ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1228-2A>G (rs727504426)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154623 SCV000204296 likely pathogenic Noonan syndrome 2014-06-04 criteria provided, single submitter clinical testing The 1228-2A>G variant in CBL has previously been identified in 5 individuals wit h juvenile myelomonocytic leukemia (JMML; Niemeyer 2010, Perez 2010, Park 2012, Loh 2009), in each of whom it was identified in the homozygous state in the leuk emia cells. At least one of these individuals also had clinical features of a No onan spectrum disorder, and this variant was not identified in either parent of this individual and likely occurred de novo (Niemeyer 2010). In addition, this v ariant was absent from large population studies. Studies have shown that the 122 8-2A>G variant is leads to deletion of exon 9 and is predicted to encode a prote in that lacks essential regions of the linker and RING finger domains (Niemeyer 2010). In summary, this variant is likely to be pathogenic, though additional st udies are required to fully establish its clinical significance.
GeneDx RCV000157861 SCV000207791 pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing The c.1228-2 A>G splice site mutation in the CBL gene has been previously reported as a homozygous variant in leukemia cells of several children with juvenile myelomonocytic leukemia (JMML) (Loh et al., 2009; Niemayer et al., 2009). As this variant destroys the canonical splice acceptor site in intron 8, it is expected to cause abnormal gene splicing and likely results in loss-of-function of the encoded tumor suppressor protein. Heterozygous germline variants in CBL typically cause clinical features that overlap with disorders of the Noonan syndrome spectrum, including growth and developmental delay, dysmorphic features, congenital heart disease, cryptorchidism, cafe'-au-lait spots, and a predisposition to JMML (Loh et al., 2009; Niemayer et al., 2009). Approximately 10-15% of children with JMML are homozygous for a CBL variant due to somatic loss of heterozygosity for a region on chromosome 11q (acquired isodisomy) in leukemia cells (Loh et al., 2009; Perez et al., 2010; Makishima et al., 2009). CBL-related JMML can follow an aggressive clinical course or resolve without treatment, occasionally leading to development of vasculitis later in life (Loh et al., 2009; Niemayer et al., 2009)
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220945 SCV000271340 pathogenic Juvenile myelomonocytic leukemia 2014-06-04 criteria provided, single submitter clinical testing The 1228-2A>G variant in CBL has previously been identified in 5 individuals wit h juvenile myelomonocytic leukemia (JMML; Niemeyer 2010, Perez 2010, Park 2012, Loh 2009), in each of whom it was identified in the homozygous state in the leuk emia cells. At least one of these individuals also had clinical features of a No onan spectrum disorder, and this variant was not identified in either parent of this individual and likely occurred de novo (Niemeyer 2010). In addition, this v ariant was absent from large population studies. Studies have shown that the 122 8-2A>G variant is leads to deletion of exon 9 and is predicted to encode a prote in that lacks essential regions of the linker and RING finger domains (Niemeyer 2010). In summary, this variant meets our criteria to be classified as pathogeni c for JMML, based on presence in the homozygous state in the leukemia cells mult iple individuals with JMML and predicted impact to the protein (http://pcpgm.par tners.org/LMM).
Invitae RCV000705134 SCV000834117 pathogenic Rasopathy 2019-08-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the CBL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of RASopathy spectrum disorder in a family (Invitae). The variant was reported to be de novo in patients with clinical features of RASopathy spectrum disorders (PMID: 20694012), and early-onset pediatric moyamoya angiopathy (PMID: 28343148). ClinVar contains an entry for this variant (Variation ID: 177959). Experimental studies have shown that this variant disrupts mRNA splicing (PMID:20694012). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CBL cause disease. For these reasons, this variant has been classified as Pathogenic.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000722039 SCV000853216 likely pathogenic Malignant germ cell tumor of ovary 2017-04-04 criteria provided, single submitter clinical testing This is a splice site alteration in which an A is replaced by a G in intron 8, two nucleotides upstream from the beginning of exon 9. Classification criteria: PVS1, PM2.
Baylor Genetics RCV000220945 SCV001523395 likely pathogenic Juvenile myelomonocytic leukemia 2020-10-23 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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