ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.229G>A (p.Ala77Thr) (rs869025191)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000578238 SCV000854624 pathogenic Noonan syndrome 8 2018-11-18 no assertion criteria provided clinical testing
GeneDx RCV000282691 SCV000330342 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing The A77T variant has been published previously in association with disorders in the Noonan syndrome spectrum, including apparently de novo occurrences (Cavé et al., 2016; Yaoita et al., 2016; Kouz et al., 2016). 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. A77T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. Additionally, functional studies have shown A77T acts as a gain-of-function variant, including increased Elk1 activation (Yaoita et al., 2016). Missense variants in the same residue (A77S/P) and in nearby residues (E81G, F82V/L) 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. Therefore, we consider this variant to be pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000578238 SCV000680357 likely pathogenic Noonan syndrome 8 2017-10-27 criteria provided, single submitter clinical testing
Invitae RCV000578238 SCV000776990 pathogenic Noonan syndrome 8 2017-09-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 77 of the RIT1 protein (p.Ala77Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome and at least two of them are known to be de novo (PMID: 26714497, 26757980, 27101134). It has also been found to be de novo in an individual with Costello syndrome (PMID: 26714497). ClinVar contains an entry for this variant (Variation ID: 183403). Experimental studies have shown that this missense change is a gain-of function variant that can enhance Elk1 transactivation (PMID: 26714497). For these reasons, this variant has been classified as Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207340 SCV000211877 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing

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