Submissions for variant NM_005188.4(CBL):c.869+4A>G

gnomAD frequency: 0.02038  dbSNP: rs77284821

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038366	SCV000062038	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	c.869+4A>G in Intron 05 of CBL: This variant is not expected to have clinical si gnificance because it has been identified in 6.8% (255/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs77284821).
GeneDx	RCV000049224	SCV000077238	benign	RASopathy	2012-05-04	criteria provided, single submitter	clinical testing	The variant is found in NOONAN panel(s).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224916	SCV000280906	benign	not provided	2015-05-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000038366	SCV000310880	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000339761	SCV000367755	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	RCV000049224	SCV000555937	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038366	SCV001362304	benign	not specified	2019-09-09	criteria provided, single submitter	clinical testing	Variant summary: CBL c.869+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.005 in 251474 control chromosomes, predominantly at a frequency of 0.07 within the African or African-American subpopulation in the gnomAD database, including 40 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28000 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 occurrence of c.869+4A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813350	SCV002060505	benign	Noonan syndrome and Noonan-related syndrome	2021-06-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371836	SCV002684122	benign	Cardiovascular phenotype	2019-08-22	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224916	SCV003799332	benign	not provided	2023-11-20	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315565	SCV004016974	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000224916	SCV005235203	benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000038366	SCV001807751	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038366	SCV001954365	benign	not specified		no assertion criteria provided	clinical testing