ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.107ACC[8] (p.His42dup) (rs373212940)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000514229 SCV000057252 benign not provided 2016-03-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038350 SCV000062022 likely benign not specified 2014-10-31 criteria provided, single submitter clinical testing c.125_127dupACC in exon 1 of CBL: This variant is not expected to have clinical significance because it has been identified in 0.2% (13/6806) of European Americ an and 0.8% (27/3260) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs397507488). This variant is an in-frame duplication which adds an additional histidine residue (His) to a short repeat of 7 histidines. Additionally, the number of histidines is not co nserved across species.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000038350 SCV000224467 likely benign not specified 2015-05-19 criteria provided, single submitter clinical testing
Invitae RCV001080766 SCV000288829 benign Rasopathy 2020-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000278774 SCV000367751 likely benign Noonan-like syndrome 2016-06-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000038350 SCV000593861 likely benign not specified 2016-01-12 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514229 SCV000610592 likely benign not provided 2017-05-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038350 SCV001362211 benign not specified 2019-12-10 criteria provided, single submitter clinical testing Variant summary: CBL c.125_127dupACC (p.His42dup) results in a in-frame duplication which adds an additional histidine residue to a short repeat of 7 histidines. The variant allele was found at a frequency of 0.002 in 151840 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4400 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 African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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