IGF1R

Chr 15ADAR

insulin like growth factor 1 receptor

Also known as: CD221, IGFIR, IGFR, JTK13

NCBI Gene: 3480 ENSG00000140443 UniProt: P08069 OMIM: 147370

The IGF1R protein is a receptor tyrosine kinase that binds insulin-like growth factor 1 and mediates critical cell growth and survival signaling pathways including PI3K-AKT and Ras-MAPK. Mutations cause insulin-like growth factor 1 resistance, which can be inherited in either autosomal dominant or autosomal recessive patterns. The gene is highly constrained against loss-of-function variants (pLI 0.97), indicating that complete loss of function is typically not tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismAD/ARLOEUF 0.311 OMIM phenotype

Clinical Summary— IGF1R

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

53 unique Pathogenic / Likely Pathogenic· 275 VUS of 500 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.31LOEUF

pLI 0.968

Z-score 5.99

OE 0.19 (0.12–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.73Z-score

OE missense 0.73 (0.69–0.78)

609 obs / 830.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.19 (0.12–0.31)

0≤0.351.4

Missense OE0.73 (0.69–0.78)

0≤0.61.4

Synonymous OE1.14

0≤1.21.6

LoF obs/exp: 12 / 63.6Missense obs/exp: 609 / 830.3Syn Z: -2.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveIGF1R-related insulin-like growth factor I, resistance toLOFAD

definitiveIGF1R-related insulin-like growth factor I, resistance toLOFAR

0.5673th %ile

GOF

0.75top 25%

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 51% of P/LP variants are LoF · LOEUF 0.31

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNHuman insulin-like growth factor I receptor function in pituitary cells is suppressed by a dominant negative mutantPMID:1430235

LOFWhile short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.PMID:23486542

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.