ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.69A>C (p.Lys23Asn) (rs1557962794)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704832 SCV000833802 pathogenic Noonan syndrome 8 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 23 of the RIT1 protein (p.Lys23Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals with clinical features suggestive of Noonan syndrome (PMID: 27101134, Invitae). Experimental studies have shown that this missense change results in increased signaling downstream of Ras, consistent with the known gain-of-function disease mechanism (PMID: 29734338). A different variant (c.69A>T) giving rise to the same protein effect observed here (p.Lys23Asn) has been reported to be de novo in an individual affected with Noonan syndrome (PMID: 26518681), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
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 Praxis fuer Humangenetik Tuebingen RCV001092173 SCV001248554 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing

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