ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.284G>C (p.Gly95Ala) (rs672601335)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000298790 SCV000927755 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000207348 SCV000805108 pathogenic Noonan syndrome 2017-04-21 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000298790 SCV000709341 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000054407 SCV000893219 pathogenic Noonan syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000298790 SCV000329956 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing The G95A pathogenic variant in the RIT1 gene has been reported previously in association with Noonan syndrome, including multiple apparently de novo occurrences (Aoki et al., 2013; Gos et al., 2014; Yaoita et al., 2016). Published functional studies have shown that G95A results in increased activity of the RIT1 protein compared to wild type (Aoki et al., 2013). It is not observed in large population cohorts (Lek et al., 2016). The G95A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in a nearby residue (M90V and M90I) have been reported in association with Noonan syndrome (Stenson et al., 2014).
Invitae RCV000054407 SCV000776991 pathogenic Noonan syndrome 8 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 95 of the RIT1 protein (p.Gly95Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 23791108, 2439608, 25124994, 27109146, 25049390, 26757980, 26714497, 27101134) and has been shown to arise de novo in at least 2 individuals (PMID: 23791108). Additionally, this variant has been reported to segregate with disease in at least 1 family (PMID: 27101134). ClinVar contains an entry for this variant (Variation ID: 60509). Experimental studies have shown that this missense change increases the activity of the RAS/MAPK pathway (PMID: 23791108) and zebrafish embryos carrying this variant showed gastrulation and heart defects (PMID: 23791108).  However, other publications have reported that this variant produces an unstable protein in vitro (PMID: 27226556) and did not show consistent hyperactivation (PMID: 25049390).  Additional functional studies are needed to fully elucidate the functional mechanism of this variant. In summary, despite inconsistent functional evidence, this variant has been reported repeatedly in individuals affected with Noonan syndrome and has been reported to segregate with disease in at least 1 family. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000207348 SCV000271447 pathogenic Noonan syndrome 2015-03-18 criteria provided, single submitter clinical testing The p.Gly112Ala variant in RIT1 (also reported as p.Gly95Ala on transcript NM_00 6912.5) has been reported in at least 9 individuals with clinical features of No onan syndrome including 2 de novo occurrences (Aoki 2013, Bertola 2014, Chen 201 4, Gos 2014), and was absent from large population studies. In vitro functional studies provide conflicting evidence on the impact of the p.Gly112Ala variant on protein function (Aoki 2013, Chen 2014), but these types of assays may not accu rately represent biological function. However, animal models in the zebrafish ha ve shown that this variant causes developmental anomalies similar to those seen in Noonan syndrome (Aoki 2013). In summary, this variant meets our criteria to b e classified as pathogenic for Noonan syndrome in an autosomal dominant manner ( http://www.partners.org/personalizedmedicine/LMM) based upon de novo occurrences , absence from controls, and functional evidence.
OMIM RCV000054407 SCV000082884 pathogenic Noonan syndrome 8 2014-11-01 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207348 SCV000211887 pathogenic Noonan syndrome no assertion criteria provided clinical testing

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