Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000157869 | SCV000207799 | uncertain significance | not provided | 2013-05-22 | criteria provided, single submitter | clinical testing | This variant is denoted p.Arg835Trp at the protein level, c.2503C>T at the cDNA level, and results in the change of an Arginine for a Tryptophan (CGG>TGG) in exon 16 of the CBL gene (NM_005188.2). The R835W missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This missense change is a non-conservative amino acid substitution with a positively charged and polar residue (Arg) being replaced by a neutral and non-polar residue (Trp). The residue at which this substitution occurs is highly conserved in the protein. However, no missense mutations have been reported in the CBL gene beyond codon Arginine 420 (Martinelli et al., 2010). The R835W variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, R835W is interpreted as a variant of unknown significance. The variant is found in NOONAN panel(s). |
| Labcorp Genetics |
RCV001850198 | SCV002259705 | uncertain significance | RASopathy | 2024-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 835 of the CBL protein (p.Arg835Trp). This variant is present in population databases (rs368696716, gnomAD 0.002%). 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: 180824). 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%. 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. |