Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV006663089 | SCV007569150 | uncertain significance | Cardiovascular phenotype | 2026-03-02 | criteria provided, single submitter | clinical testing | The p.R718Q variant (also known as c.2153G>A), located in coding exon 13 of the CBL gene, results from a G to A substitution at nucleotide position 2153. The arginine at codon 718 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13 which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is well conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. As a missense substitution, this variant is predicted to be tolerated by in silico analysis. In addition, loss of function has not been established as a mechanism of disease. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Revvity Omics, |
RCV003144456 | SCV003829280 | uncertain significance | not provided | 2019-08-02 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002499129 | SCV002812793 | uncertain significance | Juvenile myelomonocytic leukemia; CBL-related disorder | 2021-08-16 | criteria provided, single submitter | clinical testing | |
| Genome Diagnostics Laboratory, |
RCV001813540 | SCV002060755 | uncertain significance | Noonan syndrome and Noonan-related syndrome | 2020-11-19 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001290632 | SCV001478747 | uncertain significance | not specified | 2021-01-28 | criteria provided, single submitter | clinical testing | Variant summary: CBL c.2153G>A (p.Arg718Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant is located to the last nucleotide of exon 13, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes the 5' splicing donor site, while three predict the variant weakens this donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 251286 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2153G>A in individuals affected with Noonan Syndrome-Like Disorder and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV000654940 | SCV000776846 | uncertain significance | RASopathy | 2025-12-09 | 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 718 of the CBL protein (p.Arg718Gln). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs144894769, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 543979). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CBL protein function with a negative predictive value of 95%. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. |