ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.365G>T (p.Arg122Leu)

dbSNP: rs777520196
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000357501 SCV000330538 likely pathogenic not provided 2023-08-08 criteria provided, single submitter clinical testing Published functional studies demonstrate R122L results in increased phosphorylation of MEK and ERK1/2 compared to wild-type (Berger et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24469055, 35353015, 34887308)
Labcorp Genetics (formerly Invitae), Labcorp RCV001037285 SCV001200691 pathogenic Noonan syndrome 8 2024-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 122 of the RIT1 protein (p.Arg122Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RIT1-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280609). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RIT1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 24469055). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital RCV002051722 SCV001950189 likely pathogenic Megalencephaly-capillary malformation-polymicrogyria syndrome; Noonan syndrome 8 2021-09-30 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813444 SCV002060858 pathogenic Noonan syndrome and Noonan-related syndrome 2024-08-15 criteria provided, single submitter clinical testing This missense variant results in a change from arginine to alanine at amino acid position 122. It has been reported as a de novo variant in an individual with suspected RASopathy who also harbored a mosaic variant in the PIK3CA gene (PMID: 34887308). Functional studies support that this variant alters RIT1 protein function (PMID: 24469055). This variant is observed at an allele frequency of 0.000068% in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict that this variant to impact protein function. Based on the evidence above, this variant is classified as pathogenic (ACMG criteria – PS2, PS3_M, PM2, PP3, PP5).

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.