ClinVar Miner

Submissions for variant NM_005188.3(CBL):c.1459A>G (p.Met487Val) (rs17848896)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033360 SCV000057265 uncertain significance not provided 2012-09-27 criteria provided, single submitter clinical testing This variant is denoted as p.Met487Val at the protein level, c.1459A>G at the cDNA level, and results in the replacement of a Methionine with a Valine (ATG>GTG) in exon 10 of the CBL gene (NM_005188.2). The M487V missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. M487V is a conservative amino acid substitution as both Methionine and Valine are neutral, non-polar residues. The M487V missense change is located within a proline-rich region of CBL (Matinelli et al., 2010), however the Methionine residue is not well conserved at this position across species or in related proteins. Therefore, the clinical significance of M487V remains unclear. The variant is found in NOONAN panel(s).
Invitae RCV000553397 SCV000659097 likely benign Rasopathy 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001102985 SCV001259693 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.
Integrated Genetics/Laboratory Corporation of America RCV001193411 SCV001362208 benign not specified 2019-09-30 criteria provided, single submitter clinical testing Variant summary: CBL c.1459A>G (p.Met487Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251474 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 680 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. To our knowledge, no occurrence of c.1459A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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