Submissions for variant NM_006912.6(RIT1):c.104G>C (p.Ser35Thr)

gnomAD frequency: 0.00001  dbSNP: rs869025189

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000207341	SCV000271444	pathogenic	Noonan syndrome	2016-02-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000255076	SCV000322155	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate S35T results in enhanced ELK1 transactivation and altered GDP/GTP binding activities (Aoki et al., 2013; Fang et al. 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25049390, 27226556, 25124994, 25959749, 26757980, 26714497, 28666118, 27101134, 30898653, 29595814, 23791108)
Invitae	RCV000475746	SCV000541752	pathogenic	Noonan syndrome 8	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 35 of the RIT1 protein (p.Ser35Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 23791108, 25124994, 26714497, 26757980, 27101134). ClinVar contains an entry for this variant (Variation ID: 183401). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108, 27226556). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000475746	SCV000893223	pathogenic	Noonan syndrome 8	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000255076	SCV000927787	pathogenic	not provided	2018-07-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235080	SCV003933860	pathogenic	RASopathy	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.104G>C (p.Ser35Thr) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251328 control chromosomes (gnomAD). c.104G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Aoki_2013, Bertola_2014, Kouz), including some cases where the variant was confirmed to have arisen de novo (Kouz_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the variant causes gain-of-function, which is a known mechanism of disease (e.g. Fang_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23791108, 25124994, 27226556, 27101134). Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000475746	SCV004050504	pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207341	SCV000211874	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing