Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 |
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, |
RCV001813421 | SCV002060943 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2019-12-02 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
RCV000707713 | SCV002583804 | pathogenic | Noonan syndrome 8 | 2022-08-01 | criteria provided, single submitter | clinical testing | PS3, PS4_Moderate, PM1, PM2, PP3 |
Genome- |
RCV000707713 | SCV004050469 | pathogenic | Noonan syndrome 8 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000707713 | SCV005397064 | pathogenic | Noonan syndrome 8 | 2024-10-21 | criteria provided, single submitter | clinical testing | |
Service de Génétique Moléculaire, |
RCV000207342 | SCV000211886 | pathogenic | Noonan syndrome | no assertion criteria provided | clinical testing | ||
Prevention |
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. |