Submissions for variant NM_005188.4(CBL):c.1096-1G>C

dbSNP: rs397517076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038346	SCV000062018	pathogenic	Noonan syndrome	2012-12-06	criteria provided, single submitter	clinical testing	The 1096-1G>C variant in CBL has been reported in one individual with clinical f eatures of Noonan syndrome and juvenile myelomonocytic leukemia (JMML; Loh 2009, Niemeyer 2010). This variant was reported to be homozygous in a blood sample an d heterozygous in the germline. Studies have shown that the 1096-1G>A variant i mpacts splicing (Niemeyer 2010). In addition, this variant was not identified in either parent of this individual and therefore likely occurred de novo, assumin g that non-medical explanations including alternate paternity or undisclosed ado ption have been ruled out. This finding supports that this variant is disease ca using and responsible for Noonan-like syndrome and juvenile myelomonocytic leuke mia in this individual. In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM).
Ambry Genetics	RCV000624342	SCV000742135	pathogenic	Inborn genetic diseases	2017-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001270818	SCV001451582	pathogenic	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia	2020-05-18	criteria provided, single submitter	clinical testing	The CBL c.1096-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in a heterozygous state in one child with juvenile myelomonocytic leukemia who also presented with café-au-lait spots, juvenile xanthogranuloma, cryptorchidism, poor growth, developmental delay, and supraventricular tachycardia (Niemeyer et al. 2010). In addition, evaluation of non-germline cells in this child and two additional individuals showed the c.1096-1G>C variant present in a either a homozygous or heterozygous state (Loh et al. 2009; Niemeyer et al. 2010; Strullu et al. 2013). The c.1096-1G>C variant is located in intron 7. RT-PCR showed the presence of in-frame protein products lacking exon 8, which encompasses the functionally important RING finger domain (Abbas et al. 2008; Niemeyer et al. 2010). Additional splice site variants at the same genomic position with different base changes have also been described in individuals with RASopathy or Noonan-like phenotypes (Strullu et al. 2013; Bulow et al. 2015; Seaby et al. 2017). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage. Based on the collective evidence, the c.1096-1G>C variant is classified as pathogenic for Noonan syndrome-like disorder with juvenile myelomonocytic leukemia.
Invitae	RCV001852803	SCV002243231	pathogenic	RASopathy	2021-12-17	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, but is expected to preserve the integrity of the reading-frame (PMID: 25952305). ClinVar contains an entry for this variant (Variation ID: 45196). Disruption of this splice site has been observed in individual(s) with CBL-related conditions (PMID: 25358541; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor 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.
Fulgent Genetics, Fulgent Genetics	RCV002482996	SCV002789062	likely pathogenic	Juvenile myelomonocytic leukemia; CBL-related disorder	2021-08-12	criteria provided, single submitter	clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001789707	SCV002032106	not provided	not provided		no assertion provided	research