NOTCH1
protein-codingnotch receptor 1, the group of MicroRNA protein coding host genes|Notch receptors
Gene summary
This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]
- TAN1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~51.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014459
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014459
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018787
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:1060150
Submitter: ClinGen
*NOTCH1* was first reported in relation to autosomal dominant aortic valve disease in 2005 (Garg et al., PMID: 16025100). In 2014, the gene was reported in relation to autosomal dominant Adams-Oliver syndrome (Stittrich et al., PMID: 25132448). In 2016, deleterious variants in the NOTCH1 gene were reported in patients with left-sided congenital heart disease (Kerstjens-Frederikse et al., PMID: 26820064). To date, at least 4000 *NOTCH1* variants have been submitted to ClinVar in association with human diseases (PMID: 24234437). Variants in *NOTCH1* have been reported in individuals with the following disease entities: Adams-Oliver Syndrome, congenital heart disease, aortic valve disease including bicuspid aortic valve, and thoracic aortic aneurysm and dissection. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism and inheritance pattern and found considerable interfamilial and intrafamilial variability in cardiac phenotypes. Therefore, the following disease entities have been lumped into one disease entity (*NOTCH1*-related AOS spectrum disorder). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Eleven variants (nonsense and frameshift) that have been reported in eleven probands, with segregation in an additional twenty-two family members, from four publications are included in this curation (PMIDs: 16025100, 25132448, 26820064, 38778082). This gene-disease relationship is supported by animal models, expression studies, or in vitro functional assay. Expression data from human and mice tissues showed high expression levels of *NOTCH1* in cardiac valve and heart tissues with implications of *NOTCH1* playing a role in cardiac valve development (PMIDs: 16025100, 23715323). Immunohistochemistry data showed Notch1 intracellular domain expression in both normal human aorta and diseased human aortic aneurysm samples, with expression levels correlating to disease severity (PMID: 29093270). In addition, various strains of mice with Notch1 haploinsufficiency expressed postnatal lethality, bicuspid valve, or dilation of the ascending aorta or aortic root (PMIDs: 27107132, 29093270). Disease-causing variants in the NOTCH1 gene elicit a spectrum of cardiac and extracardiac phenotypes with incomplete penetrance and extensive intrafamilial variability (PMID: 38778082). Comprehensive evaluation for all potentially affected organ systems should be pursued at the time of diagnosis. Clinical surveillance for thoracic aortic aneurysm is warranted in individuals with *NOTCH1* variants as they may be asymptomatic due to incomplete penetrance and age-related manifestation of aortopathy (PMIDs: 20301299, 38778082). In summary, there is definitive evidence supporting the relationship between *NOTCH1* and autosomal dominant *NOTCH1*-related AOS spectrum disorder. 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 Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on March 7th 2025 (SOP Version 11). This gene was originally evaluated by the Heritable Thoracic Aortic Aneurysm and Dissection Expert Panel on April 6th, 2016 in relation to familial thoracic aortic aneurysm and aortic dissection. It was reevaluated on March 7th 2025. As a result of this reevaluation, the classification was changed from Limited assertion for familial thoracic aortic aneurysm and aortic dissection to Definitive assertion for *NOTCH1*-related AOS spectrum disorder.
Inheritance Pattern: AD
Disease ID:MONDO:0019046
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0003900
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014459
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0007194
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007034
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007034
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Dermatologic; Musculoskeletal
Intervention: Cardiovascular
Rationale: Individuals may have a variety of cardiovascular malformations, and early diagnosis and treatment (including surgical treatment in some individuals) may reduce morbidity and mortality
Comments: Variants in some affected individuals were also found in apparently unaffected parents
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NOTCH1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017617.5. 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 | 25 | 1314 | 46 | 1385 | ||
| missense | 5 | 32 | 1672 | 599 | 73 | 2381 |
| nonsense | 43 | 26 | 9 | 78 | ||
| start loss | 1 | 1 | ||||
| frameshift | 45 | 25 | 15 | 85 | ||
| splice donor/acceptor (+/-2bp) | 1 | 23 | 20 | 44 | ||
| Total | 94 | 107 | 1741 | 1913 | 119 | 3974 |
Highest pathogenic variant AF is 0.000006887887
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060087.3 | 34 | MANE Select | |
| Ensembl | ENSP00000498587.1 | 34 | MANE Select | |
| Ensembl | ENSP00000506241.1 | 28 | Standard | |
| Ensembl | ENSP00000505319.1 | 33 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| notch1b | Danio rerio | Structure: thoracic duct Quality: wholeness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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)
Biological Process
- negative regulation of transcription by RNA polymerase II
- in utero embryonic development
- cell fate specification
- epithelial to mesenchymal transition
- liver development
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
Cellular Component
- Golgi membrane
- acrosomal vesicle
- MAML1-RBP-Jkappa- ICN1 complex
- extracellular region
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000277541
- Coding exons
- 34
- Length
- 51419
- Individuals with no LoFs
- 124578
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 124585
- p
- 0.0000281
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.45 | 1278 | 1.67e+3 | 0.763 | 0.000125 | 16666 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00014 | 0.00013 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000037 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
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.;
Recessive Scores
- pRec
- 0.916
Intolerance Scores
- LoFtool
- 0.000207
- RVIS EVS
- -3.51
- RVIS percentile EVS
- 0.33
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.850
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |