NOTCH3

notch receptor 3, the group of Notch receptors|MicroRNA protein coding host genes

Basic information

Region (hg38): 19:15159037-15200995

Previous symbols: [ "CADASIL" ]

Links

ENSG00000074181 ∙ NCBI:4854 ∙ OMIM:600276 ∙ HGNC:7883 ∙ Uniprot:Q9UM47 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• myofibromatosis, infantile, 2 (Limited), mode of inheritance: AD
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Strong), mode of inheritance: AD
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Supportive), mode of inheritance: AD
• lateral meningocele syndrome (Supportive), mode of inheritance: AD
• infantile myofibromatosis (Supportive), mode of inheritance: AD
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Definitive), mode of inheritance: AD
• lateral meningocele syndrome (Strong), mode of inheritance: AD
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (Strong), mode of inheritance: AD
• pulmonary arterial hypertension (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL1); Myofibromatosis, infantile 2	AD	Cardiovascular; Oncologic	In Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (CADASIL1), certain agents (eg, angiography, anticoagulants, thrombolytic therapy) should be avoided; Myofibromatosis, infantile 2 involves benign tumors affecting the skin, muscle, bone, and viscera, and awareness of visceral neoplasms may be beneficial in order to diagnose and manage lesions	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Oncologic	7486874; 7564728; 7654071; 7500094; 8878478; 9188658; 9818928; 10371078; 12136071; 15096408; 15210914; 15313839; 15378071; 15666314; 16009764; 16263847; 15851739; 17135568; 16717210; 16864835; 18765654; 19174371; 20038773; 20301673; 21337686; 21671395; 22218279; 22996955; 23025651; 23696373; 23731542; 24000151; 25394726

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NOTCH3 gene.

• not provided (1139 variants)
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (311 variants)
• not specified (164 variants)
• Inborn genetic diseases (49 variants)
• Lateral meningocele syndrome (27 variants)
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1;Myofibromatosis, infantile, 2;Lateral meningocele syndrome (24 variants)
• NOTCH3-related condition (20 variants)
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (19 variants)
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1;Lateral meningocele syndrome;Myofibromatosis, infantile, 2 (7 variants)
• Lateral meningocele syndrome;Myofibromatosis, infantile, 2;Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (7 variants)
• Myofibromatosis, infantile, 2;Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1;Lateral meningocele syndrome (6 variants)
• Lateral meningocele syndrome;Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1;Myofibromatosis, infantile, 2 (4 variants)
• Myofibromatosis, infantile, 2 (4 variants)
• Pulmonary arterial hypertension (4 variants)
• Stroke disorder (4 variants)
• See cases (3 variants)
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1;Lateral meningocele syndrome (3 variants)
• Auditory neuropathy (2 variants)
• Vascular dementia (2 variants)
• NOTCH3-Related Disorders (2 variants)
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1;Myofibromatosis, infantile, 2;Sneddon syndrome;Lateral meningocele syndrome (1 variants)
• Cerebral cavernous malformation (1 variants)
• Recurrent subcortical infarcts (1 variants)
• Ischemic stroke;Transient ischemic attack (1 variants)
• Migraine;Tension-type headache;Transient ischemic attack;Abnormal brain morphology (1 variants)
• Stroke disorder;Depression;Migraine with aura (1 variants)
• Malignant tumor of prostate (1 variants)
• Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 2 (1 variants)
• Migraine without aura;Stroke disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOTCH3 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			34	191	36	261
missense	119	93	411	81	12	716
nonsense	4	2	7			13
start loss			1			1
frameshift	6	5	15			26
inframe indel	1	2	5			8
splice donor/acceptor (+/-2bp)	2	1	3			6
splice region			16	30	4	50
non coding			18	62	89	169
Total	132	103	494	334	137

Highest pathogenic variant AF is 0.0000263

Variants in NOTCH3

This is a list of pathogenic ClinVar variants found in the NOTCH3 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-15159725-A-G		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Likely benign (Apr 27, 2017)
19-15159772-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Apr 27, 2017)
19-15159817-C-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Jan 13, 2018)
19-15159825-C-T		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Apr 27, 2017)
19-15159854-C-T		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Apr 27, 2017)
19-15159945-G-C		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jan 13, 2018)
19-15159994-C-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Apr 27, 2017)
19-15160006-A-G		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jan 12, 2018)
19-15160054-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jan 12, 2018)
19-15160099-A-G		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Likely benign (Apr 27, 2017)
19-15160118-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Jan 13, 2018)
19-15160145-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jan 13, 2018)
19-15160199-C-T		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Jan 13, 2018)
19-15160280-A-C		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jan 12, 2018)
19-15160292-T-C		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Jan 13, 2018)
19-15160306-T-TAA		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jun 14, 2016)
19-15160324-T-G		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Apr 27, 2017)
19-15160356-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 • Lateral meningocele syndrome;Myofibromatosis, infantile, 2;Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Oct 13, 2021)
19-15160373-CAGA-C			Likely benign (Dec 01, 2022)
19-15160383-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Uncertain significance (Jan 12, 2018)
19-15160566-G-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Likely benign (Jun 22, 2021)
19-15160577-C-A		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Jan 12, 2018)
19-15160639-A-T		Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Mar 05, 2020)
19-15160658-C-T		not specified • Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign (Jan 13, 2018)
19-15160659-G-A		not specified • Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	Benign/Likely benign (Nov 07, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NOTCH3	protein_coding	protein_coding	ENST00000263388	33	41349

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.408	0.592	125701	0	47	125748	0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.53	1037	1.41e+3	0.735	0.0000968	14774
Missense in Polyphen		360	619.85	0.58079		6597
Synonymous	1.51	557	604	0.922	0.0000454	4842
Loss of Function	7.09	22	97.6	0.226	0.00000514	1050

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000274	0.000266
Ashkenazi Jewish	0.000102	0.0000992
East Asian	0.000292	0.000272
Finnish	0.000146	0.000139
European (Non-Finnish)	0.000201	0.000193
Middle Eastern	0.000292	0.000272
South Asian	0.000268	0.000261
Other	0.000329	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination (PubMed:15350543). 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 (By similarity). {ECO:0000250|UniProtKB:Q9R172, ECO:0000269|PubMed:15350543}.
• Disease: DISEASE: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 1 (CADASIL1) [MIM:125310]: A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. {ECO:0000269|PubMed:10227618, ECO:0000269|PubMed:10371548, ECO:0000269|PubMed:10802807, ECO:0000269|PubMed:10854111, ECO:0000269|PubMed:11058919, ECO:0000269|PubMed:11102981, ECO:0000269|PubMed:11559313, ECO:0000269|PubMed:11755616, ECO:0000269|PubMed:11810186, ECO:0000269|PubMed:12136071, ECO:0000269|PubMed:12146805, ECO:0000269|PubMed:12589106, ECO:0000269|PubMed:12810003, ECO:0000269|PubMed:15229130, ECO:0000269|PubMed:15300988, ECO:0000269|PubMed:15350543, ECO:0000269|PubMed:15364702, ECO:0000269|PubMed:15378071, ECO:0000269|PubMed:15818833, ECO:0000269|PubMed:16009764, ECO:0000269|PubMed:24000151, ECO:0000269|PubMed:9388399}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myofibromatosis, infantile 2 (IMF2) [MIM:615293]: A rare mesenchymal disorder characterized by the development of benign tumors in the skin, striated muscles, bones, and, more rarely, visceral organs. Subcutaneous or soft tissue nodules commonly involve the skin of the head, neck, and trunk. Skeletal and muscular lesions occur in about half of the patients. Lesions may be solitary or multicentric, and they may be present at birth or become apparent in early infancy or occasionally in adult life. Visceral lesions are associated with high morbidity and mortality. {ECO:0000269|PubMed:23731542}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lateral meningocele syndrome (LMNS) [MIM:130720]: A very rare skeletal disorder with facial anomalies, hypotonia and neurologic dysfunction due to meningocele, a protrusion of the meninges, unaccompanied by neural tissue, through a bony defect in the skull or vertebral column. LMNS facial features include hypertelorism and telecanthus, high arched eyebrows, ptosis, mid- facial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Additional variable features are connective tissue abnormalities, aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis. {ECO:0000269|PubMed:25394726}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Breast cancer - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Apelin 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;Neural Crest Differentiation;Notch Signaling Pathway;Pre-NOTCH Expression and Processing;Canonical and Non-canonical Notch signaling;Role of Osx and miRNAs in tooth development;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;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;Noncanonical activation of NOTCH3;NOTCH3 Activation and Transmission of Signal to the Nucleus;NOTCH3 Intracellular Domain Regulates Transcription;Signaling by NOTCH3;Signaling by NOTCH;Notch signaling pathway (Consensus)

Recessive Scores

• pRec: 0.197

Intolerance Scores

• loftool: 0.0358
• rvis_EVS: -1.29
• rvis_percentile_EVS: 5.04

Haploinsufficiency Scores

• pHI: 0.857
• hipred: Y
• hipred_score: 0.715
• ghis: 0.597

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.870

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Notch3
• 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); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; vision/eye 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); hematopoietic 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); reproductive system phenotype; neoplasm; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; hearing/vestibular/ear 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)

Zebrafish Information Network

• Gene name: notch3
• Affected structure: caudal fin blood vessel
• Phenotype tag: abnormal
• Phenotype quality: displaced

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;Notch signaling pathway;positive regulation of transcription of Notch receptor target;forebrain development;negative regulation of neuron differentiation;negative regulation of Notch signaling pathway;positive regulation of smooth muscle cell proliferation;neuron fate commitment;artery morphogenesis;glomerular capillary formation
• Cellular component: Golgi membrane;extracellular region;nucleoplasm;endoplasmic reticulum membrane;cytosol;plasma membrane;actin cytoskeleton;integral component of membrane;receptor complex
• Molecular function: calcium ion binding;protein binding;enzyme binding;signaling receptor activity;identical protein binding;cadherin binding