Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000155642 | SCV000205350 | likely pathogenic | Noonan syndrome | 2015-12-14 | criteria provided, single submitter | clinical testing | The p.Gln367Lys variant in CBL has been identified by our laboratory in 1 indivi dual with clinical features of Noonan syndrome and segregated with disease in 3 affected relatives. It was absent from large population studies. Two other amino acid changes at this position (p.Gln367Pro, p.Gln367Arg) have been reported: 1 in an individual with Noonan syndrome (Martinelli 2010) and 1 in an individual w ith chronic myelomonocytic leukemia (CMML; Kholmann 2010). Missense variants in exon 8 are located in the linker domain of CBL, are mutational hotspots in hemat ological malignancies, and have been shown to affect CBL protein function in bot h in vivo and in vitro studies (Sanada 2009, Martinelli 2010). Additional comput ational prediction tools and conservation analysis suggest that the p.Gln367Lys variant may impact the protein. In summary, although additional studies are requ ired to fully establish its clinical significance, the p.Gln367Lys variant is li kely pathogenic. |
| Ambry Genetics | RCV001265817 | SCV001443989 | uncertain significance | Inborn genetic diseases | 2018-09-07 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002514998 | SCV002956667 | likely pathogenic | RASopathy | 2022-07-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 367 of the CBL protein (p.Gln367Lys). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gln367 amino acid residue in CBL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20619386, 24458550, 25358541). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 178870). 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). |