ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.242A>G (p.Glu81Gly) (rs869025193)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255048 SCV000322478 pathogenic not provided 2016-02-18 criteria provided, single submitter clinical testing The E81G variant has been published in association with Noonan syndrome and myeloid malignancies (Aoki et al., 2013; Cavé et al., 2016; Gómez-Seguí et al. 2013). In vitro function studies demonstrated that the E81G variant results in increased ELK1 transactivation (Aoki et al., 2013). Furthermore, an in vivo animal model with the E81G variant developed craniofacial and heart defects (Aoki et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E81G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and lies within the Switch II effector domain (Gómez-Seguí et al. 2013; Cavé et al., 2016). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on this information, this variant is classified as pathogenic.
Invitae RCV000054405 SCV000541753 pathogenic Noonan syndrome 8 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 81 of the RIT1 protein (p.Glu81Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. 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, 26757980). ClinVar contains an entry for this variant (Variation ID: 183405). Experimental studies have shown that this missense change causes a gain of function in the RIT1 protein both in vitro and in vivo recapitulating Noonan syndrome phenotype in a zebrafish model system (PMID: 23791108). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508083 SCV000605037 pathogenic not specified 2017-01-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000207350 SCV000712478 pathogenic Noonan syndrome 2016-09-12 criteria provided, single submitter clinical testing The p.Glu98Gly (also reported as p.Glu81Gly) variant in RIT1 has been identified in 4 individuals with clinical features of Noonan Syndrome, one of which was de novo, and segregated with disease in 3 affected relatives (Aoki 2013 and Cave 2 016, Cave personal communication). This variant was absent from large population studies. In vitro functional studies provide some evidence that this variant ma y impact protein function (Aoki 2013). In addition, an animal model in zebrafish has shown that this variant causes developmental defects similar to those seen in zebrafish with gain-of-function NRAS variants (Aoki 2013). Computational pred iction tools and conservation analysis suggest that the p.Glu98Gly variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the p.Glu98Gly variant is pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000054405 SCV000893222 pathogenic Noonan syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174556 SCV001337716 pathogenic Rasopathy 2020-01-27 criteria provided, single submitter clinical testing Variant summary: RIT1 c.242A>G (p.Glu81Gly) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) 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 250506 control chromosomes (gnomAD). c.242A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Aoki_2013, Cave_2016, Ramond_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer significantly increased transcriptional activity by ELK1 compared to the WT (Aoki_2013), consistent with the established gain-of-function mechanism of disease for RIT1. Furthermore, zebrafish embryos with the variant displayed heart and facial abnormalities, with a small percentage of them being severely disorganized (Aoki_2013). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000054405 SCV000082882 pathogenic Noonan syndrome 8 2013-07-11 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207350 SCV000211879 pathogenic Noonan syndrome no assertion criteria provided clinical testing

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