ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.69A>C (p.Lys23Asn)

dbSNP: rs1557962794
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704832 SCV000833802 pathogenic Noonan syndrome 8 2021-11-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RIT1 function (PMID: 29734338). 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: 581105). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26518681, 27101134; Invitae). 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 lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 23 of the RIT1 protein (p.Lys23Asn).
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856799 SCV000999363 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000704832 SCV001245017 pathogenic Noonan syndrome 8 2018-10-08 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_006912.5(RIT1):c.69A>C, has been identified in exon 2 of 6 of the RIT1 gene. The variant is predicted to result in a moderate amino acid change from lysine to asparagine at position 23 of the protein (NP_008843.1(RIT1):p.(Lys23Asn)). The lysine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Ras functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), but has previously been reported as de novo in two individuals with Noonan syndrome (Nemcikova M. et al. (2016) & Kouz K. et al. (2016)). Additionally, functional studies show that this variant induces elevated ERK1/2 phosphorylation (Buschenfelde M. et al. 2018). A different variant in the same codon resulting in a change to glutamine has been reported with conflicting pathogenicity (ClinVar). Analysis of parental samples indicated this variant is de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
CeGaT Center for Human Genetics Tuebingen RCV001092173 SCV001248554 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000704832 SCV004050506 pathogenic Noonan syndrome 8 2023-04-11 criteria provided, single submitter 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.