Submissions for variant NM_005188.4(CBL):c.195+3G>A

gnomAD frequency: 0.00004  dbSNP: rs762062705

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436652	SCV000512490	benign	not specified	2015-04-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222390	SCV001394487	uncertain significance	RASopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the CBL gene. It does not directly change the encoded amino acid sequence of the CBL protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 377628). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813473	SCV002060730	uncertain significance	Noonan syndrome and Noonan-related syndrome	2021-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002418246	SCV002719364	uncertain significance	Cardiovascular phenotype	2020-05-26	criteria provided, single submitter	clinical testing	The c.195+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 1 in the CBL gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.