RIT1

protein-coding

Ras like without CAAX 1, the group of RAS type GTPase family

Gene summary

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]

Previous symbols:

MANE transcript

NM_006912.6

Inheritance

ClinVar variants

P:43U:193B:98

Top phenotype

Noonan syndrome 8

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr1:155,897,808-155,911,404

External References & Databases

Ensembl (ENSG00000143622)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There is a definitive association between alteration of the RIT1 gene and the Noonan syndrome (NS) phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as segregating variants occur in RIT1 in patients with NS (Aoki et al., 2013; Bertola et al., 2014; Chen et al., 2014; Koenighofer et al., 2016; Kouz et al., 2016). The RIT1 gene is also located in the Ras/MAPK pathway which is associated with the NS phenotype and RIT1 variants found in NS patients disrupt the RAS pathway function as demonstrated by zebrafish models (Aoki et al., 2013; Aoki et al., 2016; Koenighofer et al., 2016; Rauen, 2013). The ClinGen RASopathy Expert Panel found no evidence associating RIT1 with cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

Noonan syndrome 8STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014143

Submitter: PanelApp Australia

Noonan syndrome 8DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014143

Submitter: G2P

Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

Noonan syndrome 8STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014143

Submitter: Genomics England PanelApp

Noonan syndrome 8STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014143

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Noonan syndrome 8AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Oncologic

Intervention: Cardiovascular; Oncologic

Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis and hypertrophic cardiomyopathy as well as congenital heart defects ) can be beneficial; Individuals may be at increased risk for malignancy (a child with ALL has been described), and although specific surveillance may not be warranted, awareness may allow prompt detection and treatment

Refs: 23791108; 24939608; 25124994

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RIT1 variants in ClinVar

21 Conditions Cataloged

Noonan syndrome 8Total: 295

Cardiovascular phenotypeTotal: 133

not providedTotal: 105

not specifiedTotal: 61

RIT1-related disorderTotal: 49

Noonan syndromeTotal: 24

Noonan syndrome and Noonan-related syndromeTotal: 21

RASopathyTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006912.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	83 clinvar	2 clinvar	87
missense	17 clinvar	25 clinvar	179 clinvar	10 clinvar		231
nonsense	1 clinvar		4 clinvar	1 clinvar		6
start loss						0
frameshift			7 clinvar	2 clinvar		9
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	18	25	193	96	2	334

Highest pathogenic variant AF is 0.0000065690074

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006912.6	RefSeq	NP_008843.1	5	MANE Select
ENST00000368323.8	Ensembl	ENSP00000357306.3	5	MANE Select
NM_001256820.2	RefSeq	NP_001243749.1	4	Standard
NM_001256821.2	RefSeq	NP_001243750.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ectoderm Differentiation
Signal Transduction
Signalling to p38 via RIT and RIN
Signalling to ERKs
Signaling by NTRK1 (TRKA)

Biological Process

signal transduction
Ras protein signal transduction

Molecular Function

GTPase activity
protein binding
calmodulin binding
GTP binding

Cellular Component

plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368322
Coding exons: 6
Length: 13597
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125746
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.08	75	145	0.516	0.00000841	1550
Missense (PolyPhen)		14	56.992	0.24565		619
Synonymous	0.0940	45	45.8	0.982	0.00000212	453
Loss of Function	2.51	4	14.2	0.282	9.93e-7	135

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF- dependent neuronal differentiation. Involved in ELK1 transactivation through the Ras-MAPK signaling cascade that mediates a wide variety of cellular functions, including cell proliferation, survival, and differentiation. {ECO:0000269|PubMed:15632082, ECO:0000269|PubMed:23791108}.;

Recessive Scores

pRec: 0.212

Intolerance Scores

LoFtool: 0.351
RVIS EVS: -0.19
RVIS percentile EVS: 39.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.442

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Low	Low	Low