GRB10

Chr 7

growth factor receptor bound protein 10

Also known as: GRB-IR, Grb-10, IRBP, MEG1, RSS

NCBI Gene: 2887 ENSG00000106070 UniProt: Q13322 OMIM: 601523

The GRB10 protein is an adapter protein that negatively regulates insulin and insulin-like growth factor receptor signaling by blocking downstream pathways and promoting receptor degradation. Mutations cause Silver-Russell syndrome, characterized by severe intrauterine and postnatal growth restriction, relative macrocephaly, and feeding difficulties typically apparent from birth. This gene shows parent-of-origin effects with brain-specific paternal expression and is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner, with expression observed from the paternal allele in the brain, and from the maternal allele in the placental trophoblasts. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.34

Clinical Summary— GRB10

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

60 VUS of 107 total submissions

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GeneReview available — GRB10

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.939

Z-score 4.57

OE 0.17 (0.09–0.34)

Highly constrained

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

Missense Constraint?

1.53Z-score

OE missense 0.76 (0.69–0.85)

255 obs / 333.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.09–0.34)

0≤0.351.4

Missense OE?0.76 (0.69–0.85)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 6 / 35.3Missense obs/exp: 255 / 333.8Syn Z: 0.06

This gene — mechanism propensity

0.4586th %ile

GOF

0.5366th %ile

LOF

0.65top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.34

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

ClinVar Variant Classifications

107 submitted variants in ClinVar

ClinVar

Classification Summary

VUS60

Likely Benign15

Benign9

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	46	14	0	60
Likely Benign	4	4	7	15
Benign	4	2	3	9
Total	54	20	10	84

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap GRB10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →