ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.265T>C (p.Tyr89His) (rs869025197)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486847 SCV000568807 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The Y89H variant has been published in patients diagnosed with a disorder in the Noonan syndrome spectrum (Aoki et al., 2013; Aoki et al., 2015). In vitro functional studies have demonstrated that the Y89H variant causes enhanced Elk1 transactivation and a 4-fold faster nucleotide exchange rate in comparison to wild-type (Fang et al., 2016; Yaoita et al., 2016). The Y89H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y89H 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. Pathogenic variants in an adjacent residue (M90I/V) and nearby residues (A84V) 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.
Invitae RCV000707713 SCV000836822 pathogenic Noonan syndrome 8 2019-03-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 89 of the RIT1 protein (p.Tyr89His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome; in one case, it was observed to be de novo (PMID: 26757980, 23791108, Invitae). ClinVar contains an entry for this variant (Variation ID: 183411). Experimental studies have shown that this missense change results in a RIT1 protein with an increased GTP exchange rate and increased downstream signaling (PMID: 27226556, 26714497). For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207342 SCV000211886 pathogenic Noonan syndrome no assertion criteria provided clinical testing

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