Submissions for variant NM_005188.4(CBL):c.1647C>A (p.Asp549Glu)

gnomAD frequency: 0.00005  dbSNP: rs369030902

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156176	SCV000205892	likely benign	not specified	2015-06-16	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000466595	SCV000543491	likely benign	RASopathy	2023-12-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104890	SCV001261793	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	RCV000156176	SCV001448449	likely benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: CBL c.1647C>A (p.Asp549Glu) 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 0.0002 in 251456 control chromosomes, predominantly at a frequency of 0.00072 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 288 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 South Asian origin. To our knowledge, no occurrence of c.1647C>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813404	SCV002060491	benign	Noonan syndrome and Noonan-related syndrome	2018-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390364	SCV002703794	likely benign	Cardiovascular phenotype	2022-10-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV003422048	SCV004129483	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CBL: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV003945244	SCV004763944	likely benign	CBL-related condition	2020-12-04	criteria provided, single submitter	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).