NOTCH3

Chr 19ADAR

notch receptor 3

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

NCBI Gene: 4854 ENSG00000074181 UniProt: Q9UM47

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]

Primary Disease Associations & Inheritance

?Myofibromatosis, infantile 2MIM #615293

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1MIM #125310

ADAR

Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1MIM #621295

Lateral meningocele syndromeMIM #130720

Lipodystrophy, familial partial, type 1MIM #608600

569

ClinVar variants

Pathogenic / LP

0.41

pLI score

Active trials

Clinical Summary— NOTCH3

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Gene-Disease Validity (ClinGen)

pulmonary arterial hypertension · ADDisputed

Disputed — evidence questions this relationship

2 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

74 Pathogenic / Likely Pathogenic· 306 VUS of 569 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.16–0.32)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.70–0.77)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92

0≤1.21.6

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

ClinVar Variant Classifications

569 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic37

VUS306

Likely Benign159

Benign9

Conflicting21

Pathogenic

Likely Pathogenic

306

VUS

159

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	23	11	0	37
Likely Pathogenic	6	29	2	0	37
VUS	8	273	20	5	306
Likely Benign	0	15	51	93	159
Benign	0	2	6	1	9
Conflicting	—				21
Total	17	342	90	99	569

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

View in ClinVar →

Protein Context — Lollipop Plot

NOTCH3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NOTCH3-related infantile myofibromatosis

limited

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

NOTCH3-related cerebral arteiopathy with subcortical infarcts and leukencephalopathy

definitive

ADGain Of FunctionAltered Gene Product Structure

Skin

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

NOTCH RECEPTOR 3; NOTCH3

MIM #600276 · *

?Myofibromatosis, infantile 2

MIM #615293