rs483352822

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_StrongPM1PM2PM5PP3PP5_Very_Strong

The NM_006912.6(RIT1):c.270G>T(p.Met90Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M90V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RIT1
NM_006912.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.43

Variant links:

Genes affected

RIT1 (HGNC:10023): (Ras like without CAAX 1) 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]

RIT1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 23 ACMG points.

PS1

Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 190305

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006912.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155904472-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 561681.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

PP5

Variant 1-155904470-C-A is Pathogenic according to our data. Variant chr1-155904470-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 265328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904470-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6 link	c.270G>T	p.Met90Ile	missense_variant	Exon 5 of 6	ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 link	c.321G>T	p.Met107Ile	missense_variant	Exon 5 of 6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 link	c.162G>T	p.Met54Ile	missense_variant	Exon 4 of 5		NP_001243749.1	Q92963-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8 link	c.270G>T	p.Met90Ile	missense_variant	Exon 5 of 6	1	NM_006912.6	ENSP00000357306.3		Q92963-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 8

Pathogenic:3

Nov 18, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan spectrum disorder (PMID: 23791108, 30692697). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265328). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. This variant disrupts the Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27109146, 29734338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

not provided

Pathogenic:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 27, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The M90I variant in the RIT1 gene has been reported previously in a Noonan syndrome cohort as a de novo change in an individual with hypertrophic cardiomyopathy, pulmonic stenosis, atrial septal defect, ventricular septal defect and patent ductus arteriosus (Aoki et al., 2013). The M90I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M90I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M90I as a disease-causing variant. -

Inborn genetic diseases

Pathogenic:1

Nov 27, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Pathogenic:1

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RIT1 c.270G>T (p.Met90Ile) results in a conservative amino acid change located in the Small GTP-binding domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.270G>T has been reported in the literature in individuals affected with Noonan Syndrome, including at least one de novo occurrence (e.g. Aoki_2013, Zhang_2019). These data indicate that the variant is likely associated with disease. Two different variants resulting in the same amino acid consequence have been classified as pathogenic by our lab (c.270G>A, c.270G>C), supporting the pathogenicity of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 23791108, 30692697). ClinVar contains an entry for this variant (Variation ID: 265328). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

-0.095

N;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.8

D;D;D;.

REVEL

Pathogenic

0.84

Sift

Benign

0.076

T;T;T;.

Sift4G

Benign

0.094

T;T;T;.

Polyphen

1.0

D;.;.;.

Vest4

0.98

MutPred

0.62

Gain of catalytic residue at M90 (P = 0.0046);.;.;Gain of catalytic residue at M90 (P = 0.0046);

MVP

0.65

MPC

1.9

ClinPred

0.98

GERP RS

5.8

Varity_R

0.76

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over