EDNRB

Chr 13ARAD

endothelin receptor type B

Also known as: ABCDS, ET-B, ET-BR, ETB, ETB1, ETBR, ETRB, HSCR

NCBI Gene: 1910 ENSG00000136160 UniProt: P24530 OMIM: 131244

This gene encodes endothelin receptor type B, a G protein-coupled receptor that binds endothelin peptides and activates phosphatidylinositol-calcium signaling pathways. Mutations cause Hirschsprung disease type 2 and Waardenburg syndrome type 4A, conditions affecting enteric nervous system development and neural crest cell migration respectively. The gene shows both autosomal recessive and autosomal dominant inheritance patterns depending on the associated phenotype.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET1, ET2, and ET3. Studies suggest that the multigenic disorder, Hirschsprung disease type 2, is due to mutations in the endothelin receptor type B gene. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.593 OMIM phenotypes

Clinical Summary— EDNRB

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Gene-Disease Validity (ClinGen)

Waardenburg syndrome type 4A · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

41 unique Pathogenic / Likely Pathogenic· 224 VUS of 380 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EDNRB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.009

Z-score 3.07

OE 0.33 (0.19–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.18Z-score

OE missense 0.81 (0.72–0.90)

236 obs / 293.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.19–0.59)

0≤0.351.4

Missense OE?0.81 (0.72–0.90)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 8 / 24.3Missense obs/exp: 236 / 293.0Syn Z: 0.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEDNRB-related Waardenburg syndromeLOFAD

definitiveEDNRB-related Waardenburg syndrome with HirschsprungLOFAR

This gene — mechanism propensity

0.77top 25%

GOF

0.79top 25%

LOF

0.2775th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

LOF1 literature citation · 83% of P/LP variants are LoF

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

LOFNovel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease1

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

References

1.PMID 8852658 ↗

ClinVar Variant Classifications

380 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic24

VUS224

Likely Benign76

Benign14

Conflicting20

Pathogenic

Likely Pathogenic

224

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	2	1	0	17
Likely Pathogenic	20	4	0	0	24
VUS	4	167	50	3	224
Likely Benign	0	5	31	40	76
Benign	0	0	12	2	14
Conflicting	—				20
Total	38	178	94	45	375

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

View in ClinVar →

75 pathogenic / likely-pathogenic (of 84) ClinVar copy-number / structural variants overlap EDNRB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →