Submissions for variant NM_006912.6(RIT1):c.242A>G (p.Glu81Gly)

dbSNP: rs869025193

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255048	SCV000322478	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrated that zebrafish embryos injected with RIT1 mRNA carrying p.(E81G) exhibit craniofacial and heart defects (Aoki et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23765226, 26446362, 24803665, 25959749, 33794220, 33128510, 23791108, 26757980, 28347726)
Invitae	RCV000054405	SCV000541753	pathogenic	Noonan syndrome 8	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 81 of the RIT1 protein (p.Glu81Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 23791108, 26757980). ClinVar contains an entry for this variant (Variation ID: 183405). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt RIT1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 23791108). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508083	SCV000605037	pathogenic	not specified	2017-01-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000207350	SCV000712478	pathogenic	Noonan syndrome	2016-09-12	criteria provided, single submitter	clinical testing	The p.Glu98Gly (also reported as p.Glu81Gly) variant in RIT1 has been identified in 4 individuals with clinical features of Noonan Syndrome, one of which was de novo, and segregated with disease in 3 affected relatives (Aoki 2013 and Cave 2 016, Cave personal communication). This variant was absent from large population studies. In vitro functional studies provide some evidence that this variant ma y impact protein function (Aoki 2013). In addition, an animal model in zebrafish has shown that this variant causes developmental defects similar to those seen in zebrafish with gain-of-function NRAS variants (Aoki 2013). Computational pred iction tools and conservation analysis suggest that the p.Glu98Gly variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the p.Glu98Gly variant is pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000054405	SCV000893222	pathogenic	Noonan syndrome 8	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174556	SCV001337716	pathogenic	RASopathy	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.242A>G (p.Glu81Gly) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250506 control chromosomes (gnomAD). c.242A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions (e.g. Aoki_2013, Cave_2016, Ramond_2017, Bell_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer significantly increased transcriptional activity by ELK1 compared to the WT (Aoki_2013), consistent with the established gain-of-function mechanism of disease for RIT1. Furthermore, zebrafish embryos with the variant displayed heart and facial abnormalities, with a small percentage of them being severely disorganized (Aoki_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23791108, 33794220, 26757980, 28347726). Nine ClinVar submitters have assessed the variant since 2014: eight have classified the variant as pathogenic, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001265779	SCV001443949	pathogenic	Inborn genetic diseases	2018-02-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000054405	SCV002019054	likely pathogenic	Noonan syndrome 8	2020-10-31	criteria provided, single submitter	clinical testing
3billion	RCV000054405	SCV002058650	pathogenic	Noonan syndrome 8	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183405, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported to be associated with RIT1 related disorder (ClinVar ID: VCV000183404, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.902, 3CNET: 0.991, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 8 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813418	SCV002060938	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000054405	SCV003924369	pathogenic	Noonan syndrome 8	2023-05-10	criteria provided, single submitter	clinical testing	Heterozygous variant NM_006912.6:c.242A>G in RIT1 gene was found on the WES data in female proband, 20 y.o., sporadic case, with Noonan syndrome and diffuse generalized cardiac hypertrophy . The c.242A>G is absent in The Genome Aggregation Database (gnomAD) (Date of access: 05-05-2023). In accordance with ACMG(2015) criteria this variant is classified as a pathogenic variant with the following criteria selected: PS4_Supporting, PS3, PM2, PM6, PP3, (PP5).
Genome-Nilou Lab	RCV000054405	SCV004050481	likely pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000255048	SCV004226717	pathogenic	not provided	2023-02-06	criteria provided, single submitter	clinical testing	PP3, PM1, PM2_supporting, PM6, PS3_moderate, PS4
OMIM	RCV000054405	SCV000082882	pathogenic	Noonan syndrome 8	2013-07-11	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207350	SCV000211879	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing