NOTCH1
notch receptor 1, the group of MicroRNA protein coding host genes|Notch receptors
Basic information
Region (hg38): 9:136494432-136546048
Previous symbols: [ "TAN1" ]
Links
Phenotypes
GenCC
Source:
- aortic valve disease 1 (Strong), mode of inheritance: AD
- aortic valve disease 1 (Strong), mode of inheritance: AD
- connective tissue disorder (Moderate), mode of inheritance: AD
- Adams-Oliver syndrome (Supportive), mode of inheritance: AD
- familial bicuspid aortic valve (Supportive), mode of inheritance: AD
- Adams-Oliver syndrome 5 (Definitive), mode of inheritance: AD
- Adams-Oliver syndrome (Definitive), mode of inheritance: AD
- Adams-Oliver syndrome 5 (Strong), mode of inheritance: AD
- familial thoracic aortic aneurysm and aortic dissection (Limited), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Aortic valve disease 1 | AD | Cardiovascular | Individuals may have a variety of cardiovascular malformations, and early diagnosis and treatment (including surgical treatment in some individuals) may reduce morbidity and mortality | Cardiovascular; Dermatologic; Musculoskeletal | 16025100; 18593716; 21785343; 22307742; 23102684; 23578328; 25132448; 25963545 |
| Variants in some affected individuals were also found in apparently unaffected parents |
ClinVar
This is a list of variants' phenotypes submitted to
- Adams-Oliver syndrome 5 (2402 variants)
- Familial thoracic aortic aneurysm and aortic dissection (1167 variants)
- not provided (977 variants)
- Aortic valve disease 1 (616 variants)
- not specified (346 variants)
- Aortic valve disease 1;Adams-Oliver syndrome 5 (65 variants)
- Connective tissue disorder (64 variants)
- Inborn genetic diseases (41 variants)
- NOTCH1-related condition (41 variants)
- Adams-Oliver syndrome 5;Aortic valve disease 1 (23 variants)
- Cholesteatoma of middle ear (6 variants)
- Pulmonary arterial hypertension (5 variants)
- Hypoplastic left heart syndrome (3 variants)
- Myeloproliferative neoplasm, unclassifiable (3 variants)
- Adams-Oliver syndrome 5;Aortic valve disorder (3 variants)
- Marfan syndrome (2 variants)
- Cardiovascular phenotype (2 variants)
- Non-small cell lung carcinoma (2 variants)
- Anophthalmia-microphthalmia syndrome (2 variants)
- Heart, malformation of (2 variants)
- Abnormal vena cava morphology;Bicuspid aortic valve;Aortic tortuosity;Narrow palate (1 variants)
- Abnormal cardiovascular system morphology (1 variants)
- Adams-Oliver syndrome (1 variants)
- Thoracic aortic aneurysm (1 variants)
- Shone complex (1 variants)
- Ehlers-Danlos syndrome, type 3 (1 variants)
- Chronic adenoiditis (1 variants)
- Aortic valve disorder;Adams-Oliver syndrome 5 (1 variants)
- NOTCH1-Related Disorders (1 variants)
- Aortic valve disease 1;Familial thoracic aortic aneurysm and aortic dissection (1 variants)
- Arterial dissection (1 variants)
- Adams-Oliver syndrome;Congenital heart anomalies (1 variants)
- KA-like vemurafenib-induced squamous lesions (1 variants)
- Hemangioma (1 variants)
- Adams-Oliver syndrome 2;Aortic valve disorder (1 variants)
- Bicuspid aortic valve (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOTCH1 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 | 18 | 861 | 55 | 934 | ||
| missense | 12 | 941 | 126 | 90 | 1172 | |
| nonsense | 21 | 31 | ||||
| start loss | 1 | |||||
| frameshift | 23 | 33 | ||||
| inframe indel | 16 | 18 | ||||
| splice donor/acceptor (+/-2bp) | 12 | |||||
| splice region ? | 63 | 74 | 7 | 144 | ||
| non coding ? | 315 | 102 | 426 | |||
| Total | 47 | 36 | 995 | 1302 | 247 |
Highest pathogenic variant AF is 0.00000657
Variants in NOTCH1
This is a list of pathogenic ClinVar variants found in the NOTCH1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-136494732-A-G | Benign (Oct 17, 2019) | |||
| 9-136495935-T-C | Benign (Jun 14, 2018) | |||
| 9-136495945-C-T | Benign (Jun 14, 2018) | |||
| 9-136496057-G-T | Likely benign (May 10, 2018) | |||
| 9-136496064-G-A | NOTCH1-related disorder | Likely benign (Mar 15, 2019) | ||
| 9-136496065-C-T | not specified • Familial thoracic aortic aneurysm and aortic dissection • Adams-Oliver syndrome 5 • Aortic valve disease 1 | Benign (May 10, 2023) | ||
| 9-136496066-G-A | Familial thoracic aortic aneurysm and aortic dissection | Conflicting classifications of pathogenicity (Aug 19, 2019) | ||
| 9-136496069-G-A | Likely benign (Jan 31, 2023) | |||
| 9-136496072-T-C | Familial thoracic aortic aneurysm and aortic dissection • Adams-Oliver syndrome 5 | Likely benign (Jan 03, 2023) | ||
| 9-136496081-G-A | Adams-Oliver syndrome 5 | Uncertain significance (Oct 24, 2021) | ||
| 9-136496082-C-T | Adams-Oliver syndrome 5 | Uncertain significance (Feb 13, 2019) | ||
| 9-136496086-C-T | Adams-Oliver syndrome 5 • Familial thoracic aortic aneurysm and aortic dissection | Benign/Likely benign (Dec 25, 2023) | ||
| 9-136496087-G-A | Adams-Oliver syndrome 5 | Benign (Aug 16, 2022) | ||
| 9-136496091-T-C | not specified • Adams-Oliver syndrome 5 • Familial thoracic aortic aneurysm and aortic dissection • Aortic valve disease 1 • Aortic valve disease 1;Adams-Oliver syndrome 5 • Pulmonary arterial hypertension • NOTCH1-related disorder | Likely benign (Jan 22, 2024) | ||
| 9-136496093-C-T | Adams-Oliver syndrome 5 | Benign (Jun 23, 2023) | ||
| 9-136496094-G-A | not specified • Adams-Oliver syndrome 5 • Familial thoracic aortic aneurysm and aortic dissection | Conflicting classifications of pathogenicity (Dec 31, 2023) | ||
| 9-136496097-C-T | Familial thoracic aortic aneurysm and aortic dissection • Adams-Oliver syndrome 5 • Aortic valve disease 1 | Conflicting classifications of pathogenicity (Jun 14, 2023) | ||
| 9-136496098-G-A | Adams-Oliver syndrome 5 • Familial thoracic aortic aneurysm and aortic dissection | Likely benign (Sep 10, 2023) | ||
| 9-136496098-G-T | Adams-Oliver syndrome 5 • not specified | Likely benign (Dec 30, 2023) | ||
| 9-136496107-C-G | Adams-Oliver syndrome 5 | Benign (Aug 23, 2022) | ||
| 9-136496108-T-C | Adams-Oliver syndrome 5 • Familial thoracic aortic aneurysm and aortic dissection | Conflicting classifications of pathogenicity (Jan 05, 2024) | ||
| 9-136496112-T-C | Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Feb 06, 2023) | ||
| 9-136496117-G-A | Adams-Oliver syndrome 5 | Uncertain significance (Jul 09, 2022) | ||
| 9-136496119-G-T | Familial thoracic aortic aneurysm and aortic dissection | Likely benign (Jan 27, 2021) | ||
| 9-136496122-A-C | Adams-Oliver syndrome 5 • Familial thoracic aortic aneurysm and aortic dissection | Likely benign (Oct 13, 2022) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NOTCH1 | protein_coding | protein_coding | ENST00000277541 | 34 | 51419 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 1.72e-14 | 124578 | 0 | 7 | 124585 | 0.0000281 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.45 | 1278 | 1.67e+3 | 0.763 | 0.000125 | 16666 |
| Missense in Polyphen | 396 | 696.83 | 0.56829 | 7054 | ||
| Synonymous | -3.79 | 929 | 793 | 1.17 | 0.0000731 | 4970 |
| Loss of Function | 9.20 | 5 | 108 | 0.0462 | 0.00000509 | 1167 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000164 | 0.000157 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000373 | 0.0000355 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO). {ECO:0000269|PubMed:20616313}.;
- Disease
- DISEASE: Aortic valve disease 1 (AOVD1) [MIM:109730]: A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. {ECO:0000269|PubMed:16025100}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Adams-Oliver syndrome 5 (AOS5) [MIM:616028]: A form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. {ECO:0000269|PubMed:25132448}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Prion diseases - Homo sapiens (human);Breast cancer - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);NOTCH-Core;WNT-Core;Heart Development;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Neural Crest Differentiation;Gastric Cancer Network 1;Cardiac Progenitor Differentiation;Primary Focal Segmental Glomerulosclerosis FSGS;Notch Signaling Pathway;Pre-NOTCH Expression and Processing;Differentiation Pathway;Hematopoietic Stem Cell Differentiation;Endoderm Differentiation;Gene regulatory network modelling somitogenesis;NOTCH1 regulation of human endothelial cell calcification;Pathways Affected in Adenoid Cystic Carcinoma;Amplification and Expansion of Oncogenic Pathways as Metastatic Traits;Canonical and Non-canonical Notch signaling;BMP Signaling Pathway in Eyelid Development;Role of Osx and miRNAs in tooth development;PTF1A related regulatory pathway;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Disease;RUNX3 regulates NOTCH signaling;Signal Transduction;Gene expression (Transcription);Transcriptional regulation by RUNX3;proteolysis and signaling pathway of notch;Generic Transcription Pathway;RNA Polymerase II Transcription;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch-HLH transcription pathway;Notch;NICD traffics to nucleus;Pre-NOTCH Transcription and Translation;Pre-NOTCH Processing in the Endoplasmic Reticulum;Pre-NOTCH Processing in Golgi;Pre-NOTCH Expression and Processing;Signaling by NOTCH1;NOTCH3 Intracellular Domain Regulates Transcription;Signaling by NOTCH3;Signaling by NOTCH;A third proteolytic cleavage releases NICD;Notch signaling pathway;Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant;Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant;Constitutive Signaling by NOTCH1 HD Domain Mutants;Signaling by NOTCH1 HD Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Notch-mediated HES/HEY network;Diseases of signal transduction;Validated transcriptional targets of deltaNp63 isoforms;NOTCH1 Intracellular Domain Regulates Transcription;Presenilin action in Notch and Wnt signaling;Activated NOTCH1 Transmits Signal to the Nucleus
(Consensus)
Recessive Scores
- pRec
- 0.916
Intolerance Scores
- loftool
- 0.000207
- rvis_EVS
- -3.51
- rvis_percentile_EVS
- 0.33
Haploinsufficiency Scores
- pHI
- 0.945
- hipred
- Y
- hipred_score
- 0.825
- ghis
- 0.557
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.850
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Notch1
- Phenotype
- muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism 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); growth/size/body region phenotype; 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); endocrine/exocrine gland phenotype; neoplasm; pigmentation 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); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; embryo phenotype; liver/biliary system phenotype; respiratory system phenotype; normal phenotype; 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);
Zebrafish Information Network
- Gene name
- notch1b
- Affected structure
- thoracic duct
- Phenotype tag
- abnormal
- Phenotype quality
- wholeness
Gene ontology
- Biological process
- negative regulation of transcription by RNA polymerase II;in utero embryonic development;cell fate specification;epithelial to mesenchymal transition;liver development;heart looping;sprouting angiogenesis;positive regulation of neuroblast proliferation;inflammatory response to antigenic stimulus;outflow tract morphogenesis;endocardium development;endocardium morphogenesis;atrioventricular node development;coronary vein morphogenesis;aortic valve morphogenesis;atrioventricular valve morphogenesis;coronary sinus valve morphogenesis;pulmonary valve morphogenesis;mitral valve formation;epithelial to mesenchymal transition involved in endocardial cushion formation;endocardial cushion morphogenesis;cardiac chamber formation;cardiac ventricle morphogenesis;cardiac atrium morphogenesis;cardiac right atrium morphogenesis;cardiac left ventricle morphogenesis;cardiac right ventricle formation;ventricular trabecula myocardium morphogenesis;growth involved in heart morphogenesis;negative regulation of cell proliferation involved in heart valve morphogenesis;regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation;Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation;cell migration involved in endocardial cushion formation;negative regulation of extracellular matrix constituent secretion;pericardium morphogenesis;regulation of transcription, DNA-templated;transcription initiation from RNA polymerase II promoter;immune response;humoral immune response;cell cycle arrest;Notch signaling pathway;positive regulation of transcription of Notch receptor target;spermatogenesis;determination of left/right symmetry;compartment pattern specification;axonogenesis;foregut morphogenesis;endoderm development;heart development;positive regulation of cell population proliferation;negative regulation of cell population proliferation;auditory receptor cell fate commitment;negative regulation of cardiac muscle hypertrophy;positive regulation of gene expression;negative regulation of gene expression;positive regulation of epithelial to mesenchymal transition;negative regulation of cell-substrate adhesion;negative regulation of myotube differentiation;mesenchymal cell development;regulation of somitogenesis;cell differentiation in spinal cord;neural tube development;keratinocyte differentiation;negative regulation of ossification;lung development;positive regulation of cell migration;positive regulation of BMP signaling pathway;negative regulation of BMP signaling pathway;forebrain development;hair follicle morphogenesis;animal organ regeneration;response to corticosteroid;response to muramyl dipeptide;response to lipopolysaccharide;embryonic hindlimb morphogenesis;tube formation;skeletal muscle cell differentiation;cellular response to vascular endothelial growth factor stimulus;tissue regeneration;negative regulation of catalytic activity;positive regulation of viral genome replication;positive regulation of endothelial cell differentiation;negative regulation of inner ear auditory receptor cell differentiation;positive regulation of keratinocyte differentiation;negative regulation of myoblast differentiation;negative regulation of osteoblast differentiation;positive regulation of Notch signaling pathway;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;negative regulation of calcium ion-dependent exocytosis;negative regulation of growth rate;positive regulation of JAK-STAT cascade;negative regulation of photoreceptor cell differentiation;positive regulation of Ras protein signal transduction;somatic stem cell division;astrocyte differentiation;oligodendrocyte differentiation;positive regulation of astrocyte differentiation;negative regulation of oligodendrocyte differentiation;branching morphogenesis of an epithelial tube;homeostasis of number of cells within a tissue;positive regulation of epithelial cell proliferation;negative regulation of neurogenesis;cardiac muscle tissue morphogenesis;cardiac muscle cell proliferation;positive regulation of cardiac muscle cell proliferation;negative regulation of glial cell proliferation;cilium assembly;cardiac epithelial to mesenchymal transition;cardiac septum morphogenesis;ventricular septum morphogenesis;secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development;prostate gland epithelium morphogenesis;regulation of epithelial cell proliferation involved in prostate gland development;arterial endothelial cell differentiation;venous endothelial cell differentiation;cardiac vascular smooth muscle cell development;endocardial cell differentiation;vasculogenesis involved in coronary vascular morphogenesis;coronary artery morphogenesis;Notch signaling involved in heart development;heart trabecula morphogenesis;positive regulation of transcription from RNA polymerase II promoter in response to hypoxia;positive regulation of cardiac epithelial to mesenchymal transition;negative regulation of biomineral tissue development;positive regulation of ERK1 and ERK2 cascade;left/right axis specification;cellular response to follicle-stimulating hormone stimulus;distal tubule development;collecting duct development;glomerular mesangial cell development;interleukin-4 secretion;negative regulation of cell migration involved in sprouting angiogenesis;negative regulation of canonical Wnt signaling pathway;neuronal stem cell population maintenance;negative regulation of cold-induced thermogenesis;regulation of extracellular matrix assembly;apoptotic process involved in embryonic digit morphogenesis;positive regulation of apoptotic process involved in morphogenesis;positive regulation of aorta morphogenesis;negative regulation of stem cell differentiation;negative regulation of anoikis;negative regulation of pro-B cell differentiation;negative regulation of endothelial cell chemotaxis
- Cellular component
- Golgi membrane;acrosomal vesicle;MAML1-RBP-Jkappa- ICN1 complex;extracellular region;nucleus;nucleoplasm;endoplasmic reticulum membrane;cytosol;plasma membrane;adherens junction;cell surface;integral component of membrane;apical plasma membrane;receptor complex
- Molecular function
- RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription activator activity, RNA polymerase II-specific;enzyme inhibitor activity;transmembrane signaling receptor activity;Notch binding;calcium ion binding;protein binding;enzyme binding;chromatin DNA binding;protein heterodimerization activity