Submissions for variant NM_006912.6(RIT1):c.575C>T (p.Ala192Val)

gnomAD frequency: 0.00001  dbSNP: rs376391961

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000325585	SCV000330715	uncertain significance	not provided	2017-08-14	criteria provided, single submitter	clinical testing	The A192V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed at a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A192V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, yet, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270055	SCV001448791	uncertain significance	Noonan syndrome 8	2019-03-21	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000325585	SCV002009526	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001270055	SCV002783975	uncertain significance	Noonan syndrome 8	2021-08-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001270055	SCV003446474	uncertain significance	Noonan syndrome 8	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 192 of the RIT1 protein (p.Ala192Val). This variant is present in population databases (rs376391961, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280768). 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 with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001270055	SCV004050433	uncertain significance	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021070	SCV005025067	uncertain significance	Cardiovascular phenotype	2024-01-02	criteria provided, single submitter	clinical testing	The p.A192V variant (also known as c.575C>T), located in coding exon 5 of the RIT1 gene, results from a C to T substitution at nucleotide position 575. The alanine at codon 192 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.