Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Blueprint Genetics | RCV000788444 | SCV000927559 | uncertain significance | not provided | 2018-03-02 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001856225 | SCV002116300 | likely pathogenic | RASopathy | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 262 of the RAF1 protein (p.Asn262Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 636579). 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 RAF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn262 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20052757, 30732632). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002406717 | SCV002669374 | uncertain significance | Cardiovascular phenotype | 2021-10-01 | criteria provided, single submitter | clinical testing | The p.N262Y variant (also known as c.784A>T), located in coding exon 6 of the RAF1 gene, results from an A to T substitution at nucleotide position 784. The asparagine at codon 262 is replaced by tyrosine, an amino acid with dissimilar properties. Additional alterations at the same codon, including p.N262K (c.786T>A and c.786T>G), have been described in individuals with Noonan syndrome, with some cases reported as de novo occurrences (Kobayashi T et al. Hum Mutat, 2010 Mar;31:284-94; Al-Hassnan ZN et al. Circ Genom Precis Med, 2020 10;13:504-514; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |