ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1228-10dup (rs397517078)

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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 RCV000038349 SCV000062021 likely benign not specified 2012-06-14 criteria provided, single submitter clinical testing 1228-10_1228-9insT in intron 8 of CBL: This variant is not expected to have clin ical significance because it is not located within the splice consensus sequence .
Illumina Clinical Services Laboratory,Illumina RCV000405234 SCV000367759 likely benign Noonan-like syndrome 2016-06-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038349 SCV001362307 benign not specified 2019-10-22 criteria provided, single submitter clinical testing Variant summary: CBL c.1228-10dupT alters a 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 0.00095 in 251332 control chromosomes, predominantly at a frequency of 0.008 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3200 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 a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.1228-10dupT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (NF1 c.2540T>C, p.L847P), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV001511169 SCV001718368 benign Rasopathy 2020-12-04 criteria provided, single submitter clinical testing

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