Submissions for variant NM_006912.6(RIT1):c.229G>A (p.Ala77Thr)

dbSNP: rs869025191

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000282691	SCV000330342	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that A77T acts as a gain-of-function variant, causing increased Elk1 activation and enhanced cJun transcription (Yaoita et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 183403; ClinVar); This variant is associated with the following publications: (PMID: 27109146, 27101134, 26714497, 26757980, 30692697, 29402968, 33726816)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578238	SCV000680357	likely pathogenic	Noonan syndrome 8	2017-10-27	criteria provided, single submitter	clinical testing
Invitae	RCV000578238	SCV000776990	pathogenic	Noonan syndrome 8	2022-06-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 77 of the RIT1 protein (p.Ala77Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26714497, 26757980, 27101134, 29402968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183403). 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. Experimental studies have shown that this missense change affects RIT1 function (PMID: 26714497). For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000856755	SCV000999305	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114309	SCV003801033	pathogenic	RASopathy	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.229G>A (p.Ala77Thr) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes. c.229G>A has been reported in the literature as a de-novo occurrence in multiple individuals affected with Noonan Syndrome (example, PMID: 26757980, 26714497). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 26714497). The most pronounced variant effect results in significantly enhanced ELK transactivation, confirming the gain-of function mechanism of disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000578238	SCV004050490	likely pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207340	SCV000211877	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
Baylor Genetics	RCV000578238	SCV000854624	pathogenic	Noonan syndrome 8	2018-11-18	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000578238	SCV001190831	pathogenic	Noonan syndrome 8	2020-02-05	no assertion criteria provided	clinical testing
Molecular Genetics, Centre for Human Genetics	RCV000856755	SCV004190095	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing