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GeneBe

RET

ret proto-oncogene, the group of Cadherin related|Receptor tyrosine kinases

Basic information

Region (hg38): 10:43077063-43130351

Previous symbols: [ "HSCR1", "MEN2A", "MTC1", "MEN2B" ]

Links

ENSG00000165731 ∙ NCBI:5979 ∙ OMIM:164761 ∙ HGNC:9967 ∙ Uniprot:P07949 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • Hirschsprung disease (Supportive), mode of inheritance: AD
  • bilateral renal agenesis (Supportive), mode of inheritance: AR
  • renal agenesis, unilateral (Supportive), mode of inheritance: AD
  • familial medullary thyroid carcinoma (Supportive), mode of inheritance: AD
  • Haddad syndrome (Supportive), mode of inheritance: AD
  • multiple endocrine neoplasia type 2A (Supportive), mode of inheritance: AD
  • multiple endocrine neoplasia type 2B (Supportive), mode of inheritance: AD
  • multiple endocrine neoplasia type 2B (Definitive), mode of inheritance: AD
  • multiple endocrine neoplasia type 2A (Definitive), mode of inheritance: AD
  • renal hypodysplasia/aplasia 1 (Limited), mode of inheritance: AR
  • Hirschsprung disease, susceptibility to, 1 (Strong), mode of inheritance: AD
  • multiple endocrine neoplasia type 2B (Strong), mode of inheritance: AD
  • multiple endocrine neoplasia type 2B (Definitive), mode of inheritance: AD
  • multiple endocrine neoplasia type 2A (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Central hypoventilation syndrome, congenital; Multiple endocrine neoplasia, type IIA; Multiple endocrine neoplasia, type IIB; Medullary thyroid carcinoma, familial; Pheochromocytoma; Hirschsprung disease, susceptibility to 1AD/AREndocrine; Gastrointestinal; Neurologic; OncologicSurveillance/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 mortalityEndocrine; Gastrointestinal; Neurologic; Oncologic; Renal5844561; 4957444; 6047980; 5637238; 4968712; 4386574; 4695886; 1110583; 980061; 1063979; 554522; 3697657; 2904651; 2563193; 8103403; 8094268; 8099202; 7906417; 7977365; 7914213; 7815416; 7911697; 7906866; 7907913; 8114938; 7915165; 7633441; 7581377; 7784092; 7845675; 8825918; 8826440; 8852653; 8757765; 9111992; 9097963; 8981969; 9090527; 9497256; 9506724; 9384613; 9621513; 9824583; 9760196; 10090908; 10528857; 10521317; 10323403; 10458491; 10522989; 10922382; 11103773; 10777380; 10982477; 11739416; 11436122; 11753660; 11238493; 11502806; 11232007; 12116277; 11953745; 12355085; 12214285; 12086152; 11815959; 11932300; 11788682; 12000816; 12466368; 14561794; 14602786; 14600022; 12788868; 15138456; 15240649; 15759212; 16091499; 15829955; 15805159; 15870131; 15741265; 15827097; 16162881; 16205644; 16443855; 17108762; 17167516; 17895320; 16986122; 17898100; 18252215; 18273880; 19469690; 19856714; 20301434; 20598273; 22715565; 23114404
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

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

  • Multiple endocrine neoplasia, type 2 (2429 variants)
  • Hereditary cancer-predisposing syndrome (1726 variants)
  • not provided (478 variants)
  • Hirschsprung disease, susceptibility to, 1 (277 variants)
  • Multiple endocrine neoplasia, type 2a (232 variants)
  • not specified (188 variants)
  • Pheochromocytoma (166 variants)
  • Multiple endocrine neoplasia (155 variants)
  • Renal hypodysplasia/aplasia 1 (154 variants)
  • Multiple endocrine neoplasia, type 2b (122 variants)
  • RET-related condition (41 variants)
  • Familial medullary thyroid carcinoma (35 variants)
  • Hirschsprung Disease, Dominant (27 variants)
  • Aganglionic megacolon (22 variants)
  • Medullary thyroid carcinoma (21 variants)
  • Ovarian cancer (14 variants)
  • Multiple endocrine neoplasia type 4 (14 variants)
  • Multiple endocrine neoplasia, type 1 (14 variants)
  • Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma (13 variants)
  • Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1 (12 variants)
  • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a (11 variants)
  • 6 conditions (11 variants)
  • Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b (8 variants)
  • Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Familial medullary thyroid carcinoma (7 variants)
  • Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma (7 variants)
  • Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Pheochromocytoma (7 variants)
  • Pheochromocytoma;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b (6 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Pheochromocytoma (6 variants)
  • Hereditary cancer (6 variants)
  • Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1 (6 variants)
  • Appendicitis (5 variants)
  • MEN2 phenotype: Unclassified (5 variants)
  • Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Pheochromocytoma (5 variants)
  • Pheochromocytoma;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a (5 variants)
  • Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a (5 variants)
  • Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma (4 variants)
  • Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b (4 variants)
  • Inborn genetic diseases (4 variants)
  • Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a;Pheochromocytoma (4 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2b (3 variants)
  • Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a (3 variants)
  • Malignant tumor of breast (3 variants)
  • Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a (3 variants)
  • Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma (3 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a (3 variants)
  • Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1 (3 variants)
  • Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma (3 variants)
  • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma (3 variants)
  • Congenital anomaly of kidney and urinary tract (3 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2a (2 variants)
  • RET-related disease (2 variants)
  • Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b (2 variants)
  • Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b (2 variants)
  • Thyroid tumor (2 variants)
  • Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma (2 variants)
  • MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE (2 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1 (2 variants)
  • Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma (2 variants)
  • Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a (2 variants)
  • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a (2 variants)
  • Congenital central hypoventilation (2 variants)
  • RET-related disorders (2 variants)
  • Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Familial medullary thyroid carcinoma (2 variants)
  • Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Pheochromocytoma (2 variants)
  • Neoplasm (2 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b (2 variants)
  • Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b (2 variants)
  • Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a (2 variants)
  • 7 conditions (1 variants)
  • Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1 variants)
  • Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b (1 variants)
  • Familial cancer of breast (1 variants)
  • Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b (1 variants)
  • Microcephaly (1 variants)
  • See cases (1 variants)
  • Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b (1 variants)
  • Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Multiple endocrine neoplasia, type 2a (1 variants)
  • - (1 variants)
  • Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Medulloblastoma (1 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a (1 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma (1 variants)
  • Elevated basal serum calcitonin (1 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma (1 variants)
  • Breast carcinoma;Family history of cancer (1 variants)
  • Hirschsprung disease, protection against (1 variants)
  • Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Multiple endocrine neoplasia, type 2a (1 variants)
  • 8 conditions (1 variants)
  • Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma (1 variants)
  • Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma (1 variants)
  • Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Familial medullary thyroid carcinoma (1 variants)
  • Pheochromocytoma;Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b (1 variants)
  • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Pheochromocytoma (1 variants)
  • Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a (1 variants)
  • Multiple endocrine neoplasia II;Medullary thyroid carcinoma (1 variants)
  • Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Pheochromocytoma;Multiple endocrine neoplasia, type 2a (1 variants)
  • Familial medullary thyroid carcinoma;Pheochromocytoma (1 variants)
  • Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Multiple endocrine neoplasia, type 2;Familial medullary thyroid carcinoma (1 variants)
  • Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Thyroid carcinoma, sporadic medullary (1 variants)
  • Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Pheochromocytoma (1 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b (1 variants)
  • Ependymoma (1 variants)
  • Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Pheochromocytoma (1 variants)
  • Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma (1 variants)
  • Hirschsprung disease, susceptibility to, 1;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Pheochromocytoma (1 variants)
  • Thyroid gland carcinoma (1 variants)
  • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Pheochromocytoma;Familial medullary thyroid carcinoma (1 variants)
  • Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Pheochromocytoma;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Renal hypoplasia/aplasia (1 variants)
  • Megacolon;Abnormal facial shape (1 variants)
  • Breast-ovarian cancer, familial, susceptibility to, 1 (1 variants)
  • Multiple endocrine neoplasia, type 2;Aganglionic megacolon (1 variants)
  • Hepatocellular carcinoma (1 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma (1 variants)
  • Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Sensorineural hearing loss disorder;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Multiple endocrine neoplasia, type 2b (1 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b (1 variants)
  • Multiple endocrine neoplasia;Familial medullary thyroid carcinoma (1 variants)
  • Aganglionic megacolon;Multiple endocrine neoplasia, type 2 (1 variants)
  • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Familial medullary thyroid carcinoma;Pheochromocytoma (1 variants)
  • Multiple endocrine neoplasia, type 2b;Multiple endocrine neoplasia, type 2a;Pheochromocytoma;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1 (1 variants)
  • Pilocytic astrocytoma (1 variants)
  • Multiple endocrine neoplasia, type 2b;Familial medullary thyroid carcinoma;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Multiple endocrine neoplasia, type 2a (1 variants)
  • Ewing sarcoma of soft tissue (1 variants)
  • Multiple endocrine neoplasia, type 2a;Hirschsprung disease, susceptibility to, 1;Pheochromocytoma;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b (1 variants)
  • Familial medullary thyroid carcinoma;Multiple endocrine neoplasia, type 2b;Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia, type 2a;Pheochromocytoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RET 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
1
clinvar
23
clinvar
771
clinvar
4
clinvar
 799
missense
43
clinvar
23
clinvar
1387
clinvar
27
clinvar
 1480
nonsense
19
clinvar
4
clinvar
4
clinvar
 27
start loss
0
frameshift
18
clinvar
2
clinvar
4
clinvar
1
clinvar
 25
inframe indel
1
clinvar
3
clinvar
32
clinvar
2
clinvar
 38
splice donor/acceptor (+/-2bp)
1
clinvar
10
clinvar
2
clinvar
 13
splice region
?
    Intron variants in splice region, excluding donor/acceptor (+/-2bp)
57
92
2
 151
non coding
?
    UTR, intron and other, non coding variants
63
clinvar
300
clinvar
67
clinvar
 430
Total 82 43 1515 1101 71

Highest pathogenic variant AF is 0.0000132

Variants in RET

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

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

Position Type Phenotype Significance ClinVar
10-43077072-C-A Multiple endocrine neoplasia • Hirschsprung Disease, Dominant • Renal hypodysplasia/aplasia 1 • Pheochromocytoma Uncertain significance (Jun 14, 2016)299883
10-43077086-A-G Hirschsprung disease, susceptibility to, 1 • Renal hypodysplasia/aplasia 1 • Multiple endocrine neoplasia • Pheochromocytoma Uncertain significance (Jan 13, 2018)877684
10-43077099-G-T Renal hypodysplasia/aplasia 1 • Hirschsprung disease, susceptibility to, 1 • Pheochromocytoma • Multiple endocrine neoplasia Benign/Likely benign (Jan 01, 2023)877685
10-43077101-G-A Pheochromocytoma • Hirschsprung disease, susceptibility to, 1 • Multiple endocrine neoplasia • Renal hypodysplasia/aplasia 1 Uncertain significance (Jan 12, 2018)299884
10-43077127-G-T Multiple endocrine neoplasia • Pheochromocytoma • Renal hypodysplasia/aplasia 1 • Hirschsprung disease, susceptibility to, 1 • Hereditary cancer-predisposing syndrome Conflicting classifications of pathogenicity (Jun 01, 2021)299885
10-43077191-C-T Benign (Mar 03, 2015)1225708
10-43077208-C-T Multiple endocrine neoplasia • Renal hypodysplasia/aplasia 1 • Pheochromocytoma • Hirschsprung disease, susceptibility to, 1 Uncertain significance (Jan 12, 2018)878710
10-43077222-G-C Multiple endocrine neoplasia, type 2 Conflicting classifications of pathogenicity (Feb 19, 2022)477374
10-43077236-C-T RET-related disorder Likely benign (Oct 06, 2020)3054907
10-43077251-CACGG-C Hereditary cancer-predisposing syndrome Uncertain significance (Jul 26, 2022)1756637
10-43077253-C-T Uncertain significance (May 13, 2021)1321691
10-43077254-G-C Hereditary cancer-predisposing syndrome Uncertain significance (Sep 02, 2020)1751015
10-43077255-G-A Hereditary cancer-predisposing syndrome Uncertain significance (Jun 30, 2022)825359
10-43077255-G-T Multiple endocrine neoplasia, type 2 Uncertain significance (Dec 13, 2023)3074853
10-43077254-G-GGGCGAT Hereditary cancer-predisposing syndrome • Multiple endocrine neoplasia, type 2 Conflicting classifications of pathogenicity (Jul 22, 2023)2447524
10-43077256-G-A Hereditary cancer-predisposing syndrome • Multiple endocrine neoplasia, type 2 Uncertain significance (Dec 13, 2023)1736907
10-43077257-C-A not specified • Hereditary cancer-predisposing syndrome • Hirschsprung disease, susceptibility to, 1;Multiple endocrine neoplasia type 2B;Pheochromocytoma;Multiple endocrine neoplasia type 2A;Familial medullary thyroid carcinoma • RET-related disorder Conflicting classifications of pathogenicity (Sep 18, 2023)229201
10-43077258-G-A Hereditary cancer-predisposing syndrome Uncertain significance (Jan 17, 2020)1784210
10-43077260-T-TGGCGAAGGCGACGTCCGGTGCCGC Multiple endocrine neoplasia, type 2 • Hereditary cancer-predisposing syndrome • not specified Uncertain significance (Sep 13, 2023)1020843
10-43077263-C-A Multiple endocrine neoplasia, type 2 Uncertain significance (Dec 29, 2022)2914324
10-43077264-G-A Multiple endocrine neoplasia, type 2 • Hereditary cancer-predisposing syndrome Likely benign (Aug 30, 2022)767548
10-43077264-G-T Multiple endocrine neoplasia, type 2 Likely benign (May 27, 2023)2733287
10-43077265-A-G Hereditary cancer-predisposing syndrome • Multiple endocrine neoplasia, type 2 Uncertain significance (Dec 16, 2023)584566
10-43077268-G-A Multiple endocrine neoplasia, type 2 • Hereditary cancer-predisposing syndrome Uncertain significance (Jan 16, 2024)1023866
10-43077269-C-T Multiple endocrine neoplasia, type 2 Uncertain significance (Jun 06, 2022)860225

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
RETprotein_codingprotein_codingENST00000355710 2053325
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
1.002.34e-7125741071257480.0000278
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense0.9555946630.8960.00004497152
Missense in Polyphen149223.850.665622583
Synonymous-0.09462982961.010.00002142289
Loss of Function6.37251.20.03910.00000268578

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.00004620.0000462
European (Non-Finnish)0.00004400.0000439
Middle Eastern0.000.00
South Asian0.00003270.0000327
Other0.000.00

dbNSFP

Source: dbNSFP

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.;
Pathway
Central carbon metabolism in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Pathway_PA165959425;Sorafenib Pharmacodynamics;Aryl Hydrocarbon Receptor;Dopaminergic Neurogenesis;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Developmental Biology;Signal Transduction;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Posttranslational regulation of adherens junction stability and dissassembly;Signaling events regulated by Ret tyrosine kinase;RET signaling;Axon guidance (Consensus)

Recessive Scores

pRec
0.681

Intolerance Scores

loftool
0.00324
rvis_EVS
-1.61
rvis_percentile_EVS
3

Haploinsufficiency Scores

pHI
0.903
hipred
Y
hipred_score
0.806
ghis
0.490

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.922

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Ret
Phenotype
growth/size/body region phenotype; endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; renal/urinary system phenotype; embryo phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system 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); normal phenotype; neoplasm; 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); limbs/digits/tail phenotype; digestive/alimentary phenotype;

Zebrafish Information Network

Gene name
ret
Affected structure
enteric neuron
Phenotype tag
abnormal
Phenotype quality
decreased amount

Gene ontology

Biological process
MAPK cascade;activation of MAPK activity;ureteric bud development;neural crest cell migration;embryonic epithelial tube formation;protein phosphorylation;homophilic cell adhesion via plasma membrane adhesion molecules;neuron cell-cell adhesion;signal transduction;transmembrane receptor protein tyrosine kinase signaling pathway;nervous system development;axon guidance;posterior midgut development;positive regulation of neuron projection development;positive regulation of neuron maturation;peptidyl-tyrosine phosphorylation;neurogenesis;cell differentiation;regulation of cell adhesion;positive regulation of cell migration;positive regulation of peptidyl-serine phosphorylation of STAT protein;membrane protein proteolysis;positive regulation of cell adhesion mediated by integrin;ureter maturation;glial cell-derived neurotrophic factor receptor signaling pathway;response to drug;neuron maturation;positive regulation of MAPK cascade;positive regulation of cell size;positive regulation of transcription, DNA-templated;response to pain;enteric nervous system development;regulation of axonogenesis;positive regulation of protein kinase B signaling;retina development in camera-type eye;innervation;Peyer's patch morphogenesis;cellular response to retinoic acid;positive regulation of metanephric glomerulus development;lymphocyte migration into lymphoid organs;positive regulation of extrinsic apoptotic signaling pathway in absence of ligand
Cellular component
early endosome;cytosol;plasma membrane;integral component of plasma membrane;endosome membrane;axon;dendrite;neuronal cell body;intracellular membrane-bounded organelle;receptor complex;membrane raft;plasma membrane protein complex
Molecular function
protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;calcium ion binding;protein binding;ATP binding;signaling receptor activity