ERBB3

protein-coding

erb-b2 receptor tyrosine kinase 3, the group of Erb-b2 receptor tyrosine kinases

Gene summary

This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

Previous symbols:

LCCS2

MANE transcript

NM_001982.4

Inheritance

AR, AD

ClinVar variants

P:22U:110B:43

Top phenotype

Erythroleukemia, familial, susceptibility to; Visceral neuropathy, familial, 1, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr12:56,076,799-56,103,505

External References & Databases

Ensembl (ENSG00000065361)

Transcript & Mutation Effects

hg38 • Region Span ~26.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lethal congenital contracture syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011868

Submitter: Labcorp Genetics (formerly Invitae)

lethal congenital contracture syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011868

Submitter: Ambry Genetics

Hirschsprung diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018309

Submitter: Orphanet

lethal congenital contracture syndrome 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011868

Submitter: Orphanet

visceral neuropathy, familial, 1, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:8000011

Submitter: PanelApp Australia

lethal congenital contracture syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011868

Submitter: G2P

visceral neuropathy, familial, 1, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:8000011

Submitter: G2P

Clinical Genomic Database (CGD)

Erythroleukemia, familial, susceptibility to; Visceral neuropathy, familial, 1, autosomal recessiveAD/AR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Renal

Intervention: Audiologic/Otolaryngologic; Hematologic; Oncologic

Rationale: Erythroleukemia can involve hematologic anomalies and predisposition to certain forms of cancer, and awareness may allow prompt diagnosis and management; Visceral neuropathy can involve hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Individuals with Lethal congenital contracture syndrome 2 can have manifestations including cardiovascular anomalies (eg,cardiomyopathy and ventricular septal defects have been described) and hydronephrosis without urinary bladder abnormality

Refs: 3471269; 6948132; 12548738; 17701904; 27416908; 3035426; 33497358

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERBB3 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 83

not specifiedTotal: 61

ERBB3-related disorderTotal: 23

Visceral neuropathy, familial, 1, autosomal recessiveTotal: 16

Lethal congenital contracture syndrome 2Total: 14

Erythroleukemia, familial, susceptibility toTotal: 6

Malignant tumor of urinary bladderTotal: 4

Lethal congenital contracture syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001982.4. 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			1 clinvar	24 clinvar	2 clinvar	27
missense	4 clinvar	4 clinvar	103 clinvar	12 clinvar	4 clinvar	127
nonsense		3 clinvar	2 clinvar			5
start loss						0
frameshift	2 clinvar	3 clinvar				5
splice donor/acceptor (+/-2bp)		6 clinvar	4 clinvar	1 clinvar		11
Total	6	16	110	37	6	175

Highest pathogenic variant AF is 0.0000819607

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001982.4	RefSeq	NP_001973.2	28	MANE Select
ENST00000267101.8	Ensembl	ENSP00000267101.4	28	MANE Select
NM_001005915.1	RefSeq	NP_001005915.1	3	Standard
ENST00000411731.6	Ensembl	ENSP00000415753.2	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
erbb3b	Danio rerio	Structure: xanthophore Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

erbb3b

Danio rerio

Structure: xanthophore

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ErbB signaling pathway - Homo sapiens (human)
Calcium signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Proteoglycans in cancer - Homo sapiens (human)

Biological Process

MAPK cascade
endocardial cushion development
negative regulation of cell adhesion
signal transduction
transmembrane receptor protein tyrosine kinase signaling pathway

Molecular Function

protein tyrosine kinase activity
transmembrane receptor protein tyrosine kinase activity
transmembrane signaling receptor activity
Ras guanyl-nucleotide exchange factor activity
protein binding

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane
basal plasma membrane
basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000267101
Coding exons: 28
Length: 23649
Individuals with no LoFs: 125628
Homozygous LoFs: 0
Heterozygous LoFs: 120
Defined: 125748
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.39	633	739	0.856	0.0000449	8755
Missense (PolyPhen)		206	284.2	0.72484		3578
Synonymous	-0.608	291	278	1.05	0.0000154	2693
Loss of Function	3.71	36	69.4	0.519	0.00000454	791

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00075	0.00075	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00061	0.00054	rare
South Asian	0.00052	0.00052	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins. Binds to neuregulin-1 (NRG1) and is activated by it; ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase (PubMed:20682778). May also be activated by CSPG5 (PubMed:15358134). {ECO:0000269|PubMed:15358134, ECO:0000269|PubMed:20682778}.;
Disease: DISEASE: Lethal congenital contracture syndrome 2 (LCCS2) [MIM:607598]: A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non-progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS2 patients manifest craniofacial/ocular findings, lack of hydrops, multiple pterygia, and fractures, as well as a normal duration of pregnancy and a unique feature of a markedly distended urinary bladder (neurogenic bladder defect). The phenotype suggests a spinal cord neuropathic etiology. {ECO:0000269|PubMed:17701904}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.531

Intolerance Scores

LoFtool: 0.310
RVIS EVS: -0.66
RVIS percentile EVS: 16.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.981

Gene Damage Prediction

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