EDNRB

protein-coding

endothelin receptor type B, the group of Endothelin receptors

Gene summary

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]

Previous symbols:

HSCR2
HSCR

MANE transcript

NM_001122659.3

Inheritance

AD, AR, SD

ClinVar variants

P:49U:193B:56

Top phenotype

Waardenburg syndrome type 4A; ABCD syndrome; Hirschsprung disease, susceptibility to, 2

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr13:77,895,481-77,975,529

External References & Databases

Ensembl (ENSG00000136160)

Transcript & Mutation Effects

hg38 • Region Span ~80.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Waardenburg syndrome type 4ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010192

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 4AMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010192

Submitter: ClinGen

EDNRB was first reported in relation to autosomal recessive Waardenburg Syndrome Type 4A (WS4) in 1994 (Puffenberger et al.; PMID: 8001158). This condition is associated with sensorineural hearing loss; atypical pigmentation of the hair, skin, and eyes; and Hirschsprung’s disease (aganglionic megacolon). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the following disease entities have been split: autosomal recessive Waardenburg syndrome Type 4A and autosomal dominant Waardenburg syndrome type 4A (OMIM # for both entities: 277580). The split curation for autosomal dominant Waardenburg Syndrome Type 4A has been curated separately. Five variants (missense) that have been reported in five probands in five publications (PMIDs: 16237557, 21373256, 25852447, 28502583, 30394532) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (knockout mouse models; PMIDs: 11773966, 23360229, 21715336). In summary, there is moderate evidence to support this gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 5/8/2018. It was re-evaluated on 6/27/2023. As a result of this reevaluation, the classification did not change, although additional genetic evidence was added (PMID: 30394532). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 6/27/2023 (SOP Version 9).

Hirschsprung disease, susceptibility to, 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010833

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 4ALIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0010192

Submitter: ClinGen

The relationship between EDNRB and autosomal dominant Waardenburg syndrome was evaluated using the ClinGen Clinical Validity Framework as of 12/14/2017. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the relationship between EDNRB and autosomal recessive Waardenburg syndrome has been assessed separately. Variants in EDNRB were first reported in humans with this disease as early as 2009 (Tuysuz et al., PMID 19764031). At least 6 missense, nonsense and frameshift variants have been reported in humans (Issa et al. 2017, PMID 28236341). Variants in this gene segregate with disease in multiple family members, however phenotypes vary among family members. A mouse model from Matsushima et al. 2002 shows a heterozygous Ednrb variant mouse without Waardenburg phenotypes, and a mouse model by Ida-Eto et al. 2011 shows recovered hearing in a heterozygous Ednrb variant mouse (PMIDs 11773966, 21715336). 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. This classification was approved by the ClinGen Hearing Loss Working Group on 5/8/2018.

Waardenburg syndrome type 4AMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0010192

Submitter: Ambry Genetics

Waardenburg syndrome type 4ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010192

Submitter: G2P

Waardenburg syndrome type 4ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010192

Submitter: G2P

Waardenburg syndrome type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019517

Submitter: Orphanet

Waardenburg-Shah syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019518

Submitter: Orphanet

Waardenburg syndrome type 4ASTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0010192

Submitter: PanelApp Australia

Waardenburg syndrome type 4ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010192

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Waardenburg syndrome type 4A; ABCD syndrome; Hirschsprung disease, susceptibility to, 2AD/AR

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Gastrointestinal; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Gastrointestinal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Recognition of potential GI manifestations (eg, Hirschsprung disease) may allow prompt treatment

Refs: 7264803; 8001158; 8634719; 7778600; 10528251; 11484199; 11891690; 19764031

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EDNRB variants in ClinVar

16 Conditions Cataloged

not providedTotal: 247

Inborn genetic diseasesTotal: 50

EDNRB-related disorderTotal: 39

not specifiedTotal: 36

Waardenburg syndrome type 4ATotal: 33

Hirschsprung disease, susceptibility to, 2Total: 27

ABCD syndromeTotal: 7

Hearing impairmentTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001122659.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	45 clinvar	1 clinvar	50
missense	2 clinvar	8 clinvar	183 clinvar	7 clinvar	3 clinvar	203
nonsense	9 clinvar	5 clinvar	2 clinvar			16
start loss						0
frameshift	4 clinvar	11 clinvar	4 clinvar			19
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar				10
Total	17	32	193	52	4	298

Highest pathogenic variant AF is 0.00002790144

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001122659.3	RefSeq	NP_001116131.1	7	MANE Select
ENST00000646607.2	Ensembl	ENSP00000493527.1	7	MANE Select
NM_000115.5	RefSeq	NP_000106.1	7	Standard
NM_001201397.2	RefSeq	NP_001188326.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ednrba	Danio rerio	Structure: iridophore Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

ednrba

Danio rerio

Structure: iridophore

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Relaxin signaling pathway - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
cGMP-PKG signaling pathway - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
neural crest cell migration
positive regulation of protein phosphorylation
regulation of pH
cell surface receptor signaling pathway

Molecular Function

endothelin receptor activity
protein binding
peptide hormone binding
type 1 angiotensin receptor binding

Cellular Component

plasma membrane
integral component of plasma membrane
nuclear membrane
membrane raft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377211
Coding exons: 8
Length: 24288
Individuals with no LoFs: 125588
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125596
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.18	236	293	0.805	0.0000145	3437
Missense (PolyPhen)		31	68.129	0.45502		857
Synonymous	0.729	106	116	0.914	0.00000607	1072
Loss of Function	3.07	8	24.3	0.329	0.00000119	286

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:7536888}.;
Disease: DISEASE: Waardenburg syndrome 4A (WS4A) [MIM:277580]: 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:12189494, ECO:0000269|PubMed:8634719}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hirschsprung disease 2 (HSCR2) [MIM:600155]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:11471546, ECO:0000269|PubMed:28236341, ECO:0000269|PubMed:8001158, ECO:0000269|PubMed:8630503, ECO:0000269|PubMed:8852660}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: ABCD syndrome (ABCDS) [MIM:600501]: An autosomal recessive syndrome characterized by albinism, black lock at temporal occipital region, bilateral deafness, aganglionosis of the large intestine and total absence of neurocytes and nerve fibers in the small intestine. {ECO:0000269|PubMed:11891690}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Heterozygous mutations in EDNRB may be responsible for Waardenburg syndrome 2, an autosomal dominant disorder characterized by sensorineural deafness and pigmentary disturbances. {ECO:0000269|PubMed:28236341}.;

Recessive Scores

pRec: 0.729

Intolerance Scores

LoFtool: 0.360
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.584

Gene Damage Prediction

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