Submissions for variant NM_005188.4(CBL):c.1227+4C>T

gnomAD frequency: 0.00048  dbSNP: rs201747825

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038348	SCV000062020	likely benign	not specified	2014-03-21	criteria provided, single submitter	clinical testing	1227+4C>T in intron 8 of CBL: This variant has now been identified by our labora tory in several individuals with clinical features of Noonan syndrome. However, this variant was identified in two unaffected parents, and two of the affected i ndividuals with this variant also had a pathogenic variant in another gene assoc iated with Noonan syndrome (LMM unpublished data). This variant has also been re ported in a patient with clinical features of juvenile myelomonocytic leukemia ( JMML; Loh 2009), but has been identified in 0.05% (4/8590) of European American chromosomes from a large population study by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs201747825). This variant is located in the 5' splice region, though computational tools do not suggest an impact to splicing. In summary, this variant is not expected to have clinical significance because it has been identified in the general population and in two reportedly unaffected parents.
GeneDx	RCV000049227	SCV000077241	benign	RASopathy	2012-04-17	criteria provided, single submitter	clinical testing	The variant is found in NOONAN panel(s).
Invitae	RCV000049227	SCV000288828	likely benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001000140	SCV000367757	likely benign	CBL-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705685	SCV001156622	benign	not provided	2023-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038348	SCV001362306	benign	not specified	2019-12-24	criteria provided, single submitter	clinical testing	Variant summary: CBL c.1227+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00083 in 251398 control chromosomes. The observed variant frequency is approximately 331 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1227+4C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813344	SCV002060485	benign	Noonan syndrome and Noonan-related syndrome	2020-09-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000038348	SCV002064994	likely benign	not specified	2021-12-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490522	SCV002803563	likely benign	Juvenile myelomonocytic leukemia; CBL-related disorder	2021-07-09	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315559	SCV004016969	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001705685	SCV004129478	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	CBL: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV001000140	SCV004747660	benign	CBL-related disorder	2019-09-11	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV001705685	SCV001925986	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038348	SCV001930176	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001705685	SCV001956177	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001705685	SCV001968141	likely benign	not provided		no assertion criteria provided	clinical testing