ClinVar Miner

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

gnomAD frequency: 0.00076  dbSNP: rs146517083
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000514779 SCV000057272 benign not provided 2019-07-12 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28502479)
Laboratory for Molecular Medicine, Mass General Brigham 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, part of Exact Sciences RCV000120463 SCV000310873 benign not specified criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001001629 SCV000367778 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 RCV001080932 SCV000555938 benign RASopathy 2024-01-31 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 RCV000514779 SCV001159110 likely benign not 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813229 SCV002060497 benign Noonan syndrome and Noonan-related syndrome 2020-01-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000514779 SCV002563090 likely benign not provided 2023-11-01 criteria provided, single submitter clinical testing CBL: BP4, BS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV003315531 SCV004016973 benign Juvenile myelomonocytic leukemia 2023-07-07 criteria provided, single submitter clinical testing
ITMI RCV000120463 SCV000084616 not provided not specified 2013-09-19 no assertion provided reference population
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000514779 SCV001798709 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000120463 SCV001809493 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000514779 SCV001954858 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000514779 SCV001975446 likely benign not provided no assertion criteria provided clinical testing

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