ClinVar Miner

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

gnomAD frequency: 0.00025  dbSNP: rs201747825
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Total submissions: 12
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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i ndividuals with this variant also had a pathogenic variant in another gene assoc iated with Noonan syndrome (LMM unpublished data).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 (; 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 2021-11-24 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 RCV001000140 SCV001156622 benign CBL-related disorder 2018-08-23 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
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

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