ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1096-4_1096-1del (rs397517077)

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Total submissions: 3
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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 Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 2017-04-13 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare 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.

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