Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000457434 | SCV000543490 | uncertain significance | RASopathy | 2023-03-18 | criteria provided, single submitter | clinical testing | 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) performed at Invitae indicates that this missense variant is expected to disrupt CBL protein function. ClinVar contains an entry for this variant (Variation ID: 405365). This variant has not been reported in the literature in individuals affected with CBL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 389 of the CBL protein (p.Lys389Glu). |
| St. |
RCV001775119 | SCV002012415 | likely pathogenic | CBL-related disorder | 2021-10-07 | criteria provided, single submitter | clinical testing | The CBL c.1165A>G (p.Lys389Glu) missense change replaces lysine with glutamic acid at codon 389 of the CBL gene and is absent in population databases including gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). The lysine residue is located in the RING finger domain which is a known mutational hotspot in myeloid malignancies and the location of germline pathogenic variants causing Noonan syndrome-like disorder (PM1; PMID: 20619386). This variant has been identified in an individual with juvenile myelomonocytic leukemia (JMML) in which the tumor exhibited a second pathogenic variant in the CBL gene (PS4_supporting, PP4; internal data). This is consistent with the mechanism of leukemogenesis in individuals with JMML and pathogenic germline variants in CBL (PMID: 20694012, 33375775). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). There is a different pathogenic variant (p.Lys389Thr) previously reported at this codon (ClinVar Accession: SCV001826631.1, SCV001445234.1). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied: PS4_supporting, PM1, PM2_supporting, PP3, PP4. |
| MGZ Medical Genetics Center | RCV001775119 | SCV002579428 | likely pathogenic | CBL-related disorder | 2022-05-12 | criteria provided, single submitter | clinical testing |