ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.265T>C (p.Tyr89His)

dbSNP: rs869025197
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486847 SCV000568807 pathogenic not provided 2024-11-25 criteria provided, single submitter clinical testing Published functional studies demonstrate enhanced Elk1 transactivation and a 4-fold faster nucleotide exchange rate in comparison to wild-type (PMID: 27226556, PMID:26714497); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26446362, 26714497, 30025578, 35904599, 36274670, 33792302, 36578016, 27226556, 23791108)
Labcorp Genetics (formerly Invitae), Labcorp RCV000707713 SCV000836822 pathogenic Noonan syndrome 8 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 89 of the RIT1 protein (p.Tyr89His). 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, 26757980; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183411). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt RIT1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects RIT1 function (PMID: 26714497, 27226556). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813421 SCV002060943 pathogenic Noonan syndrome and Noonan-related syndrome 2019-12-02 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000707713 SCV002583804 pathogenic Noonan syndrome 8 2022-08-01 criteria provided, single submitter clinical testing PS3, PS4_Moderate, PM1, PM2, PP3
Genome-Nilou Lab RCV000707713 SCV004050469 pathogenic Noonan syndrome 8 2023-04-11 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000707713 SCV005397064 pathogenic Noonan syndrome 8 2024-10-21 criteria provided, single submitter clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré RCV000207342 SCV000211886 pathogenic Noonan syndrome no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003965185 SCV004777622 pathogenic RIT1-related disorder 2023-11-27 no assertion criteria provided clinical testing The RIT1 c.316T>C variant is predicted to result in the amino acid substitution p.Tyr106His. This variant is also referred to as c.265T>C (p.Tyr89His) in an alternate transcript (NM_006912). This variant has been identified in the heterozygous state in an individual with Noonan syndrome or a related phenotype (Aoki et al. 2013. PubMed ID: 23791108; Cavé et al. 2016. PubMed ID: 26757980). Functional studies determined that the p.Tyr106His variant leads to enhanced activation and a more rapid nucleotide exchange rate as compared to wildtype (Fang et al. 2016. PubMed ID: 27226556; Yaoita et al. 2016. PubMed ID: 26714497). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. In the ClinVar database, this variant is interpreted as pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/183411/). This variant is interpreted as pathogenic.

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