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

dbSNP: rs1557962794

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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