Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000038360 | SCV000062032 | uncertain significance | not specified | 2012-10-01 | criteria provided, single submitter | clinical testing | The Arg829Gln variant in CBL has not been reported in the literature nor previou sly identified by our laboratory. This variant has been identified in 0.01% (1/8 590) of European American chromosomes and 0.02% (1/4398) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/); however, this frequency is too low to confidently ru le out a role in disease. Computational analyses (biochemical amino acid propert ies, conservation across species, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of the Arg829Gln variant. |
Illumina Laboratory Services, |
RCV001103082 | SCV001259800 | likely benign | CBL-related disorder | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. |
Invitae | RCV001320329 | SCV001511110 | uncertain significance | RASopathy | 2023-12-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 829 of the CBL protein (p.Arg829Gln). This variant is present in population databases (rs374672276, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 45205). 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000038360 | SCV002548363 | uncertain significance | not specified | 2022-05-19 | criteria provided, single submitter | clinical testing | Variant summary: CBL c.2486G>A (p.Arg829Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2486G>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Ce |
RCV003326336 | SCV004033172 | uncertain significance | not provided | 2023-08-01 | criteria provided, single submitter | clinical testing | CBL: PM1, PS2:Supporting |
Prevention |
RCV003974883 | SCV004793311 | uncertain significance | CBL-related condition | 2024-02-26 | criteria provided, single submitter | clinical testing | The CBL c.2486G>A variant is predicted to result in the amino acid substitution p.Arg829Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |