ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.539G>A (p.Arg180Gln)

gnomAD frequency: 0.00001  dbSNP: rs760845441
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413457 SCV000491466 uncertain significance not specified 2016-03-02 criteria provided, single submitter clinical testing The R180Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. R180Q was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R180Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, R180Q is not located in a known functional area of the RIT1 gene and there are no similar variants reported in nearby residues (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001850986 SCV002273220 uncertain significance Noonan syndrome 8 2024-08-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 180 of the RIT1 protein (p.Arg180Gln). This variant is present in population databases (rs760845441, gnomAD 0.002%). 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: 372925). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics RCV004022165 SCV003621157 uncertain significance Cardiovascular phenotype 2022-04-22 criteria provided, single submitter clinical testing The c.539G>A (p.R180Q) alteration is located in exon 6 (coding exon 5) of the RIT1 gene. This alteration results from a G to A substitution at nucleotide position 539, causing the arginine (R) at amino acid position 180 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV001850986 SCV004050437 uncertain significance Noonan syndrome 8 2023-04-11 criteria provided, single submitter clinical testing

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