Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000809966 | SCV000950152 | uncertain significance | RASopathy | 2025-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 840 of the CBL protein (p.Cys840Trp). This variant is present in population databases (rs112330156, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 31057598). ClinVar contains an entry for this variant (Variation ID: 654074). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420768 | SCV001623119 | uncertain significance | not specified | 2023-01-23 | criteria provided, single submitter | clinical testing | Variant summary: CBL c.2520T>G (p.Cys840Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.2520T>G has been reported in the literature in at-least one individual reportedly affected with Noonan Syndrome (example, Tekendo-Ngongang_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV002487751 | SCV002785545 | uncertain significance | Juvenile myelomonocytic leukemia; CBL-related disorder | 2021-10-17 | criteria provided, single submitter | clinical testing |