Submissions for variant NM_005188.4(CBL):c.2710G>A (p.Val904Ile)

gnomAD frequency: 0.00454  dbSNP: rs17122769

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120465	SCV000167559	benign	not specified	2012-04-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120465	SCV000204372	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Val904Ile in Exon 16 of CBL: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (57/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs17122769).
PreventionGenetics, part of Exact Sciences	RCV000120465	SCV000310876	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000298937	SCV000367783	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.
Invitae	RCV001084617	SCV000555932	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514119	SCV000602913	benign	not provided	2022-03-21	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514119	SCV000609852	likely benign	not provided	2017-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120465	SCV001338403	benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing	Variant summary: CBL c.2710G>A (p.Val904Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 282710 control chromosomes, predominantly at a frequency of 0.014 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 5600 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. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Four clinical ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813379	SCV002060501	likely benign	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120465	SCV002068786	benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426667	SCV002741399	benign	Cardiovascular phenotype	2019-10-31	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315742	SCV004016983	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514119	SCV004698948	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CBL: BP4, BS1, BS2
ITMI	RCV000120465	SCV000084618	not provided	not specified	2013-09-19	no assertion provided	reference population