ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000159101 SCV000927839 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000054406 SCV000893221 pathogenic Noonan syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
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.
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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