ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.2363G>A (p.Arg788Gln)

gnomAD frequency: 0.00036  dbSNP: rs150811339
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157868 SCV000207798 benign not provided 2020-03-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001089115 SCV000776904 likely benign RASopathy 2024-01-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818347 SCV002064793 uncertain significance not specified 2021-06-18 criteria provided, single submitter clinical testing DNA sequence analysis of the CBL gene demonstrated a sequence change, c.2363G>A, in exon 15 that results in an amino acid change, p.Arg788Gln. This sequence change has been described in the gnomAD database with a frequency of 0.08% in the African American/African subpopulation (dbSNP rs150811339). The p.Arg788Gln change affects a moderately conserved amino acid residue located in a domain of the CBL protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg788Gln substitution. This sequence change does not appear to have been previously described in patients with CBL-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg788Gln change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818347 SCV002572233 likely benign not specified 2022-08-22 criteria provided, single submitter clinical testing Variant summary: CBL c.2363G>A (p.Arg788Gln) results in a 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 0.00011 in 251456 control chromosomes. The observed variant frequency is approximately 45 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. To our knowledge, no occurrence of c.2363G>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity RCV000157868 SCV003829278 uncertain significance not provided 2020-02-04 criteria provided, single submitter clinical testing

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