ClinVar Miner

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

dbSNP: rs483352822
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Total submissions: 10
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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)
Invitae RCV000170493 SCV000659223 pathogenic Noonan syndrome 8 2022-10-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25959749). 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. ClinVar contains an entry for this variant (Variation ID: 190305). 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. This variant is not present in population databases (gnomAD no frequency). 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).
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 (, indicating this variant is rare, and is reported as pathogenic/likely pathogenic in ClinVar ( 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

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