Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000155901 | SCV000205612 | uncertain significance | not specified | 2013-06-28 | criteria provided, single submitter | clinical testing | The Arg585Leu variant in CBL has not been previously reported in individuals wi th clinical features of Noonan syndrome or in large population studies. Computat ional analyses (biochemical amino acid properties, conservation, AlignGVGD, Poly Phen2, and SIFT) do not provide strong support for or against an impact to the p rotein. In summary, additional information is needed to fully assess the clinica l significance of the Arg585Leu variant. |
Institute Of Molecular Biology And Genetics, |
RCV000492503 | SCV000494670 | likely pathogenic | CBL-related disorder | criteria provided, single submitter | research | ||
Invitae | RCV001244706 | SCV001417948 | uncertain significance | RASopathy | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 585 of the CBL protein (p.Arg585Leu). This variant is present in population databases (rs727504640, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 25731833). ClinVar contains an entry for this variant (Variation ID: 179116). 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 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. |