On this page
RIT1
Ras like without CAAX 1
RIT1 encodes a small GTPase that regulates cellular stress responses and RAS/MAPK pathway signalling, with variants causing Noonan syndrome and linked to certain blood cancers. The RIT1 gene provides instructions for making a protein that helps cells respond to metabolic stress by transmitting growth and survival signals.
RIT1 is located on the long (q) arm of chromosome 1, at band 1q22. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
RIT1 (Ras like without CAAX 1) is located on chromosome 1q22 and encodes a 219-amino-acid protein that functions as a small GTPase within the RAS/MAPK signalling pathway. This pathway controls fundamental cellular processes including proliferation, differentiation, and survival. The RIT1 protein becomes particularly important during periods of cellular stress, when energy demands are elevated and cells require additional survival signals.
As a member of the RAS oncogene family, RIT1 shares functional characteristics with better-known relatives such as KRAS, HRAS, and NRAS. Pathogenic variants in RIT1 predominantly cause Noonan syndrome, an autosomal dominant condition affecting multiple organ systems. Additionally, acquired mutations in this gene have been identified in several types of blood cancer, highlighting its dual role in development and oncogenesis.
What the gene does
The RIT1 protein operates as a molecular switch that relays signals from the cell surface to the nucleus, particularly when cells face metabolic or oxidative stress. Like other small GTPases, it alternates between active and inactive states by binding and converting guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When bound to GTP, the protein adopts an active conformation that transmits growth and survival signals; conversion to the GDP-bound form switches the protein off.
This cycling between active and inactive states allows RIT1 to serve as a tightly regulated node within the RAS/MAPK cascade. The pathway ultimately controls the expression of genes involved in cell division, maturation, and programmed cell death (apoptosis). During periods of heightened cellular demand, RIT1 activation helps coordinate appropriate responses to ensure cell survival. The protein's specific role in stress response distinguishes it somewhat from other RAS family members, which have broader functions in growth factor signalling.
Because RIT1 participates in pathways governing cell proliferation, alterations that disrupt its normal regulation can contribute to both developmental disorders and cancer. Pathogenic variants typically impair the protein's ability to switch off, resulting in constitutive signal transmission even when activation is not required.
Video: Genetics 101
Chromosome location
The RIT1 gene is located on the long arm of chromosome 1 at position 1q22. This chromosomal region contains numerous genes involved in developmental processes and signal transduction. The precise genomic coordinates and exon structure contribute to the gene's susceptibility to certain types of pathogenic variation, though detailed structural information about intron-exon boundaries has not been comprehensively catalogued in public databases for clinical reference.
Protein structure
The RIT1 protein comprises 219 amino acids and contains structural features characteristic of small GTPases, including regions that bind GTP/GDP and coordinate magnesium ions essential for nucleotide binding. Domain architecture analyses identify a disordered region spanning amino acids 193-219 at the C-terminus. Disordered regions lack fixed three-dimensional structure and often participate in protein-protein interactions or regulatory modifications that modulate enzyme activity. The functional significance of this disordered C-terminal region in RIT1 regulation remains an area of ongoing research, though such flexible domains in related GTPases frequently influence binding partner specificity and signal duration.
Key variants
Pathogenic variants in RIT1 that cause Noonan syndrome typically result in amino acid substitutions that impair the protein's GTPase activity, leading to prolonged signalling even in the absence of appropriate stimuli. At least 14 distinct mutations have been associated with this developmental disorder. Somatic mutations identified in blood cancers, including acute myeloid leukaemia, chronic myelomonocytic leukaemia, and a bone marrow disease called myelodysplastic syndrome, often show similar functional consequences, promoting uncontrolled proliferation through constitutive pathway activation. The variant landscape reflects the gene's dual role in normal development and oncogenic transformation.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.268A>G | p.Met90Val | Pathogenic | ★★★☆ | RASopathy |
c.104G>C | p.Ser35Thr | Pathogenic | ★★☆☆ | Noonan syndrome |
c.170C>G | p.Ala57Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Noonan syndrome 8 |
c.229G>A | p.Ala77Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Noonan syndrome |
c.229G>C | p.Ala77Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Noonan syndrome |
c.229G>T | p.Ala77Ser | Pathogenic/Likely pathogenic | ★★☆☆ | RIT1-related disorder |
c.230C>G | p.Ala77Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.241G>C | p.Glu81Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Noonan syndrome |
c.242A>G | p.Glu81Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Noonan syndrome 8 |
c.244T>A | p.Phe82Ile | Pathogenic | ★★☆☆ | Noonan syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
The primary inherited condition associated with germline RIT1 variants is Noonan syndrome, an autosomal dominant disorder. People with RIT1-related Noonan syndrome often present with mildly distinctive facial characteristics, short stature, congenital heart defects (particularly pulmonary valve stenosis), bleeding tendencies, skeletal abnormalities, and developmental delays. Lymphoedema, caused by fluid accumulation in tissues, appears particularly common in individuals with RIT1 mutations compared to Noonan syndrome resulting from variants in other genes. Beyond developmental presentations, acquired RIT1 mutations have been documented in several blood cell malignancies, though these somatic changes differ from the inherited variants that cause Noonan syndrome.
Inheritance pattern
Conditions caused by pathogenic RIT1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
RIT1 appears on multiple NHS Genomic Medicine Service gene panels with green (diagnostic-grade evidence) ratings, reflecting strong clinical validity for genetic testing in specific contexts. The gene is included in the DDG2P panel, the Fetal anomalies panel (R21), Fetal hydrops, Intellectual disability (R29), IUGR and IGF abnormalities, Monogenic short stature (R453), Paediatric or syndromic cardiomyopathy (R135), Pigmentary skin disorders (R236), Primary lymphoedema (R136), and the RASopathies panel. This broad panel representation underscores the gene's relevance across multiple clinical presentations and supports its inclusion in diagnostic pathways for children and adults with features suggestive of RASopathy-spectrum conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is RIT1-related Noonan syndrome inherited?
RIT1-related Noonan syndrome follows an autosomal dominant inheritance pattern, meaning a pathogenic variant in one copy of the gene is sufficient to cause the condition. Each child of an affected parent has a 50% chance of inheriting the variant, though many cases arise from new (de novo) mutations with no family history.
What distinguishes RIT1-related Noonan syndrome from other genetic causes?
Individuals with Noonan syndrome caused by RIT1 variants often experience lymphoedema more frequently than those with variants in other RASopathy genes. Otherwise, clinical features substantially overlap with Noonan syndrome due to alterations in PTPN11, SOS1, and related genes, making genetic testing important for precise diagnosis.
Are RIT1 mutations found in cancer?
Somatic RIT1 mutations have been identified in several blood cell cancers, including acute myeloid leukaemia, chronic myelomonocytic leukaemia, and myelodysplastic syndrome. These acquired mutations in blood cells differ from the inherited variants that cause Noonan syndrome and typically promote uncontrolled cell proliferation.
References
- Yaoita M, Niihori T, Mizuno S. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. Human genetics. 2016. PMID: 26714497
- Kouz K, Lissewski C, Spranger S. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genetics in medicine : official journal of the American College of Medical Genetics. 2016. PMID: 27101134
- Milosavljević D, Overwater E, Tamminga S. Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature. American journal of medical genetics. Part A. 2016. PMID: 27109146
- Berger AH, Imielinski M, Duke F. Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene. 2014. PMID: 24469055
- Gómez-Seguí I, Makishima H, Jerez A. Novel recurrent mutations in the RAS-like GTP-binding gene RIT1 in myeloid malignancies. Leukemia. 2013. PMID: 23765226
- Shi GX, Jin L, Andres DA. A rit GTPase-p38 mitogen-activated protein kinase survival pathway confers resistance to cellular stress. Molecular and cellular biology. 2011. PMID: 21444726