Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV005520358 | SCV006209049 | uncertain significance | Cardiovascular phenotype | 2025-05-27 | criteria provided, single submitter | clinical testing | The p.C421W variant (also known as c.1263T>G), located in coding exon 9 of the CBL gene, results from a T to G substitution at nucleotide position 1263. The cysteine at codon 421 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV000822129 | SCV000962916 | uncertain significance | RASopathy | 2022-10-14 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 421 of the CBL protein (p.Cys421Trp). ClinVar contains an entry for this variant (Variation ID: 664109). This variant has not been reported in the literature in individuals affected with CBL-related conditions. 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CBL protein function. |