ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.365G>T (p.Arg122Leu)

dbSNP: rs777520196
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000357501 SCV000330538 likely pathogenic not provided 2023-08-08 criteria provided, single submitter clinical testing Published functional studies demonstrate R122L results in increased phosphorylation of MEK and ERK1/2 compared to wild-type (Berger et al., 2014); 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: 24469055, 35353015, 34887308)
Invitae RCV001037285 SCV001200691 pathogenic Noonan syndrome 8 2022-02-08 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: 24469055). 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 not expected to disrupt RIT1 protein function. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 122 of the RIT1 protein (p.Arg122Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RIT1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280609).
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital RCV002051722 SCV001950189 likely pathogenic Megalencephaly-capillary malformation-polymicrogyria syndrome; Noonan syndrome 8 2021-09-30 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813444 SCV002060858 uncertain significance Noonan syndrome and Noonan-related syndrome 2017-06-14 criteria provided, single submitter clinical testing

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