ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000282691 SCV000330342 pathogenic not provided 2021-05-11 criteria provided, single submitter clinical testing Published functional studies demonstrate that A77T acts as a gain-of-function variant, causing increased Elk1 activation and enhanced cJun transcription (Yaoita et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 183403; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27109146, 27101134, 26714497, 26757980, 30692697, 29402968)
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 2020-10-25 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 (PMID: 29402968), and was found to be de novo in several of them (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.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856755 SCV000999305 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000207340 SCV000211877 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing
Baylor Genetics RCV000578238 SCV000854624 pathogenic Noonan syndrome 8 2018-11-18 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000578238 SCV001190831 pathogenic Noonan syndrome 8 2020-02-05 no assertion criteria provided clinical testing

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