ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1096-1G>C (rs397517076)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,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.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV001789707 SCV002032106 not provided not provided no assertion provided research

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