ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.251C>T (p.Ala84Val) (rs869025196)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492853 SCV000583365 likely pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing The A84V variant has been published previously in association with Noonan syndrome (Cavé et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). A84V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E81G, F82V/S/L, T83P, Y89H) 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, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000207351 SCV000713165 likely pathogenic Noonan syndrome 2017-04-07 criteria provided, single submitter clinical testing The p.Ala101Val variant (reported as p.Ala84Val on transcript NM_006912.5) in RI T1 has been reported in 1 individual with clinical features of Noonan syndrome a nd segregated in 2 affected relatives from 1 family (Cave 2016). This variant is absent from large population studies. This variant has been reported in ClinVar (Variation ID 183410). Computational prediction tools and conservation analysis suggest that the p.Ala101Val variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, th e p.Ala101Val variant is likely pathogenic.
Invitae RCV001384932 SCV001584626 pathogenic Noonan syndrome 8 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 84 of the RIT1 protein (p.Ala84Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 26757980, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183410). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This missense change is located in a region of the RIT1 protein where a significant number of previously reported RIT1 missense mutations are found (PMID: 27101134, 30872527, 26757980). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207351 SCV000211885 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing

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