Submissions for variant NM_005188.4(CBL):c.2060C>T (p.Pro687Leu)

gnomAD frequency: 0.00012  dbSNP: rs146705974

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704138	SCV000207797	likely benign	not provided	2020-05-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000287851	SCV000367774	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654929	SCV000776835	likely benign	RASopathy	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280639	SCV001467875	uncertain significance	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: CBL c.2060C>T (p.Pro687Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251364 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2060C>T in individuals affected with Noonan Syndrome-Like Disorder and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign and uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813408	SCV002060754	uncertain significance	Noonan syndrome and Noonan-related syndrome	2017-01-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001280639	SCV002065039	uncertain significance	not specified	2018-11-09	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001280639	SCV001917991	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001704138	SCV001958263	likely benign	not provided		no assertion criteria provided	clinical testing