Submissions for variant NM_006912.6(RIT1):c.246T>G (p.Phe82Leu)

dbSNP: rs730881014

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159101	SCV000209044	pathogenic	not provided	2022-03-21	criteria provided, single submitter	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000054406	SCV000541750	pathogenic	Noonan syndrome 8	2022-09-02	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000054406	SCV000893221	pathogenic	Noonan syndrome 8	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000159101	SCV000927839	pathogenic	not provided	2018-08-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000054406	SCV001159742	pathogenic	Noonan syndrome 8	2021-11-30	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV000159101	SCV001247929	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255602	SCV001432125	pathogenic	RASopathy	2020-08-24	criteria provided, single submitter	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.
Genomic Medicine Lab, University of California San Francisco	RCV001375970	SCV001572965	pathogenic	Non-immune hydrops fetalis	2019-08-22	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159101	SCV001762139	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813414	SCV002060941	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2017-01-05	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000054406	SCV002556615	pathogenic	Noonan syndrome 8	2021-12-13	criteria provided, single submitter	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).
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000054406	SCV002818140	pathogenic	Noonan syndrome 8	2024-10-04	criteria provided, single submitter	research	PS2_VeryStrong, PP4, PM2
Genome-Nilou Lab	RCV000054406	SCV004050475	likely pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398818	SCV004112509	pathogenic	RIT1-related disorder	2023-03-13	criteria provided, single submitter	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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003483526	SCV004176287	pathogenic	Congenital heart disease; Noonan syndrome	2023-06-16	criteria provided, single submitter	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000054406	SCV005086750	pathogenic	Noonan syndrome 8	2023-07-17	criteria provided, single submitter	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
OMIM	RCV000054406	SCV000082883	pathogenic	Noonan syndrome 8	2013-07-11	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207343	SCV000211883	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing