ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.2569C>T (p.Leu857Phe)

gnomAD frequency: 0.00029  dbSNP: rs201631570
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000338492 SCV000367781 benign CBL-related disorder 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000861286 SCV001001555 likely benign not provided 2018-07-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420785 SCV001623145 likely benign not specified 2021-05-10 criteria provided, single submitter clinical testing Variant summary: CBL c.2569C>T (p.Leu857Phe) results in a non-conservative amino acid change located in the Ubiquitin-associated domain (IPR015940) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251474 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 920-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. c.2569C>T has been reported in the literature in an individual affected with myelodysplastic syndrome (Taguchi_2020). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV001469615 SCV001673695 likely benign RASopathy 2021-04-11 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV001813454 SCV002060499 likely benign Noonan syndrome and Noonan-related syndrome 2020-05-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001420785 SCV002068642 benign not specified 2019-03-18 criteria provided, single submitter clinical testing

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