ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000298790 SCV000709341 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing
Invitae RCV000054407 SCV000776991 pathogenic Noonan syndrome 8 2019-11-29 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.
Fulgent Genetics,Fulgent Genetics RCV000054407 SCV000893219 pathogenic Noonan syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000298790 SCV000927755 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000054407 SCV001190410 pathogenic Noonan syndrome 8 2019-11-13 criteria provided, single submitter clinical testing RIT1 NM_006912.5 exon 5 p.Gly95Ala (c.284G>C): This variant has been reported in the literature in at least 11 individuals with Noonan syndrome (Aoki 2013 PMID:23791108, Chen 2013 PMID:25049390, Bertola 2014 PMID:25124994, Gos 2014 PMID:24939608, Milosavljević 2016 PMID:27109146); two of these individuals were identified as de novo (Aoki 2013 PMID:23791108). This variant was also reported in at least 2 additional individuals with features of a RAS-opathy (Yaoita 2016 PMID:26714497) as de novo. This variant is not present in large control databases but is present in ClinVar with several labs classifying this variant as pathogenic (Variation ID:60509). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In-vivo functional studies in zebrafish also support a deleterious effect of this variant (Aoki 2013 PMID:23791108). In summary, this variant is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192384 SCV001360455 pathogenic Rasopathy 2019-10-29 criteria provided, single submitter clinical testing Variant summary: RIT1 c.284G>C (p.Gly95Ala) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225), in the switch II region (Chen_2014) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes (gnomAD). c.284G>C has been reported in the literature in heterozygous state in several individuals affected with Noonan Syndrome and Related Conditions, including confirmed de novo occurrences, and segregation with disease in at least 1 family (Aoki_2013, Chen_2014, Kouz_2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein increases the activity of the RAS/MAPK pathway (Aoki_2013, Chen_2014). In addition, transfection of the variant into zebrafish embryos resulted in a variety of developmental defects, consistent with the disease phenotype observed in humans (Aoki_2013). Seven ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000207348 SCV000805108 pathogenic Noonan syndrome 2017-04-21 no assertion criteria provided clinical testing

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