ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.170C>G (p.Ala57Gly) (rs672601334)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159100 SCV000209043 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing The A57G pathogenic variant in the RIT1 gene has been reported in association with Noonan syndrome, including instances of de novo inheritance (Aoki et al., 2013; Bertola et al., 2014; Koenighofer et al., 2015). The A57G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis predicts this variant is probably damaging to the protein structure/function, and functional studies by Aoki et al. demonstrated that A57G enhanced ELK1 trans-activation in a luciferase assay above wild-type levels (Aoki et al., 2013).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000207349 SCV000271446 pathogenic Noonan syndrome 2016-02-10 criteria provided, single submitter clinical testing The p.Ala74Gly variant in RIT1 (reported as p.Ala57Gly based on amino acid seque nce predicted from NM_006912.5) has been identified in more than 10 individuals with Noonan syndrome and occurred de novo in four of these individuals (Aoki 201 3, Chen 2014, Bertola 2014, Iglesias 2014, Koenighofer 2015, LMM data). It has n ot been identified in large population studies. Pathogenic variants in RIT1 clus ter in the Switch I domain of the protein, where this variant is located (Aoki 2 013, Chen 2014). In summary, this variant meets our criteria to be classified a s pathogenic for Noonan syndrome in an autosomal dominant manner based upon its de novo and over-represented occurrences in affected individuals compared to the general population.
Invitae RCV000054404 SCV000541749 pathogenic Noonan syndrome 8 2020-08-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 57 of the RIT1 protein (p.Ala57Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in many individuals with Noonan syndrome (PMID: 23791108, 25124994, 25049390, 26757980, 24901346, 27101134). In at least three affected individuals, this variant was found to be de novo (PMID: 23791108, 25959749, 26714497). ClinVar contains an entry for this variant (Variation ID: 60506). Experimental studies have found that this missense variant results in craniofacial and eye abnormalities in a zebrafish model system, and results in increased activity in vitro (PMID: 25959749, 25049390, 27226556). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000054404 SCV000586722 pathogenic Noonan syndrome 8 2017-08-01 criteria provided, single submitter clinical testing The missense variant c.221C>G, p.(Ala74Gly) in RIT1 was identified in a boy with clinically suspected Noonan syndrome and osteogenesis imperfecta due to a de novo mutation in COL1A1. The variant in RIT1 was shown to be de novo and had been reported in several other patients with Noonan syndrome.
Blueprint Genetics RCV000159100 SCV000927326 pathogenic not provided 2017-07-04 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856747 SCV000999295 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000054404 SCV001164408 pathogenic Noonan syndrome 8 2018-12-03 criteria provided, single submitter research The heterozygous p.Ala74Gly variant in RIT1 was identified by our study in one individual with Noonan syndrome. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in ClinVar with an alternate name, p.Ala57Gly (Variation ID: 60506). There are at least five individuals with Noonan syndrome and de novo inheritance of this variant in ClinVar and the literature (PMID: 25959749, 26714497, 23791108). In summary, the p.Ala74Gly variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731346 SCV001983617 pathogenic Rasopathy 2021-09-08 criteria provided, single submitter clinical testing Variant summary: RIT1 c.170C>G (p.Ala57Gly) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225; also called as the G2 domain, 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 252130 control chromosomes (gnomAD and publication data). c.170C>G has been reported in the literature in multiple individuals affected with Noonan Syndrome or a related phenotype, including de novo occurrences (Aoki_2013, Bertola_2014, Chen_2014, Fang_2016, Koenighofer_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant activated RAS-ERK pathway, exhibited more rapid nucleotide exchange on GTPase assay, revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism in zebrafish, exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation in mice (Chen_2014, Fang_2016, Koenighofer_2016, Takahara_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000054404 SCV000082881 pathogenic Noonan syndrome 8 2014-11-01 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207349 SCV000211876 pathogenic Noonan syndrome no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000159100 SCV001743162 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000159100 SCV001954504 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000054404 SCV002020800 pathogenic Noonan syndrome 8 2020-07-10 no assertion criteria provided clinical testing

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