ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.268A>G (p.Met90Val)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681030 SCV000808482 pathogenic not provided 2020-11-06 criteria provided, single submitter clinical testing Published functional studies have shown M90V results in increased ERK1/2 activation in response to serum activation compared to wild type (Meyer et al., 2018).; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29565699, 29734338, 27109146, 30293990, 31324109, 30712878, 32304219)
Fulgent Genetics,Fulgent Genetics RCV000762859 SCV000893220 pathogenic Noonan syndrome 8 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192383 SCV001360454 pathogenic Rasopathy 2021-05-24 criteria provided, single submitter clinical testing Variant summary: RIT1 c.268A>G (p.Met90Val) results in a conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.268A>G has been reported in the literature as a de-novo occurrence in multiple fetal cases affected with Noonan Syndrome And Related Conditions (example, Milosavljevic_2016, Quinan-Jones_2019, Becher_2020, Stuurman_2019, Petrovski_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased activation of ERK signaling supporting a gain of function outcome (Buschenfelde_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000762859 SCV001403953 pathogenic Noonan syndrome 8 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 90 of the RIT1 protein (p.Met90Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Noonan syndrome (PMID: 27109146). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561681). This variant has been reported to affect RIT1 protein function (PMID: 29734338). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 24939608, 25959749, 7109146, 27101134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000762859 SCV001984804 pathogenic Noonan syndrome 8 2020-08-28 criteria provided, single submitter clinical testing This variant, also known in the literature as c.268A>G (p.Met90Val) based on transcript NM_006912.6, has been previously reported as a de novo heterozygous change in at least two patients with Noonan syndrome (PMID: 27109146, 30293990). Missense variants at the same amino acid residue (p.Met90Ile) and (p.Met90Thr) and at neighboring amino acid residues (p.Tyr89His) and (p.Gly95Ala) have been reported in individuals with Noonan Syndrome (PMID: 23791108, 24939608). Functional studies have demonstrated that this variant leads to increased ERK1/2 phosphorylation compared to wild-type RIT1 (PMID: 29734338). It is absent from the gnomAD population database and thus is presumed to be rare. The c.319A>G (p.Met107Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.319A>G (p.Met107Val) variant is classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261143 SCV001438552 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000762859 SCV002020797 pathogenic Noonan syndrome 8 2020-04-26 no assertion criteria provided clinical testing

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