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

gnomAD frequency: 0.00001  dbSNP: rs397517076

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157858	SCV000207788	pathogenic	not provided	2023-11-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 20694012, 25358541, 26796102, 25952305, 20595524, 23823657, 28589114, 34345822, 30417923, 31935506, 20619386, 22315494, 25533962)
Laboratory for Molecular Medicine, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702743	SCV000831611	pathogenic	RASopathy	2020-04-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this splice variant disrupts the canonical splice site and causes the in-frame skipping of exon 8 (PMID: 25952305). This variant has been observed in individual(s) affected with Noonan or Noonan-like syndrome (PMID: 25358541, 28589114, 25952305, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 180815). This variant is not present in population databases (ExAC no frequency). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989335	SCV004805958	pathogenic	CBL-related disorder	2024-03-25	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001249230	SCV001423165	not provided	Fragile site 11b; CBL-related disorder		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.