ClinVar Miner

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

dbSNP: rs483352822
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255338 SCV000322095 pathogenic not provided 2017-03-27 criteria provided, single submitter clinical testing The M90I variant in the RIT1 gene has been reported previously in a Noonan syndrome cohort as a de novo change in an individual with hypertrophic cardiomyopathy, pulmonic stenosis, atrial septal defect, ventricular septal defect and patent ductus arteriosus (Aoki et al., 2013). The M90I variant was not observed in approximately 6500 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 M90I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M90I as a disease-causing variant.
Ambry Genetics RCV001267162 SCV001445343 pathogenic Inborn genetic diseases 2019-11-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000722172 SCV002239119 pathogenic Noonan syndrome 8 2022-12-02 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27109146, 29734338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 265328). This missense change has been observed in individual(s) with Noonan spectrum disorder (PMID: 23791108, 30692697). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile).
Genome-Nilou Lab RCV000722172 SCV004050464 pathogenic Noonan syndrome 8 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000722172 SCV000854625 pathogenic Noonan syndrome 8 2018-11-18 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255338 SCV001739815 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255338 SCV001957708 pathogenic not provided no assertion criteria provided clinical testing

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