ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157858 SCV000207788 pathogenic not provided 2013-11-12 criteria provided, single submitter clinical testing This variant is denoted c.1096-1 G>T (IVS7-1 G>T) at the cDNA level in intron 7 of the CBL gene (NM_005188.2). The c.1096-1 G>T mutation in the CBL gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The c.1096-1 G>T substituition in the CBL gene impacts the canonical splice acceptor site of exon 8, which is an in-frame exon encoding portions of the Zn-finger ring and linker region. Another splice site change affecting the same nucleotide (c.1096-1 G>C) has been reported in a homozygous state in a patient with juvenile myelomonocytic leukemia (JMML) (Niemeyer et al., 2010). In addition, this mutation was demonstrated to impact splicing (Niemeyer et al., 2010). Observation of this mutation in the heterozygous state is consistent with a diagnosis of a Noonan spectrum disorder. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217231 SCV000271339 pathogenic Noonan syndrome 2016-01-26 criteria provided, single submitter clinical testing The c.1096-1G>T variant in CBL has been previously reported in as a de novo, con stitutional (germline) variant in 2 individuals with a RASopathy disorder and a somatic variant in 1 individual with JMML (Matsuda 2010, Bulow 2015, Martinelli 2015). It was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Three additiona l disease-causing variants affecting the same position (c.1096-1G>C, c.1096-1del GG, and c.1096-1delGAAA) have been previously reported in individuals with clini cal features of Noonan syndrome (Niemeyer 2010, Strullu 2013, Bulow 2015, Martin elli 2015). In vitro studies provide some evidence for exon 8 skipping for the c .1096-1G>T variant (Martinelli 2015). In summary, this variant meets our criteri a to be classified as pathogenic for Noonan syndrome in an autosomal dominant ma nner based upon de novo occurrences, absence from controls, and functional evide nce.
Invitae RCV000702743 SCV000831611 pathogenic Rasopathy 2018-04-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 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 reported to occur de novo in several individuals affected with Noonan or Noonan-like syndrome (PMID: 25358541, 25952305, 28589114). ClinVar contains an entry for this variant (Variation ID: 180815). Experimental studies have shown that this splice variant disrupts the canonical splice site and causes the in-frame skipping of exon 8 (PMID: 25952305). For these reasons, this variant has been classified as Pathogenic.
GenomeConnect, ClinGen RCV001249230 SCV001423165 not provided Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 02-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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