1-155904739-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_006912.6(RIT1):c.229G>A(p.Ala77Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A77G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RIT1
NM_006912.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 5.89

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp

RIT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr1-155904738-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 850519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

PP5

Variant 1-155904739-C-T is Pathogenic according to our data. Variant chr1-155904739-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6 link	c.229G>A	p.Ala77Thr	missense_variant	Exon 4 of 6	ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 link	c.280G>A	p.Ala94Thr	missense_variant	Exon 4 of 6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 3 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.229G>A	p.Ala77Thr	missense_variant	Exon 4 of 6	1	NM_006912.6	ENSP00000357306.3		Q92963-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 8

Pathogenic:5

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 27, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 183403). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26714497, 26757980, 27101134, 29402968). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 77 of the RIT1 protein (p.Ala77Thr). Experimental studies have shown that this missense change affects RIT1 function (PMID: 26714497). For these reasons, this variant has been classified as Pathogenic. -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 18, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Apr 20, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that A77T acts as a gain-of-function variant, causing increased Elk1 activation and enhanced cJun transcription (Yaoita et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 183403; ClinVar); This variant is associated with the following publications: (PMID: 27109146, 27101134, 26714497, 26757980, 30692697, 29402968, 33726816) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RIT1: PS2, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Mar 07, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM2, PM6_strong, PS3_supporting, PS4 -

Noonan syndrome 1

Pathogenic:2

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Molecular Genetics, Centre for Human Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

RIT1-related disorder

Pathogenic:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RIT1 c.280G>A variant is predicted to result in the amino acid substitution p.Ala94Thr. This variant has also been referred to as p.Ala77Thr in literature. This variant has been reported in multiple individuals with Noonan syndrome; three times as a de novo event and once transmitted from an affected parent (Yaoita et al. 2016. PubMed: 26714497; Cavé et al 2016. PubMed ID: 26757980; Kouz et al 2016. PubMed ID: 27101134). Different missense variants that affect the same amino acid (p.Ala94Pro, p.Ala94Ser) have also been reported to be causative for Noonan spectrum disorders (Chen et al. 2014. PubMed ID: 25049390; Yaoita. 2016. PubMed ID: 26714497). In addition, it has been identified in multiple individuals tested for Noonan spectrum disorders in our internal database. This variant is interpreted as pathogenic. This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Noonan syndrome

Pathogenic:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

RASopathy

Pathogenic:1

Jan 16, 2023

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.229G>A (p.Ala77Thr) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes. c.229G>A has been reported in the literature as a de-novo occurrence in multiple individuals affected with Noonan Syndrome (example, PMID: 26757980, 26714497). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 26714497). The most pronounced variant effect results in significantly enhanced ELK transactivation, confirming the gain-of function mechanism of disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.0

H;.;.;.

PhyloP100

5.9

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.9

D;D;D;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.016

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.88

MutPred

0.86

Gain of glycosylation at T76 (P = 0.1101);.;.;Gain of glycosylation at T76 (P = 0.1101);

MVP

0.84

MPC

1.6

ClinPred

0.99

GERP RS

4.0

Varity_R

0.79

gMVP

0.90

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over