rs730881014
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 same amino acid change has been previously reported as Pathogenicin 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
NM_006912.6 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 0.0180
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]
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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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RIT1 | NM_006912.6 | c.246T>G | p.Phe82Leu | missense_variant | 5/6 | ENST00000368323.8 | NP_008843.1 | |
| RIT1 | NM_001256821.2 | c.297T>G | p.Phe99Leu | missense_variant | 5/6 | NP_001243750.1 | ||
| RIT1 | NM_001256820.2 | c.138T>G | p.Phe46Leu | missense_variant | 4/5 | NP_001243749.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RIT1 | ENST00000368323.8 | c.246T>G | p.Phe82Leu | missense_variant | 5/6 | 1 | NM_006912.6 | ENSP00000357306.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Noonan syndrome 8 Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 02, 2022 | This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 24469055, 26714497). 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: 181522). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PS2_VeryStrong, PP4, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 13, 2021 | 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). - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 07, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2022 | 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) - |
Noonan syndrome;C0152021:Congenital heart disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Jun 16, 2023 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 13, 2023 | 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
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Non-immune hydrops fetalis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Aug 22, 2019 | - - |
RASopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2020 | 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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 05, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;T;T;.
Sift4G
Benign
T;T;T;.
Polyphen
D;.;.;.
Vest4
MutPred
Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);
MVP
MPC
2.0
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at