ERBB3

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

Basic information

Region (hg38): 12:56076798-56103505

Previous symbols: [ "LCCS2" ]

Links

ENSG00000065361 ∙ NCBI:2065 ∙ OMIM:190151 ∙ HGNC:3431 ∙ Uniprot:P21860 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lethal congenital contracture syndrome 2 (Limited), mode of inheritance: AR
• lethal congenital contracture syndrome 2 (Limited), mode of inheritance: AR
• Hirschsprung disease (Supportive), mode of inheritance: AD
• lethal congenital contracture syndrome 2 (Supportive), mode of inheritance: AR
• lethal congenital contracture syndrome 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Erythroleukemia, familial, susceptibility to; Visceral neuropathy, familial, 1, autosomal recessive	AD/AR	Audiologic/Otolaryngologic; Hematologic; Oncologic	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	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Renal	3471269; 6948132; 12548738; 17701904; 27416908; 3035426; 33497358
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

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERBB3 gene.

• not provided (76 variants)
• Inborn genetic diseases (23 variants)
• Lethal congenital contracture syndrome 2 (10 variants)
• Visceral neuropathy, familial (4 variants)
• Visceral neuropathy, familial, 1, autosomal recessive (4 variants)
• ERBB3-related condition (3 variants)
• Erythroleukemia, familial, susceptibility to (1 variants)
• Lethal congenital contracture syndrome 1 (1 variants)
• not specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERBB3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				9	4	13
missense		2	39	6	3	50
nonsense		1	1			2
start loss						0
frameshift	1	1				2
inframe indel			1			1
splice donor/acceptor (+/-2bp)		3				3
splice region	1				3	4
non coding				10	24	34
Total	1	7	41	25	31

Highest pathogenic variant AF is 0.000315

Variants in ERBB3

This is a list of pathogenic ClinVar variants found in the ERBB3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-56079996-G-A			Benign (Oct 28, 2019)
12-56080024-T-C			Benign (Nov 11, 2018)
12-56080106-T-A			Benign (Jan 11, 2020)
12-56080108-A-T			Likely benign (Nov 11, 2018)
12-56080378-G-A			Benign (Jul 04, 2018)
12-56080595-T-C			Benign (Nov 11, 2018)
12-56083705-G-T			Benign (Nov 15, 2019)
12-56083757-C-T		ERBB3-related disorder	Benign/Likely benign (May 01, 2023)
12-56083789-G-A			Uncertain significance (May 23, 2019)
12-56083792-G-A		not specified	Uncertain significance (Jun 24, 2022)
12-56083848-G-A		Malignant tumor of urinary bladder	Pathogenic (-)
12-56083889-T-G			Uncertain significance (Sep 16, 2018)
12-56083899-G-A		ERBB3-related disorder	Likely benign (Jun 01, 2019)
12-56083910-A-T		Lethal congenital contracture syndrome 2 • Visceral neuropathy, familial	Benign (Jul 30, 2021)
12-56084218-A-C			Benign (Nov 11, 2018)
12-56084823-G-A			Benign (Oct 21, 2019)
12-56084830-A-G			Benign (Jan 11, 2020)
12-56084874-A-C			Benign (Sep 04, 2019)
12-56084898-A-G			Benign (Jan 11, 2020)
12-56085018-T-C			Likely benign (Mar 29, 2018)
12-56085050-T-C		not specified	Uncertain significance (May 04, 2022)
12-56085067-C-T		Malignant tumor of urinary bladder	Pathogenic (-)
12-56085070-G-A		Gastric adenocarcinoma • Uterine carcinosarcoma • Neoplasm of uterine cervix • Breast neoplasm • Neoplasm of the large intestine • Malignant neoplasm of body of uterus • Transitional cell carcinoma of the bladder • Gallbladder carcinoma • Malignant tumor of urinary bladder	Pathogenic/Likely pathogenic (May 31, 2016)
12-56085070-G-T		Transitional cell carcinoma of the bladder • Neoplasm of the large intestine • Breast neoplasm • Gallbladder carcinoma • Uterine carcinosarcoma • Gastric adenocarcinoma • Malignant neoplasm of body of uterus • Neoplasm of uterine cervix	Likely pathogenic (May 31, 2016)
12-56085154-C-T		not specified	Uncertain significance (Feb 17, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERBB3	protein_coding	protein_coding	ENST00000267101	28	23649

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.70e-15	1.00	125628	0	120	125748	0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.39	633	739	0.856	0.0000449	8755
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000998	0.000998
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000326	0.000326
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000611	0.000536
Middle Eastern	0.000326	0.000326
South Asian	0.000523	0.000523
Other	0.000489	0.000489

dbNSFP

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.
• Pathway: 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);MicroRNAs in cancer - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;EGF-Core;Heart Development;miR-targeted genes in muscle cell - TarBase;Signaling Pathways in Glioblastoma;Apoptosis-related network due to altered Notch3 in ovarian cancer;ErbB Signaling Pathway;SHC1 events in ERBB2 signaling;Signaling by PTK6;Disease;Signal Transduction;neuroregulin receptor degredation protein-1 controls erbb3 receptor recycling;role of erbb2 in signal transduction and oncology;ERBB2 Activates PTK6 Signaling;Oncostatin_M;Downregulation of ERBB2:ERBB3 signaling;Downregulation of ERBB2 signaling;EGFR1;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;PIP3 activates AKT signaling;Signaling by Non-Receptor Tyrosine Kinases;a6b1 and a6b4 Integrin signaling;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K events in ERBB2 signaling;GRB7 events in ERBB2 signaling;Signaling by ERBB2;ERBB2 Regulates Cell Motility;PI3K/AKT Signaling in Cancer;Signaling by ERBB4;IL6;TNFalpha;Signaling by Receptor Tyrosine Kinases;ErbB2/ErbB3 signaling events;Intracellular signaling by second messengers;Diseases of signal transduction;ErbB receptor signaling network (Consensus)

Recessive Scores

• pRec: 0.531

Intolerance Scores

• loftool: 0.310
• rvis_EVS: -0.66
• rvis_percentile_EVS: 16.12

Haploinsufficiency Scores

• pHI: 0.984
• hipred: Y
• hipred_score: 0.683
• ghis: 0.599

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.981

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Erbb3
• Phenotype: muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; neoplasm; pigmentation phenotype

Zebrafish Information Network

• Gene name: erbb3b
• Affected structure: xanthophore
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: MAPK cascade;endocardial cushion development;negative regulation of cell adhesion;signal transduction;transmembrane receptor protein tyrosine kinase signaling pathway;nervous system development;peripheral nervous system development;heart development;positive regulation of cell population proliferation;negative regulation of signal transduction;positive regulation of gene expression;Schwann cell differentiation;phosphatidylinositol 3-kinase signaling;positive regulation of phosphatidylinositol 3-kinase signaling;peptidyl-tyrosine phosphorylation;cranial nerve development;ERBB2 signaling pathway;wound healing;regulation of cell population proliferation;negative regulation of neuron apoptotic process;phosphatidylinositol phosphorylation;negative regulation of secretion;neuron apoptotic process;positive regulation of protein kinase B signaling;positive regulation of cardiac muscle tissue development;positive regulation of protein tyrosine kinase activity;positive regulation of calcineurin-NFAT signaling cascade;extrinsic apoptotic signaling pathway in absence of ligand;regulation of cell motility
• Cellular component: extracellular space;plasma membrane;integral component of plasma membrane;basal plasma membrane;basolateral plasma membrane;apical plasma membrane;lateral plasma membrane;receptor complex
• Molecular function: protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;transmembrane signaling receptor activity;Ras guanyl-nucleotide exchange factor activity;protein binding;ATP binding;growth factor binding;protein tyrosine kinase activator activity;ubiquitin protein ligase binding;neuregulin receptor activity;neuregulin binding;identical protein binding;protein homodimerization activity;phosphatidylinositol-4,5-bisphosphate 3-kinase activity;protein heterodimerization activity