Submissions for variant NM_005188.4(CBL):c.1858C>T (p.Leu620Phe)

gnomAD frequency: 0.00121  dbSNP: rs2227988

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038354	SCV000062026	benign	not specified	2016-05-26	criteria provided, single submitter	clinical testing	p.Leu620Phe in Exon 11 of CBL: This variant is not expected to have clinical sig nificance because it has been identified in 3.3% (286/8638) of East Asian chromo somes (including 2 homozygous individuals) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs2227988).
GeneDx	RCV000038354	SCV000167555	benign	not specified	2013-04-15	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.
Eurofins Ntd Llc (ga)	RCV000038354	SCV000225351	benign	not specified	2014-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV000229556	SCV000288832	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000038354	SCV000310871	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001000367	SCV000367770	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001701577	SCV001157117	benign	not provided	2023-10-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038354	SCV001362210	benign	not specified	2019-10-29	criteria provided, single submitter	clinical testing	Variant summary: CBL c.1858C>T (p.Leu620Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251406 control chromosomes, predominantly at a frequency of 0.033 within the East Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13200-folds over 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 East Asian origin. Three ClinVar submissions (evaluation after 2014) cite the variant twice as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813347	SCV002060492	benign	Noonan syndrome and Noonan-related syndrome	2021-06-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408519	SCV002724066	benign	Cardiovascular phenotype	2020-11-09	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.
Fulgent Genetics, Fulgent Genetics	RCV002496610	SCV002805887	benign	Juvenile myelomonocytic leukemia; CBL-related disorder	2021-08-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315562	SCV004016975	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000038354	SCV000084610	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000038354	SCV001808742	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701577	SCV001931855	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038354	SCV001955985	benign	not specified		no assertion criteria provided	clinical testing