RIT1

Chr 1AD

Ras like without CAAX 1

Also known as: NS8, RIBB, RIT, ROC1

NCBI Gene: 6016 ENSG00000143622 OMIM: 609591

The protein functions as a Ras-related GTPase that regulates p38 MAPK signaling cascades, promotes neuronal development and regeneration with nerve growth factor, and controls T-lymphocyte differentiation and survival during thymocyte development. Mutations cause Noonan syndrome 8, a multisystem disorder typically presenting in infancy with characteristic facial features, short stature, and cardiac abnormalities. Inheritance is autosomal dominant.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.651 OMIM phenotype

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

Clinical Summary— RIT1

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Gene-Disease Validity (ClinGen)

Noonan syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.133

Z-score 2.51

OE 0.28 (0.14–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.08Z-score

OE missense 0.52 (0.43–0.63)

75 obs / 145.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.28 (0.14–0.65)

0≤0.351.4

Missense OE?0.52 (0.43–0.63)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 4 / 14.2Missense obs/exp: 75 / 145.4Syn Z: 0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRIT1-related Noonan syndromeGOFAD

This gene — mechanism propensity

0.81top 10%

GOF

0.72top 25%

LOF

0.3261th %ile

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

GOFprediction above median · 1 literature citation

DNprediction above median

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

GOFGain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References