RET

Chr 10AD

ret proto-oncogene

Also known as: CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1, PTC, RET-ELE1

NCBI Gene: 5979 ENSG00000165731 UniProt: P07949

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]

Primary Disease Associations & Inheritance

{Hirschsprung disease, protection against}MIM #142623

{Hirschsprung disease, susceptibility to, 1}MIM #142623

Medullary thyroid carcinomaMIM #155240

Multiple endocrine neoplasia IIAMIM #171400

Multiple endocrine neoplasia IIBMIM #162300

PheochromocytomaMIM #171300

UniProtMultiple neoplasia 2B

UniProtMultiple neoplasia 2A

592

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— RET

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Gene-Disease Validity (ClinGen)

multiple endocrine neoplasia type 2B · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

22 Pathogenic / Likely Pathogenic· 316 VUS of 592 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.12LOEUF

pLI 1.000

Z-score 6.37

OE 0.04 (0.01–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.96Z-score

OE missense 0.90 (0.84–0.96)

594 obs / 663.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.12)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.84–0.96)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01

0≤1.21.6

LoF obs/exp: 2 / 51.2Missense obs/exp: 594 / 663.2Syn Z: -0.09

ClinVar Variant Classifications

592 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic11

VUS316

Likely Benign218

Benign32

Conflicting4

Pathogenic

Likely Pathogenic

316

VUS

218

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	0	4	0	11
Likely Pathogenic	3	5	3	0	11
VUS	7	276	28	5	316
Likely Benign	0	13	86	119	218
Benign	0	0	2	30	32
Conflicting	—				4
Total	17	294	123	154	592

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RET · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RET-related multiple endocrine neoplasia IIA

definitive

ADGain Of FunctionAltered Gene Product Structure

SkinCancer

G2P ↗

missense variantinframe deletioninframe insertion

RET-related multiple endocrine neoplasia IIB

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinCancer

G2P ↗

missense variantinframe deletioninframe insertion

RET-related renal agenesis

limited

ARLoss Of FunctionAbsent Gene Product

Skin

G2P ↗

RET-related pheochromocytoma

definitive

ADGain Of FunctionAltered Gene Product Structure

Skin

G2P ↗

RET-related medullary thyroid carcinoma

definitive

ADUndeterminedUncertain

SkinCancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

RET PROTOONCOGENE; RET

MIM #164761 · *

{Hirschsprung disease, protection against}

MIM #142623