Submissions for variant NM_005188.4(CBL):c.2569C>T (p.Leu857Phe)

gnomAD frequency: 0.00008  dbSNP: rs201631570

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000338492	SCV000367781	benign	CBL-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420785	SCV001623145	likely benign	not specified	2021-05-10	criteria provided, single submitter	clinical testing	Variant summary: CBL c.2569C>T (p.Leu857Phe) results in a non-conservative amino acid change located in the Ubiquitin-associated domain (IPR015940) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251474 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 920-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 a benign polymorphism found primarily in populations of East Asian origin. c.2569C>T has been reported in the literature in an individual affected with myelodysplastic syndrome (Taguchi_2020). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001469615	SCV001673695	likely benign	RASopathy	2021-04-11	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813454	SCV002060499	likely benign	Noonan syndrome and Noonan-related syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001420785	SCV002068642	benign	not specified	2019-03-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000338492	SCV004714087	likely benign	CBL-related disorder	2022-01-17	no assertion criteria provided	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).