ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.270G>C (p.Met90Ile) (rs483352822)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000355969 SCV000329957 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing The M90I missense variant in the RIT1 gene has been reported previously as de novo and in association with disorders in the Noonan syndrome spectrum (Gos et al. 2014; Koenighofer et al., 2015). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position within the Switch II region that is conserved across species and is involved in GTP hydrolysis (Berger et al. 2014). Functional studies have shown M90I induces morphological abnormalities in zebrafish embryos and results in increased phosphorylation of MEK and ERK compared to wild type (Koenighofer et al., 2015). Another nucleotide change (c.270 G>T) leading to the same M90I missense variant has been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this residue. Therefore, the c.270 G>C (M90I) variant is considered to be pathogenic.
Invitae RCV000170493 SCV000659223 pathogenic Noonan syndrome 8 2017-08-29 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 90 of the RIT1 protein (p.Met90Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. The frequency data for this variant (rs483352822) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in several individuals affected with Noonan syndrome (PMID: 27109146, 27101134). In at least a few of these individuals, the variant arose de novo (PMID: 23791108, 24939608, 25959749). ClinVar contains an entry for this variant (Variation ID: 190305). Experimental studies have shown that this missense results in increased RIT1 activity in vitro, and disrupts normal zebrafish development (PMID: 25959749). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000170493 SCV000680026 pathogenic Noonan syndrome 8 2017-11-03 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_006912.5(RIT1):c.270G>C in exon 5 of the RIT1 gene. This substitution creates a minor amino acid change from a methionine to a isoleucine at position 90, NP_008843.1(RIT1):p.(Met90Ile). The methionine at this position has very high conservation (100 vertebrates, UCSC). In silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). This variant is not present in the gnomAD population database but it has been previously reported in patients with Noonan syndrome (ClinVar). It is situated in the switch II domain. Additionally, functional studies show that this variant causes gain of function through increased phosphorylation of MEK and ERK (Koenighofer M. et al., (2016)). Based on current information, this variant has been classified as PATHOGENIC. This variant has also been reported with an alternative transcript: NM_001256821.1(RIT1):c.321G>C; NP_001243750.1(RIT1):p.(Met107Ile).
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000355969 SCV001450252 likely pathogenic not provided 2015-07-03 criteria provided, single submitter clinical testing
OMIM RCV000170493 SCV000222925 pathogenic Noonan syndrome 8 2014-09-01 no assertion criteria provided literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000170493 SCV001482334 pathogenic Noonan syndrome 8 2019-05-31 no assertion criteria provided research

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