ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.104G>C (p.Ser35Thr) (rs869025189)

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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 RCV000255076 SCV000927787 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000475746 SCV000893223 pathogenic Noonan syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000255076 SCV000322155 pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing The S35T variant in the RIT1 gene has been reported previously in multiple individuals with Noonan syndrome (Aoki et al., 2013; Bertola et al., 2014; Cave et al., 2016; Yaoita et al., 2016). In one case, this variant was inherited from a parent who also had features of Noonan syndrome (Aoki et al., 2013). This variant has also been observed de novo in cases referred for RASopathy testing at GeneDx. The S35T variant was not observed in large population cohorts (Lek et al., 2016). The S35T variant is a conservative amino acid substitution that occurs at a position that is conserved across species. Functional studies indicate S35T results in enhanced ELK1 transactivation and altered GDP/GTP binding activities (Aoki et al., 2013; Fang et al. 2016). Therefore, the S35T variant is considered to be pathogenic.
Invitae RCV000475746 SCV000541752 pathogenic Noonan syndrome 8 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 35 of the RIT1 protein (p.Ser35Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with Noonan syndrome (PMID: 23791108, 25124994, 26757980, 26714497, 27101134). ClinVar contains an entry for this variant (Variation ID: 183401). Experimental studies have shown that this missense change increases nucleotide exchange and downstream signaling (PMID: 23791108, 27226556). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000207341 SCV000271444 pathogenic Noonan syndrome 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207341 SCV000211874 pathogenic Noonan syndrome no assertion criteria provided clinical testing

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