GeneBe

EDN3

protein-coding

endothelin 3, the group of Endothelins

Gene summary

The protein encoded by this gene is a member of the endothelin family. Endothelins are endothelium-derived vasoactive peptides involved in a variety of biological functions. The active form of this protein is a 21 amino acid peptide processed from the precursor protein. The active peptide is a ligand for endothelin receptor type B (EDNRB). The interaction of this endothelin with EDNRB is essential for development of neural crest-derived cell lineages, such as melanocytes and enteric neurons. Mutations in this gene and EDNRB have been associated with Hirschsprung disease (HSCR) and Waardenburg syndrome (WS), which are congenital disorders involving neural crest-derived cells. Altered expression of this gene is implicated in tumorigenesis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

MANE transcript

NM_207034.3

Inheritance

AD, AR, SD

ClinVar variants

P:12U:93B:32

Top phenotype

Waardenburg syndrome, type 4B; Central hypoventilation syndrome, congenital; Hirschsprung disease, susceptibility to, 4

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr20:59,300,443-59,325,992

External References & Databases

Ensembl (ENSG00000124205)NCBI Gene (1908)OMIM (131242)HGNC:3178GenCCUniProt (P14138)AlphaFoldClinVar (EDN3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~25.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Waardenburg syndrome type 4BLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013201

Submitter: Labcorp Genetics (formerly Invitae)

Hirschsprung disease, susceptibility to, 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013384

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 4BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013201

Submitter: G2P

Waardenburg syndrome type 4BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013201

Submitter: ClinGen

The EDN3 gene has been associated with autosomal recessive Waardenburg syndrome using the ClinGen Clinical Validity Framework as of 12/8/2017. This association was made using case-level data only. At least 7 variants (missense and frameshift) have been reported in humans. EDN3 was first associated with this disease in humans as early as 1996 (Edery et al.). Association is seen in at least 8 probands in 8 publications (8630502, 19764030, 22876130, 20583152, 30394532, 33713422, 8630503, 12189494). Variants in this gene segregated with disease in one additional family member. This gene-disease association is supported by two mouse models with homozygous missense EDN3 variants, which display white spotting, aganglionic megacolon, and early death. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 5/8/2018. It was reevaluated on 5/17/2023. As a result of this reevaluation, the classification did not change. However additional genetic evidence has been included and scoring adjusted to the current Gene Clinical Validity SOP Version 9. The new genetic evidence included these publications (PMID: 20583152, 30394532, 33713422, 8630503, 12189494) and an additional proband was identified in Moghadam et al 2020 and scored 1.1 (http://repozytorium.ur.edu.pl/handle/item/5791). As the paper did not have a pubmed ID the relevant information was entered under non-scorable evidence. Therefore, the actual score for genetic evidence is 3.9 (including the score from Moghadam et al 2020 (1.1) and score for consanguineous probands (-0.4)). The final total points are 8.4 (MODERATE).

Hirschsprung disease, susceptibility to, 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013384

Submitter: Ambry Genetics

Waardenburg syndrome type 4BLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013201

Submitter: ClinGen

The EDN3 gene has been associated with autosomal dominant Waardenburg syndrome using the ClinGen Clinical Validity Framework as of 12/8/2017. This association was made using case-level data only. At least 1 frameshift variant has been reported in humans. EDN3 was first associated with this disease in humans as early as 1999 (Svensson et al.). This gene-disease association is supported by relevant experimental evidence including expression data and a mouse model with white belly spots carrying a heterozygous p.Arg96His variant. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association.

Waardenburg syndrome type 4BDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013201

Submitter: G2P

Waardenburg syndrome type 4BMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0013201

Submitter: Ambry Genetics

Waardenburg-Shah syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019518

Submitter: PanelApp Australia

Waardenburg-Shah syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019518

Submitter: Orphanet

Waardenburg syndrome type 4BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013201

Submitter: Ambry Genetics

Waardenburg syndrome type 4BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013201

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg-Shah syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019518

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Waardenburg syndrome, type 4B; Central hypoventilation syndrome, congenital; Hirschsprung disease, susceptibility to, 4AD/AR

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Gastrointestinal; Neurologic; Ophthalmologic; Pulmonary

Intervention: Audiologic/Otolaryngologic; Gastrointestinal; Neurologic; Pulmonary

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In conditions that may involve Hirschsprung disease, recognition of potential GI anomalies (eg, aganglionosis) may allow prompt recognition and treatment; In Central hypoventilation syndrome, congenital, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality

Refs: 8696331; 8630502; 8630503; 9279758; 9359047; 10231870; 11303518; 19764030; 20009762Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EDN3 variants in ClinVar

12 Conditions Cataloged
not providedTotal: 83
Inborn genetic diseasesTotal: 35
EDN3-related disorderTotal: 29
not specifiedTotal: 19
Hirschsprung disease, susceptibility to, 4Total: 17
Waardenburg syndrome type 4BTotal: 17
MegacolonTotal: 1
Aganglionic megacolonTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207034.3. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
25
clinvar
1
clinvar
 29
missense
3
clinvar
2
clinvar
86
clinvar
4
clinvar
1
clinvar
 96
nonsense
1
clinvar
 1
start loss
0
frameshift
1
clinvar
5
clinvar
3
clinvar
1
clinvar
 10
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total5793302137

Highest pathogenic variant AF is 0.000003422529

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_207034.3RefSeqNP_996917.15MANE Select
ENST00000337938.7EnsemblENSP00000337128.25MANE Select
NM_001302455.2RefSeqNP_001289384.15Standard
NM_001302456.2RefSeqNP_001289385.14Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
edn3bDanio rerio

Structure: melanocyte

Quality: decreased pigmentation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling by GPCR
  • Signal Transduction
  • GPCR signaling-G alpha q
  • GPCR signaling-cholera toxin
  • GPCR signaling-pertussis toxin

Biological Process

  • neural crest cell migration
  • positive regulation of leukocyte chemotaxis
  • regulation of systemic arterial blood pressure by endothelin
  • cellular calcium ion homeostasis
  • signal transduction

Molecular Function

  • signaling receptor binding
  • hormone activity
  • endothelin B receptor binding

Cellular Component

  • extracellular region
  • extracellular space
  • cell

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000337938
Coding exons
5
Length
25566
Individuals with no LoFs
125666
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125671
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.9391681371.230.000008741519
Missense (PolyPhen)3334.7570.94946366
Synonymous0.1185758.10.9800.00000390492
Loss of Function1.6549.500.4214.99e-7107

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.000099rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.00000900.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Endothelins are endothelium-derived vasoconstrictor peptides.;
Disease
DISEASE: Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. {ECO:0000269|PubMed:8696331}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Waardenburg syndrome 4B (WS4B) [MIM:613265]: A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). {ECO:0000269|PubMed:11303518, ECO:0000269|PubMed:12189494, ECO:0000269|PubMed:8630503}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.370

Intolerance Scores

LoFtool
0.0739
RVIS EVS
-0.36
RVIS percentile EVS
28.93

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0610

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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