Submissions for variant NM_005188.4(CBL):c.2345C>T (p.Pro782Leu)

gnomAD frequency: 0.00281  dbSNP: rs2229073

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000680286	SCV000057274	benign	not provided	2021-03-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27244893, 24896146, 31057598, 32604168)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038358	SCV000062030	uncertain significance	not specified	2013-06-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro782Leu varia nt in CBL has been identified by our laboratory in this patient's son, however i t has not been seen in the literature. This variant has been identified in 0.7% (30/4398) of African American chromosomes from a large population study by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs222907 3). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) suggest that the Pro782Leu variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. In summary, additional information is needed to fully assess the clinical s ignificance of the Pro782Leu variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088335	SCV000260563	benign	RASopathy	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000106328	SCV000367779	benign	CBL-related disorder	2018-01-12	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	RCV000038358	SCV001426998	benign	not specified	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: CBL c.2345C>T (p.Pro782Leu) results in a non-conservative amino acid change in 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 0.00078 in 251460 control chromosomes, predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3280 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 African or African-American origin. c.2345C>T has been reported in the literature in at least one individual affected with Noonan Syndrome (Justino_2015). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000680286	SCV001471960	benign	not provided	2020-05-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813231	SCV002060498	benign	Noonan syndrome and Noonan-related syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000038358	SCV002064862	benign	not specified	2021-03-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426535	SCV002731881	likely benign	Cardiovascular phenotype	2019-11-20	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.
CeGaT Center for Human Genetics Tuebingen	RCV000680286	SCV004129487	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	CBL: BS1, BS2
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	RCV000106328	SCV000143826	not provided	CBL-related disorder		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000038358	SCV001925329	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038358	SCV001958387	benign	not specified		no assertion criteria provided	clinical testing