Submissions for variant NM_005188.4(CBL):c.1384C>T (p.Arg462Ter)

dbSNP: rs886041425

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000386480	SCV000330066	uncertain significance	not provided	2015-12-18	criteria provided, single submitter	clinical testing	The R462X variant in the CBL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R462X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R462X as a variant of uncertain significance
Genetic Services Laboratory, University of Chicago	RCV001820803	SCV002067447	uncertain significance	not specified	2020-03-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CBL gene demonstrated a sequence change, c.1384C>T, which results in the creation of a premature stop codon at amino acid position 462, p.Arg462*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CBL protein with potentially abnormal function. This sequence change is absent from large population databases (ExAC and gnomAD). This sequence change does not appear to have been previously described in patients with CBL-related disorders. Other truncating variants described in this gene have been reported upstream to this position. Due to the lack of additional studies that conclusively demonstrate the effect of this variant on protein function and the fact that no other truncating changes associated with a detrimental effect on CBL protein function have been described downstream to this variant position, the clinical significance of the p.Arg462* change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519043	SCV003005941	uncertain significance	RASopathy	2024-08-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg462*) in the CBL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CBL cause disease. This variant is not present in population databases (gnomAD no frequency). 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: 280170). 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.