Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001054701 | SCV001219049 | pathogenic | Noonan syndrome 8 | 2019-04-12 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with glycine at codon 77 of the RIT1 protein (p.Ala77Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of RIT1-related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Ala77 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been observed in individuals with RIT1-related conditions (PMID: 25049390, 26714497, 29402968, 26757980, 27101134, 26714497), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| Institute of Medical Genetics and Applied Genomics, |
RCV001683730 | SCV001905548 | likely pathogenic | not provided | 2021-09-15 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001683730 | SCV002569842 | pathogenic | not provided | 2023-07-28 | 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; Has not been previously published as pathogenic or benign to our knowledge |
| Genome- |
RCV001054701 | SCV004050486 | likely pathogenic | Noonan syndrome 8 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003372960 | SCV004096821 | likely pathogenic | Cardiovascular phenotype | 2023-07-20 | criteria provided, single submitter | clinical testing | The p.A77G variant (also known as c.230C>G), located in coding exon 3 of the RIT1 gene, results from a C to G substitution at nucleotide position 230. The alanine at codon 77 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in individuals with Noonan syndrome, including a de novo occurrence in one individual (Ambry external communication). Another alteration at the same codon, p.A77T (c.229G>A), has been detected in individuals with RASopathies, having de novo occurrences in a few individuals (Cavé H et al. Eur J Hum Genet, 2016 Aug;24:1124-31; Kouz K et al. Genet Med, 2016 Dec;18:1226-1234; Yaoita M et al. Hum Genet, 2016 Feb;135:209-22; Leung GKC et al. Sci Rep, 2018 Feb;8:2421; Yang H et al. Front Genet, 2021 Jun;12:669841; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261; Westenius E et al. Ultrasound Obstet Gynecol, 2022 Oct;60:487-493). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |