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

dbSNP: rs373212940

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000540192	SCV000659090	uncertain significance	RASopathy	2024-01-31	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
PreventionGenetics, part of Exact Sciences	RCV003945336	SCV004773850	likely benign	CBL-related condition	2020-09-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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