ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1566T>C (p.Ala522=)

gnomAD frequency: 0.00009  dbSNP: rs371065029
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002060779 SCV002468158 likely benign RASopathy 2025-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV002397329 SCV002709945 likely benign Cardiovascular phenotype 2019-08-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387901 SCV004099778 uncertain significance not specified 2023-09-12 criteria provided, single submitter clinical testing Variant summary: CBL c.1566T>C (p.Ala522Ala) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 282860 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.1566T>C in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014, and both classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003736870 SCV004563375 likely benign not provided 2023-08-11 criteria provided, single submitter clinical testing

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