Submissions for variant NM_005188.4(CBL):c.2269G>A (p.Ala757Thr)

gnomAD frequency: 0.00076  dbSNP: rs146517083

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000514779	SCV000057272	benign	not provided	2019-07-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28502479)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120463	SCV000197243	benign	not specified	2015-10-08	criteria provided, single submitter	clinical testing	p.Ala757Thr in exon 15 of CBL: This variant is not expected to have clinical sig nificance it has been identified in 0.5% (81/16512) of South Asian chromosomes ( including 1 homozygous individual) and 0.1% (62/66732) of European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146517083).
PreventionGenetics, part of Exact Sciences	RCV000120463	SCV000310873	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001001629	SCV000367778	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	RCV001080932	SCV000555938	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514779	SCV000611031	likely benign	not provided	2017-05-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514779	SCV001159110	likely benign	not provided	2020-03-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120463	SCV001339181	benign	not specified	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: CBL c.2269G>A (p.Ala757Thr) results in a non-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 251422 control chromosomes, predominantly at a frequency of 0.006 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2400 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 experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813229	SCV002060497	benign	Noonan syndrome and Noonan-related syndrome	2020-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514779	SCV002563090	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CBL: BP4, BS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315531	SCV004016973	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004601091	SCV005098170	benign	Cardiovascular phenotype	2024-05-20	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.
ITMI	RCV000120463	SCV000084616	not provided	not specified	2013-09-19	no assertion provided	reference population
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514779	SCV001798709	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120463	SCV001809493	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514779	SCV001954858	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514779	SCV001975446	likely benign	not provided		no assertion criteria provided	clinical testing