Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV003222276 | SCV003916792 | likely pathogenic | not provided | 2023-08-01 | criteria provided, single submitter | clinical testing | CBL: PM1:Strong, PM2 |
| Invitae | RCV003770311 | SCV004619560 | uncertain significance | RASopathy | 2023-08-03 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 975833). This variant has not been reported in the literature in individuals affected with CBL-related conditions. This variant is present in population databases (rs757456261, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 416 of the CBL protein (p.Cys416Ser). 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 CBL protein function. 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. |
| Clinical Genomics Program, |
RCV001252955 | SCV001427018 | likely pathogenic | CBL-related disorder | 2018-10-22 | no assertion criteria provided | clinical testing | The p.Cys416Ser variant in the CBL gene has not been previously reported in association with disease. The p.Cys416Ser variant has been identified in (1/111,608) non-Finnish European alleles by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Cys416Ser variant is located in the RING-finger domain of CBL and other disease-associated variants have been described in this domain which disrupt the function of CBL. This variant was confirmed to have occurred de novo in this individual. Computational tools predict that the p.Cys416Ser variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Cys416Ser variant as likely pathogenic for Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_moderate, PM1, PM2] |