ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1528C>G (p.Pro510Ala)

gnomAD frequency: 0.00005  dbSNP: rs538054260
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000355691 SCV000367764 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 RCV000654950 SCV000776858 likely benign RASopathy 2021-12-09 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001820887 SCV002072334 uncertain significance not specified 2019-03-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001820887 SCV002103770 likely benign not specified 2022-02-14 criteria provided, single submitter clinical testing Variant summary: CBL c.1528C>G (p.Pro510Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251478 control chromosomes (gnomAD). The observed variant frequency is approximately 25 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. c.1528C>G has been reported in the literature in a CBL mutation-associated syndrome affected individual who inherited the variant from an unaffected parent, further evidence the variant is benign (Martinelli_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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