Submissions for variant NM_006912.6(RIT1):c.270G>A (p.Met90Ile)

dbSNP: rs483352822

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220792	SCV000271445	pathogenic	Noonan syndrome	2016-02-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000301748	SCV000330351	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Published functional studies have shown that the variant induces the phosphorylation of ERK through activation of MEK (Berger et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the critical Switch II domain which is involved in GTP hydrolysis (Berger et al., 2014); This variant is associated with the following publications: (PMID: 34906519, 24469055, 22980975, 23791108, 24896146, 26757980, 26714497, 33144663, 34008892, 34704406)
Invitae	RCV000106331	SCV001589498	pathogenic	Noonan syndrome 8	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cardio-facio-cutaneous syndrome (PMID: 23791108, 24896146, 24939608, 25959749). ClinVar contains an entry for this variant (Variation ID: 120250). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000106331	SCV001976941	pathogenic	Noonan syndrome 8	2021-10-01	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP2, PP3, PP4, PP5
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813378	SCV002060945	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844039	SCV002103826	pathogenic	RASopathy	2022-02-21	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.270G>A (p.Met90Ile) results in a conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.270G>A has been reported in the literature in individuals affected with Noonan Syndrome as a de novo variant (examples: Lallar_2020, Aoi_2021). The variant was reported to lead to increased RIT1 expression levels and accelerated the rate of mitotic progression in asynchronously growing cells (Cuevas-Navarro_2021). Additionally, a different variant affecting the same codon has been reported as pathogenic by our lab (p.Met90Val). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000106331	SCV003921836	pathogenic	Noonan syndrome 8	2022-02-23	criteria provided, single submitter	clinical testing	0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 8 (MIM#615355). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (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 very high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two different variants in the same codon resulting in changes to leucine and valine have also been reported as likely pathogenic and pathogenic in ClinVar respectively. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with Noonan syndrome (ClinVar. PMID: 24896146). Two alternative nucleotide changes (c.270G>T and c.270G>C) resulting in the same amino acid change as this variant (p.Met90Ile) have also been reported as pathogenic in ClinVar. (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV000106331	SCV004050467	likely pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	RCV000106331	SCV000143829	not provided	Noonan syndrome 8		no assertion provided	not provided