcription, DNA-templated;thymus development;neuron fate commitment;embryonic cranial skeleton morphogenesis;skeletal system morphogenesis;mesenchymal cell differentiation;artery morphogenesis;cell motility;positive regulation of cellular component movement;positive regulation of filopodium assembly;positive regulation of stress fiber assembly;positive regulation of protein kinase B signaling;parathyroid gland development;roof of mouth development;pharyngeal system development;regulation of cardiac muscle cell proliferation;cardiac epithelial to mesenchymal transition;pathway-restricted SMAD protein phosphorylation;positive regulation of SMAD protein signal transduction;ventricular septum morphogenesis;angiogenesis involved in coronary vascular morphogenesis;coronary artery morphogenesis;response to cholesterol;cellular response to transforming growth factor beta stimulus;positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation;positive regulation of tight junction disassembly;epicardium morphogenesis;positive regulation of apoptotic signaling pathway;negative regulation of extrinsic apoptotic signaling pathway
• Cellular component: endosome;plasma membrane;integral component of plasma membrane;bicellular tight junction;cell surface;intracellular membrane-bounded organelle;receptor complex;membrane raft;activin receptor complex
• 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;protein binding;ATP binding;growth factor binding;SMAD binding;metal ion binding;activin binding;transforming growth factor beta binding;I-SMAD binding