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

dbSNP: rs727504426

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-06-06	criteria provided, single submitter	clinical testing	Identified as homozygous in peripheral blood of patients with juvenile myelomonocytic leukemia (JMML). In one patient with additional features of poor growth and developmental delay, variant was heterozygous in normal tissues and presumed to be germline (Loh et al., 2009; Niemayer et al., 2010).; Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame deletion of a critical region (part of RING-Type zinc finger and linker region); This variant is associated with the following publications: (PMID: 32637631, 21901340, 20694012, 20955399, 23823657, 28343148, 34026204, 20619386, 22315494, 19571318)
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-11-17	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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), 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). Disruption of this splice site has been observed in individuals with clinical features of CBL-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
St. Jude Molecular Pathology, 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].
3billion	RCV001808423	SCV002058377	pathogenic	CBL-related disorder	2022-01-03	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000177959). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV001678585	SCV000043986	pathogenic	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia	2010-09-01	no assertion criteria provided	literature only