Submissions for variant NM_006912.6(RIT1):c.284G>C (p.Gly95Ala)

dbSNP: rs672601335

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000207348	SCV000271447	pathogenic	Noonan syndrome	2015-03-18	criteria provided, single submitter	clinical testing	The p.Gly112Ala variant in RIT1 (also reported as p.Gly95Ala on transcript NM_00 6912.5) has been reported in at least 9 individuals with clinical features of No onan syndrome including 2 de novo occurrences (Aoki 2013, Bertola 2014, Chen 201 4, Gos 2014), and was absent from large population studies. In vitro functional studies provide conflicting evidence on the impact of the p.Gly112Ala variant on protein function (Aoki 2013, Chen 2014), but these types of assays may not accu rately represent biological function. However, animal models in the zebrafish ha ve shown that this variant causes developmental anomalies similar to those seen in Noonan syndrome (Aoki 2013). In summary, this variant meets our criteria to b e classified as pathogenic for Noonan syndrome in an autosomal dominant manner ( http://www.partners.org/personalizedmedicine/LMM) based upon de novo occurrences , absence from controls, and functional evidence.
GeneDx	RCV000298790	SCV000329956	pathogenic	not provided	2021-06-24	criteria provided, single submitter	clinical testing	Reported previously in association with Noonan spectrum disorders (Gos et al., 2014); Published functional studies demonstrate an increased activity of the RIT1 protein compared to wild type (Aoki et al., 2013); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27109146, 25959749, 24939608, 27535533, 25124994, 25049390, 23791108, 26757980, 26446362, 27226556, 24803665, 26714497, 27101134)
Eurofins Ntd Llc (ga)	RCV000298790	SCV000709341	pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Invitae	RCV000054407	SCV000776991	pathogenic	Noonan syndrome 8	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RIT1 function (PMID: 23791108, 25049390, 27226556). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 60509). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 2439608, 23791108, 25049390, 25124994, 26714497, 26757980, 27101134, 27109146). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the RIT1 protein (p.Gly95Ala).
Fulgent Genetics, Fulgent Genetics	RCV000054407	SCV000893219	pathogenic	Noonan syndrome 8	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000298790	SCV000927755	pathogenic	not provided	2018-06-19	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000054407	SCV001190410	pathogenic	Noonan syndrome 8	2022-08-16	criteria provided, single submitter	clinical testing	RIT1 NM_006912.5 exon 5 p.Gly95Ala (c.284G>C): This variant has been reported in the literature in at least 11 individuals with Noonan syndrome (Aoki 2013 PMID:23791108, Chen 2013 PMID:25049390, Bertola 2014 PMID:25124994, Gos 2014 PMID:24939608, Milosavljević 2016 PMID:27109146); two of these individuals were identified as de novo (Aoki 2013 PMID:23791108). This variant was also reported in at least 2 additional individuals with features of a RAS-opathy (Yaoita 2016 PMID:26714497) as de novo. This variant is not present in large control databases but is present in ClinVar with several labs classifying this variant as pathogenic (Variation ID:60509). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In-vivo functional studies in zebrafish also support a deleterious effect of this variant (Aoki 2013 PMID:23791108). In summary, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192384	SCV001360455	pathogenic	RASopathy	2019-10-29	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.284G>C (p.Gly95Ala) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225), in the switch II region (Chen_2014) 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 251438 control chromosomes (gnomAD). c.284G>C has been reported in the literature in heterozygous state in several individuals affected with Noonan Syndrome and Related Conditions, including confirmed de novo occurrences, and segregation with disease in at least 1 family (Aoki_2013, Chen_2014, Kouz_2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein increases the activity of the RAS/MAPK pathway (Aoki_2013, Chen_2014). In addition, transfection of the variant into zebrafish embryos resulted in a variety of developmental defects, consistent with the disease phenotype observed in humans (Aoki_2013). Seven ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000298790	SCV001449825	pathogenic	not provided	2015-11-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000054407	SCV002020798	pathogenic	Noonan syndrome 8	2021-04-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813374	SCV002060948	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433549	SCV002751805	pathogenic	Cardiovascular phenotype	2019-03-21	criteria provided, single submitter	clinical testing	The p.G95A pathogenic mutation (also known as c.284G>C), located in coding exon 4 of the RIT1 gene, results from a G to C substitution at nucleotide position 284. The glycine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration has been observed in multiple individuals with Noonan syndrome (Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31; Milosavljevi D et al. Am. J. Med. Genet. A, 2016 07;170:1874-80; Chen PC et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Aug;111:11473-8; Bertola DR et al. Am. J. Med. Genet. A, 2014 Nov;164A:2952-7; Kouz K et al. Genet. Med., 2016 12;18:1226-1234; Gos M et al. Am. J. Med. Genet. A, 2014 Sep;164A:2310-6) and occurred de novo in three individuals with Noonan syndrome (Aoki Y et al. Am. J. Hum. Genet., 2013 Jul;93:173-80; Yaoita M et al. Hum. Genet., 2016 Feb;135:209-22). Based on the available evidence, this variant is classified as a pathogenic mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000054407	SCV002767340	pathogenic	Noonan syndrome 8	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome (MIM#615335). Disease-causing variants have been shown to result in increased phosphorylation of ERK1/2, increased transactivation of ELK1, and enhanced protein complex formation (PMID: 23791108, 29734338). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional Switch II domain. The Switch II domain is involved in protein-protein interactions, and pathogenic variants in this domain result in enhanced protein complex formation (PMID: 29734338). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as pathogenic in many individuals with Noonan syndrome (ClinVar, LOVD, PMID: 23791108, 26714497). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant results in in increased phosphorylation of ERK1/2, increased transactivation of ELK1, and enhanced protein complex formation (PMID: 23791108, 29734338). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed; LABID). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion	RCV000054407	SCV003841372	pathogenic	Noonan syndrome 8	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000060509). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 23791108, 26714497). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23791108, 26714497). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000054407	SCV004050463	pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915017	SCV004734120	pathogenic	RIT1-related condition	2024-02-15	criteria provided, single submitter	clinical testing	The RIT1 c.335G>C variant is predicted to result in the amino acid substitution p.Gly112Ala. This variant is also referred to as p.Gly95Ala in an alternate transcript (NM_006912.6). This variant has been reported in at least 11 individuals with Noonan syndrome and was documented as a de novo event in at least two individuals (Aoki et al. 2013. PubMed ID: 23791108; Bertola et al. 2014. PubMed ID: 25124994; Chen et al. 2014. PubMed ID: 25049390; Gos et al. 2014. PubMed ID: 24939608; Milosavljević et al. 2016. PubMed ID: 27109146). Functional studies provide conflicting evidence on the effect of this variant on RIT1 function (Aoki et al. 2013. PubMed ID: 23791108; Chen et al. 2014. PubMed ID: 25049390). In ClinVar, this variant has been interpreted as pathogenic by multiple clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/60509/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000054407	SCV000082884	pathogenic	Noonan syndrome 8	2014-11-01	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207348	SCV000211887	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000207348	SCV000805108	pathogenic	Noonan syndrome	2017-04-21	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000298790	SCV001742421	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000298790	SCV001955713	pathogenic	not provided		no assertion criteria provided	clinical testing
Molecular Genetics, Centre for Human Genetics	RCV003450918	SCV004190092	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing