ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.91G>C (p.Gly31Arg)

dbSNP: rs1571999498
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856810 SCV000999377 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003396492 SCV004106037 likely pathogenic RIT1-related disorder 2023-04-03 criteria provided, single submitter clinical testing The RIT1 c.142G>C variant is predicted to result in the amino acid substitution p.Gly48Arg. This variant has been reported in a parent and child with features overlapping with Noonan syndrome (Kouz et al. 2016. PubMed ID: 27101134). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Invitae RCV003581735 SCV004292897 likely pathogenic Noonan syndrome 8 2023-11-09 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 31 of the RIT1 protein (p.Gly31Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with RIT1-related conditions (PMID: 27101134; Invitae). ClinVar contains an entry for this variant (Variation ID: 694723). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 29734338). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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