ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.2269G>A (p.Ala757Thr) (rs146517083)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000514779 SCV000057272 likely benign not provided 2018-05-21 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 RCV000120463 SCV000197243 benign not specified 2015-10-08 criteria provided, single submitter clinical testing p.Ala757Thr in exon 15 of CBL: This variant is not expected to have clinical sig nificance it has been identified in 0.5% (81/16512) of South Asian chromosomes ( including 1 homozygous individual) and 0.1% (62/66732) of European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146517083).
PreventionGenetics,PreventionGenetics RCV000120463 SCV000310873 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001001629 SCV000367778 benign Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 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 RCV001080932 SCV000555938 benign Rasopathy 2020-11-25 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514779 SCV000611031 likely benign not provided 2017-05-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282832 SCV001159110 likely benign none provided 2020-03-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120463 SCV001339181 benign not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: CBL c.2269G>A (p.Ala757Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251422 control chromosomes, predominantly at a frequency of 0.006 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2400 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 South Asian 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 (2x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
ITMI RCV000120463 SCV000084616 not provided not specified 2013-09-19 no assertion provided reference population

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