NOTCH3

Chr 19

notch receptor 3

Also known as: CADASIL, CADASIL1, CARASIL1, CASIL, FPLD1, IMF2, LMNS

NCBI Gene: 4854 ENSG00000074181 UniProt: Q9UM47

The NOTCH3 protein functions as a receptor for membrane-bound ligands (Jagged1, Jagged2, and Delta1) that regulates cell-fate determination and affects differentiation, proliferation, and apoptotic programs. Mutations cause cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), lateral meningocele syndrome, infantile myofibromatosis, and familial partial lipodystrophy, with both autosomal dominant and recessive inheritance patterns reported. The gene shows high constraint against loss-of-function variants (LOEUF 0.32), indicating intolerance to protein-disrupting mutations.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.32

Clinical Summary— NOTCH3

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Gene-Disease Validity (ClinGen)

pulmonary arterial hypertension · ADDisputed

Disputed — evidence questions this relationship

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

328 unique Pathogenic / Likely Pathogenic· 841 VUS of 2081 total submissions

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Clinical Trials

9 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NOTCH3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.32LOEUF

pLI 0.408

Z-score 7.09

OE 0.23 (0.16–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.53Z-score

OE missense 0.74 (0.70–0.77)

1037 obs / 1410.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.23 (0.16–0.32)

0≤0.351.4

Missense OE?0.74 (0.70–0.77)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 22 / 97.6Missense obs/exp: 1037 / 1410.4Syn Z: 1.51

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNOTCH3-related infantile myofibromatosisGOFAD

definitiveNOTCH3-related cerebral arteiopathy with subcortical infarcts and leukencephalopathyGOFAD

This gene — mechanism propensity

0.4388th %ile

GOF

0.6052th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF15% of P/LP variants are LoF · LOEUF 0.32

GOF1 literature citation · 82% of P/LP are missense

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn a follow-up to the study of Joutel et al. (2004), Monet-Lepretre et al. (2009) found that the C428S mutation exerted a dominant-negative effect in transgenic mice, and antagonized the function of wildtype Notch3 when coexpressed.1

GOFInvestigation of CADASIL mutant Notch3 shows that the majority of mutations do not change CBF1/JBP-Jkappa mediated classic Notch activation, so the pathological consequences of NOTCH3 mutations in CADASIL patients can not be simply explained by loss- or gain-of-function in the classic Notch signalli2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

2081 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic168

Likely Pathogenic160

VUS841

Likely Benign537

Benign132

Conflicting210

168

Pathogenic

160

Likely Pathogenic

841

VUS

537

Likely Benign

132

Benign

210

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	130	8	0	168
Likely Pathogenic	20	139	1	0	160
VUS	35	728	42	36	841
Likely Benign	0	79	142	316	537
Benign	0	7	97	28	132
Conflicting	—				210
Total	85	1,083	290	380	2,048

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap NOTCH3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →