rs730881014

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_006912.6(RIT1):c.246T>G(p.Phe82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F82C) has been classified as 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:19

Conservation

PhyloP100: 0.0180

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 26 ACMG points.

PS1

Transcript NM_006912.6 (RIT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 370035

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-155904495-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 372863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 1-155904494-A-C is Pathogenic according to our data. Variant chr1-155904494-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155904494-A-C is described in Lovd as [Pathogenic]. Variant chr1-155904494-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6 link	c.246T>G	p.Phe82Leu	missense_variant	Exon 5 of 6	ENST00000368323.8	NP_008843.1	Q92963-1
RIT1	NM_001256821.2 link	c.297T>G	p.Phe99Leu	missense_variant	Exon 5 of 6		NP_001243750.1	Q92963-3
RIT1	NM_001256820.2 link	c.138T>G	p.Phe46Leu	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.246T>G	p.Phe82Leu	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/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 8

Pathogenic:9

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS2_VeryStrong, PP4, PM2 -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 25124994, 26242988, 26714497, 26757980, 27101134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 181522). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt RIT1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 24469055, 26714497). This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 25049390, 26446362, 26757980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 8 (MIM#615355). Missense variants have been functionally proven to have improved transactivation ability (PMID: 23791108). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed in individuals with Noonan syndrome and hydrops fetalis in the literature (PMID: 36274670). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 13, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RIT1 c.246T>G variant is a single nucleotide change in exon 5/6 of the RIT1 gene, which is predicted to change the amino acid phenylalanine at position 82 in the protein to leucine. This variant has been identified as a de novo variant in this patient with no family history of this condition (PS2). This variant has been reported multiple times in the literature, including as a de novo variant and in a prenatal setting, in patients with Noonan syndrome (PS4) (PMID: 23791108; 27699752; 33190430; 30266093; 25124994). A different de novo pathogenic variant has also been reported at this same amino acid position (Phe82Val, PMID: 23791108). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs730881014). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 181522). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Jul 11, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RIT1 c.246T>G; p.Phe82Leu variant (rs730881014), is reported in the literature in multiple individuals affected with Noonan syndrome, including several cases in which the variant was de novo (Aoki 2013, Bertola 2014, Cave 2016, Joyce 2016, Kiel 2014, Kouz 2016, Yaoita 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 181522), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.246T>A; p.Phe82Leu and p.Phe82Val/Ile/Ser) have been reported in individuals with Noonan syndrome and are considered pathogenic (Aoki 2013, Cave 2016, Kouz 2016, Yaoita 2016). The phenylalanine at codon 82 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the p.Phe82Leu variant protein show increased RIT1 activity (Aoki 2013, Berger 2014, Yaoita 2016), and codon 82 lies within the functionally conserved switch II domain where many pathogenic variants in RIT1 are located (Aoki 2016). Based on available information, the c.246T>G; p.Phe82Leu variant is considered to be pathogenic. References: Aoki Y et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11;93(1):173-80. Aoki Y et al. Recent advances in RASopathies. J Hum Genet. 2016 Jan;61(1):33-9. Berger AH et al. Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene. 2014 Aug 28;33(35):4418-23. Bertola DR et al. Further evidence of the importance of RIT1 in Noonan syndrome. Am J Med Genet A. 2014 Nov;164A(11):2952-7. Cave H et al. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. Eur J Hum Genet. 2016 Aug;24(8):1124-31. Joyce S et al. The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. Eur J Hum Genet. 2016 May;24(5):690-6. Kiel C and Serrano L. Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Mol Syst Biol. 2014 May 6;10:727. Kouz K et al. Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation. Genet Med. 2016 Dec;18(12):1226-1234. Yaoita M et al. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. Hum Genet. 2016 Feb;135(2):209-22. -

Jan 15, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in a c.246T>G (p.Phe82Leu) change in an alternate transcript (NM_006912.6). The c.297T>G (p.Phe99Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a known Pathogenic variant that has been previously reported as a de novo heterozygous change in patients with Noonan syndrome (PMID: 23791108, 26242988, 36304179, 36238151, 36274670). The c.297T>G (p.Phe99Leu) variant is located in the switch II domain, which is a known hotspot domain for pathogenic variations associated with Noonan syndrome (PMID: 30872527, 23791108). Different nucleotide changes resulting in the same amino acid change (c.244T>C and c.246T>A) have been previously reported in individuals with Noonan syndrome (PMID: 27699752; 35574990, 35627109, 33190430). Additionally, different amino acid changes at the same residue (p.Phe82Ser, p.Phe82Val, p.Phe82Cys, and p.Phe82Ile) have been previously reported in individuals with Noonan syndrome or related phenotypes (PMID: 27101134, 23791108, 25049390, 24939608, 34306696, 34184824). Experimental studies have demonstrated this variant has a gain-of-function effect on the variant protein (PMID: 23791108). The c.297T>G (p.Phe99Leu) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.297T>G (p.Phe99Leu) is classified as Pathogenic. -

not provided

Pathogenic:4

Mar 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that p.(F82L) is a gain-of-function variant, which is an established mechanism of disease in the RIT1 gene (Aoki et al., 2013; Fang et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27942422, 24803665, 27226556, 24469055, 25124994, 26242988, 27101134, 26757980, 23791108, 26714497, 24939608, 27699752, 33258288, 30266093) -

Aug 07, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RIT1: PS2:Very Strong, PS1, PS4, PM1, PM2, PM5, PP3 -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome;C0152021:Congenital heart disease

Pathogenic:1

Jun 16, 2023

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygous variant NM_006912:c.246T>G (p.Phe82Leu) in the RIT1 gene was found on WES data in female proband (7 month.old., Caucasian) with Noonan Syndrome and Congenital Heart Disease. No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is absent in The Genome Aggregation Database (gnomAD) v2.1.1 and v.3.1.2 (Date of access with 16-06-2023). Clinvar contains entry on this variant (Variation ID: 181522). This variant has been reported in 9 articles with consistent phenotypes (PMID: 33258288, 30266093, 28323383, 27101134, 26757980, 26714497, 26242988, 24469055, 23791108). Alternative nucleotide changes have been described in this codon (PMID: 33190430, 27699752, 25049390, 24939608). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Pathogenic (V) with following criteria selected: PS1, PS4, PM1, PM2, PM5, PP3. -

RIT1-related disorder

Pathogenic:1

Mar 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RIT1 c.297T>G variant is predicted to result in the amino acid substitution p.Phe99Leu. In an alternate transcript (NM_006912.5) this variant is referred to as c.246T>G (p.Phe82Leu). This variant has been reported in multiple individuals with Noonan syndrome, including several cases in which the variant was de novo (Bertola et al. 2014. PubMed ID: 25124994; Aoki et al. 2016. PubMed ID: 26446362; Joyce et al. 2016. PubMed ID: 26242988; Kouz et al. 2016. PubMed ID: 27101134; Yaoita et al. 2016. PubMed ID: 26714497). Additionally, other variants impacting the same amino acid (p.Phe82Val/Ile/Ser) have been reported in individuals with Noonan syndrome (Aoki et al. 2016. PubMed ID: 26446362; Cavé et al. 2016. PubMed ID: 26757980; Kouz et al. 2016. PubMed ID: 27101134; Yaoita et al. 2016. PubMed ID: 26714497). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Noonan syndrome

Pathogenic:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Non-immune hydrops fetalis

Pathogenic:1

Aug 22, 2019

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Pathogenic:1

Aug 24, 2020

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.246T>G (p.Phe82Leu) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes (gnomAD). c.246T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome. In addition, the variant was reported as de novo in several patients (Aoki_2013, Bertola_2014, Joyce_2015, Kouz_2016, Yaoita_2016). These data indicate that the variant is very likely to be associated with disease. Moreover, variants in the same residue (F82S, F82V) were found in individuals affected with Noonan Syndrome (Aoki_2013, Kouz_2016) and nearby residues (p.A77P/S/T, p.E81G, p.T83P, p.A84V) have been reported in HGMD in association with Noonan Syndrome, supporting the functional importance of this residue and region of the protein. Functional studies report this variant has an impact on protein function and results in increased RIT1 activity in cells (Aoki_2013, Berger_2014). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jan 05, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.042

MutationAssessor

Uncertain

2.2

M;.;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.4

D;D;D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.026

D;T;T;.

Sift4G

Benign

0.069

T;T;T;.

Polyphen

1.0

D;.;.;.

Vest4

0.97

MutPred

0.87

Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);

MVP

0.94

MPC

2.0

ClinPred

0.98

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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