ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.107ACC[9] (p.His41_His42dup)

dbSNP: rs373212940
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540192 SCV000659090 uncertain significance RASopathy 2021-10-31 criteria provided, single submitter clinical testing This variant, c.122_127dup, results in the insertion of 2 amino acid(s) of the CBL protein (p.His41_His42dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs373212940, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 477693). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 RCV001255559 SCV001432037 likely benign not specified 2021-08-05 criteria provided, single submitter clinical testing Variant summary: CBL c.122_127dupACCACC (p.His41_His42dup) results in an in-frame duplication that is predicted to duplicate 2 amino acids into the encoded protein. The variant allele was found at a frequency of 7.2e-05 in 151840 control chromosomes. The observed variant frequency is approximately 29 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.122_127dupACCACC in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported ( Internal data; PTPN11 c.854T>C, p.Phe285Ser), providing supporting evidence for a benign role. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001529039 SCV001796584 likely benign not provided 2019-07-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001255559 SCV002071582 uncertain significance not specified 2019-10-14 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529039 SCV001741819 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001529039 SCV001965862 likely benign not provided no assertion criteria provided clinical testing

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