Submissions for variant NM_005188.4(CBL):c.1096-4_1096-1del

dbSNP: rs397517077

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157871	SCV000207801	pathogenic	RASopathy	2014-04-14	criteria provided, single submitter	clinical testing	This mutation is denoted c.1096-4_1096-1delAAAG (IVS7-4_IVS7-1delAAAG) at the cDNA level. Using lower case letters to denote intronic sequence and capital letters to denote exonic sequence, the normal sequence with the bases that are deleted in braces is: aatc{aaag}GAAC. The c.1096-4_1096_1delAAAG mutation in intron 7 in the CBL gene (NM_005188.2) has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. This mutation has previously been observed at GeneDx in a patient referred for testing of the comprehensive panel for Noonan syndrome and related disorders. The c.1096-4_1096-1delAAAG mutation 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. The c.1096-4_1096-1delAAAG mutation in the CBL gene destroys the splice acceptor site of exon 8, which is an in-frame exon encoding portions of the Zn-finger ring and linker region. The c.1096-4_1096-1delAAAG mutation is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Another splice site mutation that destroys this acceptor site (c.1096-1 G>C) has been reported in a homozygous state in a patient with juvenile myelomonocytic leukemia (JMML), caf‚ au lait spots, cryptorchidism, juvenile xanthogranuloma, poor growth, and developmental delay (Niemeyer et al., 2010). We interpret c.1096-4_1096-1delAAAG as a disease-causing mutation. The presence of this mutation is consistent with the diagnosis of Noonan syndrome-like disorder. The variant is found in NOONAN panel(s).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000038347	SCV000576478	likely pathogenic	CBL-related disorder	2017-04-13	criteria provided, single submitter	research
Invitae	RCV000157871	SCV003440957	pathogenic	RASopathy	2022-10-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8 or part of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 25952305). ClinVar contains an entry for this variant (Variation ID: 45197). Disruption of this splice site has been observed in individuals with CBL-related conditions (PMID: 25358541, 25952305, 28589114; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 7 of the CBL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844689	SCV000062019	likely pathogenic	Noonan syndrome	2012-11-08	no assertion criteria provided	clinical testing	The 1096-4_1096-1del variant in CBL has not been reported in the literature nor previously identified by our laboratory. This deletion removes 4 base pairs incl uding the invariant region (-1/2) of the splice consensus sequence and is predic ted to cause a likely impact on splicing. Importantly, another variant (1096-1G> C) affecting the same splice site has been identified in a patient with clinical features of Noonan syndrome and juvenile myelomonocytic leukemia (Niemeyer 2010 ). Loss of this splice site has been shown to cause skipping of exon 8 or retent ion of intron 7, resulting in proteins that lack essential regions of the linker and ring finger domains (Niemeyer 2010). Loss of CBL function results in Ras hy peractivation, which is associated with Noonan syndrome-like disorder with or wi thout JMML. In summary, the 1096-4-1096-1del variant in CBL is likely to be path ogenic, though additional studies are required to fully establish its pathogenic ity.