ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.229G>C (p.Ala77Pro) (rs869025191)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000218943 SCV000271261 likely pathogenic Noonan syndrome 2016-02-03 criteria provided, single submitter clinical testing The p.Ala94Pro variant in RIT1 (reported as p.Ala77Pro on NM_006912.5) has been identified in 1 individual with Noonan syndrome (Chen 2014). It was absent from large population studies. In vitro functional studies suggest that this variant promotes ERK activation (Chen 2014); however, these assays may not accurately re present biological function. In addition, another variant at the same position ( p.Ala77Thr) has been reported in 2 individuals with Noonan syndrome, occurring d e novo in one family and segregating with the disease in 1 affected family membe r in the other family (Cave 2016). Computational prediction tools and conservati on analysis suggest that the p.Ala94Pro variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical signif icance, the p.Ala94Pro variant is likely pathogenic.
Invitae RCV000467706 SCV000541751 pathogenic Noonan syndrome 8 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 77 of the RIT1 protein (p.Ala77Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with Noonan syndrome (PMID: 25049390). ClinVar contains an entry for this variant (Variation ID: 228289). Experimental studies have shown that cells expressing this variant demonstrate enhanced p-ERK levels compared with wildtype (PMID: 25049390). Variants that disrupt the p.Ala77 amino acid residue in RIT1 have been observed in affected individuals (PMID: 26714497, 2657980, 27101134). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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