ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.247A>C (p.Thr83Pro) (rs869025195)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414438 SCV000491310 pathogenic not provided 2016-12-07 criteria provided, single submitter clinical testing The T83P missense variant in the RIT1 gene has been reported previously as de novo and in association with Noonan syndrome (Aoki et la., 2013). The T83P 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 T83P 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. In vitro functional studies demonstrated that the T83P variant results in enhanced Elk1 levels in comparison to wild-type (Yaoita et al., 2016). Additionally, missense variants in nearby residues (E81G/Q, F82V/I/L, 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.
Ambry Genetics RCV000622399 SCV000741154 pathogenic Inborn genetic diseases 2015-11-19 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856766 SCV000999320 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175490 SCV001339083 pathogenic Rasopathy 2020-03-16 criteria provided, single submitter clinical testing Variant summary: RIT1 c.247A>C (p.Thr83Pro) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes (gnomAD). c.247A>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (examples- Aoki_2013, Cave_2016, Kouz_2016). These data indicate that the variant may be associated with disease. In-vitro studies evaluating an impact on protein function showed that the variant results in impaired GTP-hydrolysis and increased activation as assessed by Ras-binding domain pull-down assays (Fang_2016) and higher levels of activation of Elk1 (Yaoita_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001384933 SCV001584627 pathogenic Noonan syndrome 8 2020-05-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 83 of the RIT1 protein (p.Thr83Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Noonan syndrome (PMID: 23791108). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183409). This variant has been reported to affect RIT1 protein function (PMID: 27226556). This missense change is located in a region of the RIT1 protein where a significant number of previously reported RIT1 missense mutations are found (PMID: 26757980, 27101134). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207345 SCV000211884 pathogenic Noonan syndrome no assertion criteria provided clinical testing
Genomics England Pilot Project,Genomics England RCV001384933 SCV001759991 likely pathogenic Noonan syndrome 8 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.