ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.2153G>A (p.Arg718Gln)

gnomAD frequency: 0.00002  dbSNP: rs144894769
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654940 SCV000776846 uncertain significance RASopathy 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 718 of the CBL protein (p.Arg718Gln). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs144894769, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 543979). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290632 SCV001478747 uncertain significance not specified 2021-01-28 criteria provided, single submitter clinical testing Variant summary: CBL c.2153G>A (p.Arg718Gln) results in a 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 is located to the last nucleotide of exon 13, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes the 5' splicing donor site, while three predict the variant weakens this donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 251286 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2153G>A in individuals affected with Noonan Syndrome-Like Disorder and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813540 SCV002060755 uncertain significance Noonan syndrome and Noonan-related syndrome 2020-11-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002499129 SCV002812793 uncertain significance Juvenile myelomonocytic leukemia; CBL-related disorder 2021-08-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003144456 SCV003829280 uncertain significance not provided 2019-08-02 criteria provided, single submitter clinical testing

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