ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.270G>A (p.Met90Ile) (rs483352822)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000220792 SCV000271445 pathogenic Noonan syndrome 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000301748 SCV000330351 pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing The M90I missense variant in the RIT1 gene has been published previously in association with disorders in the Noonan syndrome spectrum (Justino et al., 2014) and observed de novo in patients with features consistent with a RASopathy spectrum disorder at GeneDx. M90I is not observed in large population cohorts (Lek et al., 2016). This substitution occurs at a position within the Switch II region that is conserved across species and is involved in GTP hydrolysis (Berger et al. 2014). Functional studies of M90I have shown that the variant induces the phosphorylation of ERK through activation of MEK (Berger et al., 2014). Other nucleotide changes (c.270 G>T, c.270 G>C) leading to the same M90I missense variant and missense variants in nearby residues (Y89H, G95A) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the c.270 G>A (M90I) variant is considered to be pathogenic.
Invitae RCV000106331 SCV001589498 pathogenic Noonan syndrome 8 2020-07-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 90 of the RIT1 protein (p.Met90Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of cardio-facio-cutaneous syndrome (PMID: 24896146). ClinVar contains an entry for this variant (Variation ID: 120250). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. A different variant (c.270G>C) giving rise to the same protein effect observed here (p.Met90Ile) has been determined to be pathogenic (PMID: 23791108, 24939608, 25959749). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000106331 SCV000143829 not provided Noonan syndrome 8 no assertion provided not provided

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