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

dbSNP: rs483352822

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000355969	SCV000329957	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased MEK-ERK signaling compared to wild-type (Koenighofer et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24939608, 24803665, 25959749, 30732632, 34006472, 35118825, 33726816, 33686258)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000170493	SCV000659223	pathogenic	Noonan syndrome 8	2022-10-22	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 Noonan syndrome (PMID: 23791108, 24939608, 25959749, 27101134, 27109146). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190305). 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. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25959749). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000170493	SCV000680026	pathogenic	Noonan syndrome 8	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0601 - Variant affects at least one well established (essential) functional domain or motif. The Switch II domain is involved in GTP hydrolysis (PMID: 24469055), and missense variants cluster within this domain (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with Noonan syndrome, as have alternate nucleotide changes resulting in the same missense substitution (ClinVar, Mastermind). (P) 1102 - Strong phenotype match. (P) 1208 - Segregation information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000355969	SCV001450252	likely pathogenic	not provided	2015-07-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813422	SCV002060947	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020021	SCV003646693	pathogenic	Cardiovascular phenotype	2022-11-02	criteria provided, single submitter	clinical testing	The c.270G>C (p.M90I) alteration is located in exon 5 (coding exon 4) of the RIT1 gene. This alteration results from a G to C substitution at nucleotide position 270, causing the methionine (M) at amino acid position 90 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with clinical features of RASopathy; it has been reported to have occurred de novo in some individuals (Gos, 2014; Koenighofer, 2015; Yaoita, 2016; Chen, 2019). The same amino acid substitution resulting from c.270G>T has also been observed in individuals with RASopathy (Aoki, 2016; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies showed that M90I enhances RAS-MAPK signaling (Yaoita, 2016; Koenighofer, 2015; Castel, 2019). In addition, a mouse model harboring M90I had a phenotype resembling Noonan syndrome in humans (Castel, 2019). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Genome-Nilou Lab	RCV000170493	SCV004050466	likely pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416059	SCV004116477	pathogenic	RIT1-related disorder	2023-03-21	criteria provided, single submitter	clinical testing	The RIT1 c.321G>C variant is predicted to result in the amino acid substitution p.Met107Ile. In the literature this variant is also referred to as c.270G>C (p.Met90Ile) via NM_006912. This variant has been reported to be de novo in individuals with Noonan syndrome (Gos et al. 2014. PubMed ID: 24939608; Koenighofer et al. 2015. PubMed ID: 25959749; Chen et al. 2019. PubMed ID: 30732632; Frisk et al. 2022. PubMed ID: 35118825). This variant was also reported to be de novo in a fetus undergoing testing for nonimmune hydrops fetalis (Al-Kouatly et al. 2021. PubMed ID: 33686258) and in another individual undergoing testing for short stature (Table S3, Fan et al. 2021. PubMed ID: 34006472). Functional studies have shown this variant alters protein function (Koenighofer et al, 2015. PubMed ID: 25959749; Yaoita et al. 2016. PubMed ID: 26714497; Castel et al. 2019. PubMed ID: 30872527). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/190305/). This variant is interpreted as pathogenic.
OMIM	RCV000170493	SCV000222925	pathogenic	Noonan syndrome 8	2014-09-01	no assertion criteria provided	literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000170493	SCV001482334	pathogenic	Noonan syndrome 8	2019-05-31	no assertion criteria provided	research