Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 | 2023-10-27 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 89 of the RIT1 protein (p.Tyr89His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 26757980; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183411). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt RIT1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 26714497, 27226556). For these reasons, this variant has been classified as Pathogenic. |
Genome Diagnostics Laboratory, |
RCV001813421 | SCV002060943 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2019-12-02 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
RCV000707713 | SCV002583804 | pathogenic | Noonan syndrome 8 | 2022-08-01 | criteria provided, single submitter | clinical testing | PS3, PS4_Moderate, PM1, PM2, PP3 |
Genome- |
RCV000707713 | SCV004050469 | pathogenic | Noonan syndrome 8 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Service de Génétique Moléculaire, |
RCV000207342 | SCV000211886 | pathogenic | Noonan syndrome | no assertion criteria provided | clinical testing |