Submissions for variant NM_005188.4(CBL):c.595A>G (p.Ile199Val)

gnomAD frequency: 0.00001  dbSNP: rs397517082

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038365	SCV000062037	uncertain significance	not specified	2012-10-18	criteria provided, single submitter	clinical testing	The Ile199Val variant in CBL has not been previously reported in the literature or been previously identified by our laboratory. Computational analyses (biochem ical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the normal function of the p rotein. In summary, additional information is needed to fully assess the clinica l significance of the Ile199Val variant.
GeneDx	RCV000766699	SCV000329208	uncertain significance	not provided	2015-12-24	criteria provided, single submitter	clinical testing	The I199V variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The I199V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I199V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Genetic Services Laboratory, University of Chicago	RCV000038365	SCV000593864	uncertain significance	not specified	2015-09-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317408	SCV001508067	likely benign	RASopathy	2023-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038365	SCV005077100	uncertain significance	not specified	2024-04-22	criteria provided, single submitter	clinical testing	Variant summary: CBL c.595A>G (p.Ile199Val) results in a conservative amino acid change located in the Adaptor protein Cbl, EF hand-like domain (IPR014741) of 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 4.4e-05 in 251430 control chromosomes. To our knowledge, no occurrence of c.595A>G in individuals affected with Noonan Syndrome-Like Disorder and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 45210). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004609298	SCV005098172	uncertain significance	Cardiovascular phenotype	2024-06-13	criteria provided, single submitter	clinical testing	The p.I199V variant (also known as c.595A>G), located in coding exon 4 of the CBL gene, results from an A to G substitution at nucleotide position 595. The isoleucine at codon 199 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.