ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1477C>T (p.Leu493Phe)

gnomAD frequency: 0.00010  dbSNP: rs730880434
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157864 SCV000207794 uncertain significance not provided 2014-12-01 criteria provided, single submitter clinical testing This variant is denoted p.Leu493Phe (L493F) at the protein level, c.1477 C>T at the cDNA level and results in the change of a Leucine for a Phenylalanine (CTT>TTT) in exon 10 of the CBL gene (NM_005188.2). The L493F missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Server reports L493F was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The L493F variant is a conservative amino acid substitution since both Leucine and Phenylalanine are neutral non-polar residues; however, Leucine is highly conserved at this position across species. Therefore, based on the currently available information, it is unclear whether L493F is a disease-causing mutation or a rare benign variant. The variant is found in CBL panel(s).
Ambry Genetics RCV000622732 SCV000742159 uncertain significance Inborn genetic diseases 2017-01-23 criteria provided, single submitter clinical testing
Invitae RCV000707567 SCV000836668 likely benign RASopathy 2021-11-19 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001102986 SCV001259694 uncertain significance CBL-related disorder 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory,University of Chicago RCV001818346 SCV002071193 uncertain significance not specified 2019-10-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818346 SCV002556016 likely benign not specified 2022-06-20 criteria provided, single submitter clinical testing Variant summary: CBL c.1477C>T (p.Leu493Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251480 control chromosomes. The observed variant frequency is approximately 38.17 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.1477C>T has not, to our knowledge, been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions nor has experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three labs classified the variant as VUS while one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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