ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.244T>G (p.Phe82Val) (rs869025194)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000263369 SCV000329958 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The F82V variant has been reported previously as de novo and in association with Noonan syndrome (Aoki et al., 2013; Gos et al., 2014; Kouz et al., 2016). The F82V variant is not observed in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies demonstrate that the F82V variant results in enhanced p-ERK levels in comparison to wild-type (Chen et al., 2014; Fang et al., 2016) and increased Elk1 transactivation (Yaoita et al., 2016). Additionally, missense variants at the same residue (F82L/C/S) and nearby residues (A77T/P/S, E81G, T83P, A84V) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret F82V as a pathogenic variant.
Invitae RCV000170492 SCV000659221 pathogenic Noonan syndrome 8 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 82 of the RIT1 protein (p.Phe82Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 25049390, 26757980) and was observed to be de novo in several of these individuals (PMID: 23791108, 24939608, 27101134). ClinVar contains an entry for this variant (Variation ID: 183408). Experimental studies have shown that this missense change increases protein activity and enhances ERK and Elk1 transactivation in vitro (PMID: 25049390, 27226556, 26714497). For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207352 SCV000211882 pathogenic Noonan syndrome no assertion criteria provided clinical testing
OMIM RCV000170492 SCV000222924 pathogenic Noonan syndrome 8 2014-09-01 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000170492 SCV001133063 likely pathogenic Noonan syndrome 8 2019-09-26 no assertion criteria provided clinical testing

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