ClinVar Miner

Submissions for variant NM_005188.3(CBL):c.1477C>T (p.Leu493Phe) (rs730880434)

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Total submissions: 4
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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 Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae RCV000707567 SCV000836668 uncertain significance Rasopathy 2019-03-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 493 of the CBL protein (p.Leu493Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs730880434, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CBL-related disease. ClinVar contains an entry for this variant (Variation ID: 180819). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001102986 SCV001259694 uncertain significance Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 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.

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