ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.246T>G (p.Phe82Leu) (rs730881014)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159101 SCV000209044 pathogenic not provided 2018-03-19 criteria provided, single submitter clinical testing The F82L (c.246 T>G) pathogenic variant in the RIT1 gene has been published numerous times in association with Noonan syndrome and has been reported to be de novo in several of these published probands (Aoki e tal., 2013; Gos et al., 2014; Joyce et al., 2015; Cavé et al., 2016; Yaoita et al., 2016). Furthermore, two different substitutions at the same nucleotide residue (c.246 T>C and c.246T>A) that also result in F82L have each been described in an individual with Noonan syndrome (Cavé et al., 2016; Yaoita et al., 2016). The F82L variant has also been reported in association with Noonan syndrome in additional publications, although the exact nucleotide change was not specified (Bertola et al., 2014; Jouz et al., 2016).The F82L (c.246 T>G) variant results in a conservative amino acid substitution at a position that is conserved across species. Functional studies have demonstrated that F82L is a gain-of-function variant, as are other Noonan associated changes in the RIT1 gene (Aoki et al., 2013). Moreover, variants in the same residue (F82S, F82V) and nearby residues (A77P, E81G, T83P, A84V) have been reported in HGMD in association with Noonan syndrome, (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Lastly, F82L (c.246 T>G) is not observed in large population cohorts (Lek et al., 2016).In summary, F82L (c.246 T>G) in the RIT1 gene is interpreted as a pathogenic variant.
Invitae RCV000054406 SCV000541750 pathogenic Noonan syndrome 8 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 82 of the RIT1 protein (p.Phe82Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome (PMID: 23791108, 25124994, 26242988, 26714497, 26757980, 27101134). In several of these individuals, the variant was de novo. ClinVar contains an entry for this variant (Variation ID: 181522). Experimental studies have shown that this missense change results in increased RIT1 activity in vitro and in cell culture (PMID: 23791108, 26714497, 24469055). This missense change is located within the functionally conserved switch II domain of the RIT1 protein, where a number of other RIT1 missense mutations have been found (PMID: 26446362). A different missense substitution at this codon (p.Phe82Val) has been determined to be pathogenic (PMID: 23791108, 26757980, 25049390), suggesting that the phenylalanine residue is critical for RIT1 protein function. For these reasons, this variant has been classified as Pathogenic.
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 2018-08-28 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 Praxis fuer Humangenetik Tuebingen RCV000159101 SCV001247929 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
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

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