ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.244T>C (p.Phe82Leu)

dbSNP: rs869025194
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254958 SCV000322581 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing 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: 25124994, 35627109, 35574990, 27699752, 27101134, 26757980)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000254958 SCV001446501 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813419 SCV002060939 pathogenic Noonan syndrome and Noonan-related syndrome 2020-05-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001850287 SCV002247028 pathogenic Noonan syndrome 8 2022-08-17 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Leu). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 27699752). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 24939608, 25049390, 26757980, 27101134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 183407).
MGZ Medical Genetics Center RCV001850287 SCV002581035 pathogenic Noonan syndrome 8 2022-06-24 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001850287 SCV003824920 pathogenic Noonan syndrome 8 2022-12-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317110 SCV004021061 pathogenic RASopathy 2023-06-12 criteria provided, single submitter clinical testing Variant summary: RIT1 c.244T>C (p.Phe82Leu) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes (gnomAD). c.244T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome, including several cases where it has been reported as a de novo occurrence (e.g.Cave_2016, Arroyo-Carrera_2016, Kouz_2016). These data indicate that the variant is very likely to be associated with disease. Furthermore, another variant resulting in the same amino acid change (c.246T>G, p.Phe82Leu) has been previously classified as pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 27699752, 25124994, 26757980, 27101134). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001850287 SCV004046099 pathogenic Noonan syndrome 8 criteria provided, single submitter clinical testing This variant is also referred to as c.244T>C (p.Phe82Leu) in the literature due to use of an alternate transcript. The c.295T>C (p.Phe99Leu) variant has been previously reported as a de novo change in an individual with Noonan syndrome (PMID: 27699752). The p.Phe99 amino acid residue is a mutational hotspot for pathogenic variants associated with Rasopathy phenotypes (PMID: 33190430, 23791108, 30266093, 26242988, 32596782). The c.295T>C (p.Phe99Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It is absent from the gnomAD population database and thus presumed to be rare. Based on the available evidence, c.295T>C (p.Phe99Leu) is classified as Pathogenic.
Genome-Nilou Lab RCV001850287 SCV004050479 pathogenic Noonan syndrome 8 2023-04-11 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV001850287 SCV004847111 pathogenic Noonan syndrome 8 2024-01-19 criteria provided, single submitter clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré RCV000207346 SCV000211881 pathogenic Noonan syndrome no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000254958 SCV001951089 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000254958 SCV001969315 likely pathogenic not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003927532 SCV004738222 pathogenic RIT1-related disorder 2023-12-26 no assertion criteria provided clinical testing The RIT1 c.295T>C variant is predicted to result in the amino acid substitution p.Phe99Leu. This variant, also referred to as p.Phe82Leu (NM_006912.5), has been reported in multiple individuals with Noonan syndrome and confirmed as de novo in multiple cases (Dufke et al. 2022. PubMed ID: 35574990; Kucińska-Chahwan et al. 2022. PubMed ID: 35627109). Additionally, alternate nucleotide substitutions (c.246T>A, c.246T>G) resulting in the same missense variant have been reported as pathogenic (Aoki et al. 2013. PubMed ID: 23791108; Normand et al. 2018. PubMed ID: 30266093; Liu et al. 2020. PubMed ID: 33190430). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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