RET
protein-codingret proto-oncogene, the group of Cadherin related|Receptor tyrosine kinases
Gene summary
This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
- HSCR1
- MEN2A
- MTC1
- MEN2B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~53.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007723
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0015986
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020493
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008234
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008082
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007958
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019636
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018309
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008082
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008082
Submitter: ClinGen
The gene RET was first reported in relation to autosomal dominant multiple endocrine neoplasia type 2B (MEN2B) characterized by very early onset medullary thyroid cancer, pheochromocytoma, parathyroid tumors and dysmorphic features first reported in in 1994 (Hofstra et al, 1994 PMID:7906866; Carlson et al. 1994 PMID:7977365). Earlier evidence suggested that the disease MEN2B mapped to chromosome 10 (where the RET gene is located) as early as 1990 (Norum et al., 1990 PMID:1979053). One variant, p.Met918Thr, is responsible for nearly all cases of MEN2B, and it is estimated that around 50% of the reported cases of MEN2B are de novo (Carlson et al. 1994 PMID:7977365; Plaza-Menaho et al., 2006; PMID: 16979782). Another RET variant (p. Ala883Phe) has been asserted to be responsible for the development of ~5% of MEN2B (Smith et al., 1997 PMID:9294615). The molecular mechanism for the gene RET in the disease entity MEN2B is gain of function. While similar to RET-MEN2A (described in a separate curation), in that the mechanism is GOF, the mechanism(s) responsible for the two disease entities are distinct. In MEN2B the p.Met918Thr variation occurs in exon 16 of RET in the tyrosine kinase domain which causes autophosphorylation and activation of RET. There is a significant amount of case-level data with the maximum points for genetic evidence reached (12 points). This gene-disease relationship is supported by functional studies including expression, cell assays and animal models, several that were patient derived pathogenic variants expressed in the mouse (reviewed in Wiedmann et al, 2016 PMID: 26184857). These animal models developed carcinomas consistent with the disease multiple endocrine neoplasia type 2B. The RET gene is asserted to be associated with multiple disease entities by germline inheritance , including: (1) Central hypoventilation syndrome, congenital (MIM:209880), (2) Medullary thyroid carcinoma (MIM:155240), (3) Multiple endocrine neoplasia IIA/2A (MIM:171400), (4)Pheochromocytoma (MIM:171300). These disease entities all follow an inheritance pattern of autosomal dominant. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we did find a difference in the molecular mechanism (defined above) and phenotypic expressivity between the disease entities MEN2A (MIM:171400) and MEN2B (162300), and therefore have split these curations. Therefore, the curation for RET-MEN2A can be found separately. In summary, RET is DEFINITIVELY associated with autosomal dominant multiple endocrine neoplasia type 2B. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0018470
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008233
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008082
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008234
Submitter: ClinGen
The gene RET is associated with the autosomal dominant disorder multiple endocrine neoplasia type 2A characterized by medullary thyroid cancer, pheochromocytoma and parathyroid tumors first reported in 1993 (Mulligan et al, 1993; PMID: 8099202). Early evidence began to show linkage of multiple endocrine neoplasia type 2 (not discerning between type A vs. type B) as early as 1992 (Narod et al., 1992; PMID: 2572534). Numerous variants have been reported in RET in relation to multiple endocrine neoplasia type A , the majority being missense mutation in conserved cysteine (p. Cys or p.C) amino acid residues within the dimerization and activation domain, including p.C609, p.C611, p.C618, p. C620, p. C630, p.C634 (reviewed Plaza-Menaho et al., 2006; PMID: 16979782). The molecular mechanism for the RET-multiple endocrine neoplasia type 2A is gain of function (GOF), as the missense mutations result in ligand-independent dimerization that induces activation of the RET protein that is a receptor tyrosine kinase (Plaza-Menaho et al., 2006; PMID: 16979782; Drilon et al., 2017, PMID 29134959). There are variant databases specific to the RET gene including the Multiple Endocrine Neoplasia type 2 (MEN2) and RET database (http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php) and the RET gene LOVD database (https://databases.lovd.nl/shared/genes/RET). Substantial evidence supports this gene-disease relationship includes case-level data, segregation and experimental data with the maximum score (12) for genetic evidence reached. This gene-disease relationship is supported by functional studies including expression, cell assays and animal models, several that were patient derived pathogenic variants expressed in the mouse (reviewed in Wiedmann et al, 2016; PMID: 26184857). These animal models developed MEN2A related tumors including medullary thyroid carcinomas. The RET gene is asserted to be associated with multiple disease entities by germline inheritance, including: (1) Central hypoventilation syndrome, congenital (MIM:209880), (2) Medullary thyroid carcinoma (MIM:155240), (3) Multiple endocrine neoplasia IIB (MIM:162300), (4) Pheochromocytoma (MIM:171300). These disease entities all follow an autosomal dominant inheritance pattern. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found no difference in molecular mechanisms, inheritance pattern, or phenotypic expressivity between Medullary thyroid carcinoma (MIM:155240), Pheochromocytoma (MIM:171300), and multiple endocrine neoplasia type 2A (MIM:171400), and therefore have lumped the above listed disease entities into the curation for RET in Multiple Endocrine neoplasia type 2A. Of note, Multiple endocrine neoplasia IIB (MIM:162300) follows a different GOF mechanism and has variants specific to this disease entity and has been curated separately. Due to variants asserted in Medullary thyroid carcinoma (MIM:155240), Pheochromocytoma (MIM:171300) with both multiple endocrine neoplasia type 2A and type 2B, the evidence for each of these was lumped into the appropriate gene-disease relationship based on the variant asserted for the evidence. Furthermore, Central hypoventilation syndrome, congenital (MIM:209880) has distinct variants associated with it and also has a separate curation. However, it should be noted that CCHS can be a phenotypic feature observed in individuals with multiple endocrine neoplasia, so care was taken in the curation and assessing evidence based on the variant of interest asserted. In addition, the Hirsphrung disease which is associated with LOF in RET is not included in this curation. In summary, RET is DEFINITIVELY associated with autosomal dominant multiple endocrine neoplasia type 2A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008234
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007958
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Gastrointestinal; Neurologic; Oncologic; Renal
Intervention: Endocrine; Gastrointestinal; Neurologic; Oncologic
Rationale: Surveillance/early diagnosis for and treatment of associated neoplasms (eg, including thyroidectomy at an early age, and diagnosis and treatment of sequelae of pheochromocytoma) may reduce morbidity and mortality; Due to risk of Hirschsprung disease, awareness of disease risk may allow prompt diagnosis and treatment, decreasing potential morbidity and mortality; In Central Hypoventilation, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality
Comments: In Central hypoventilation syndrome the data are mixed related to causality (eg, one reported patient was later found to have a variant in a gene with more evidence for involvement in the condition)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RET variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020975.6. 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 | 1 | 20 | 1087 | 38 | 1147 |
| missense | 45 | 50 | 1979 | 191 | 6 | 2271 |
| nonsense | 26 | 6 | 6 | 38 | ||
| start loss | 1 | 1 | ||||
| frameshift | 32 | 7 | 10 | 49 | ||
| splice donor/acceptor (+/-2bp) | 1 | 13 | 10 | 1 | 25 | |
| Total | 105 | 78 | 2025 | 1278 | 45 | 3531 |
Highest pathogenic variant AF is 0.00012208005
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_066124.1 | 20 | MANE Select | |
| Ensembl | ENSP00000347942.3 | 20 | MANE Select | |
| RefSeq | NP_001342145.1 | 16 | Standard | |
| RefSeq | NP_001393672.1 | 20 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ret | Danio rerio | Structure: enteric neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Central carbon metabolism in cancer - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Thyroid cancer - Homo sapiens (human)
- Pathway_PA165959425
- Sorafenib Pharmacodynamics
Biological Process
- MAPK cascade
- activation of MAPK activity
- ureteric bud development
- neural crest cell migration
- embryonic epithelial tube formation
Molecular Function
- protein tyrosine kinase activity
- transmembrane receptor protein tyrosine kinase activity
- Ras guanyl-nucleotide exchange factor activity
- calcium ion binding
- protein binding
Cellular Component
- early endosome
- cytosol
- plasma membrane
- integral component of plasma membrane
- endosome membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000355710
- Coding exons
- 20
- Length
- 53325
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125748
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.955 | 594 | 663 | 0.896 | 0.0000449 | 7152 |
| Missense (PolyPhen) | 149 | 223.85 | 0.66562 | 2583 | ||
| Synonymous | -0.0946 | 298 | 296 | 1.01 | 0.0000214 | 2289 |
| Loss of Function | 6.37 | 2 | 51.2 | 0.0391 | 0.00000268 | 578 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut- associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell- signaling in the brainstem which induces inhibition of food- intake. Activates MAPK- and AKT-signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099). {ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.;
- Disease
- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Hirschsprung disease 1 (HSCR1) [MIM:142623]: 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:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|Ref.60}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple neoplasia 2B (MEN2B) [MIM:162300]: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. {ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866, ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615, ECO:0000269|PubMed:9360560}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315). {ECO:0000269|PubMed:10439047, ECO:0000269|PubMed:10980597, ECO:0000269|PubMed:12787916, ECO:0000269|PubMed:2406025, ECO:0000269|PubMed:2734021, ECO:0000269|PubMed:3037315}.; DISEASE: Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.; 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:12086152, ECO:0000269|PubMed:14566559, ECO:0000269|PubMed:9497256}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.681
Intolerance Scores
- LoFtool
- 0.00324
- RVIS EVS
- -1.61
- RVIS percentile EVS
- 3
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.922
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |