Submissions for variant NM_005188.4(CBL):c.107ACC[8] (p.His42dup)

dbSNP: rs373212940

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000514229	SCV000057252	benign	not provided	2016-03-11	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	RCV000038350	SCV000062022	likely benign	not specified	2014-10-31	criteria provided, single submitter	clinical testing	c.125_127dupACC in exon 1 of CBL: This variant is not expected to have clinical significance because it has been identified in 0.2% (13/6806) of European Americ an and 0.8% (27/3260) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs397507488). This variant is an in-frame duplication which adds an additional histidine residue (His) to a short repeat of 7 histidines. Additionally, the number of histidines is not co nserved across species.
Eurofins Ntd Llc (ga)	RCV000038350	SCV000224467	likely benign	not specified	2015-05-19	criteria provided, single submitter	clinical testing
Invitae	RCV001080766	SCV000288829	benign	RASopathy	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278774	SCV000367751	likely benign	Noonan-like syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000038350	SCV000593861	benign	not specified	2022-01-04	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514229	SCV000610592	likely benign	not provided	2017-05-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038350	SCV001362211	benign	not specified	2019-12-10	criteria provided, single submitter	clinical testing	Variant summary: CBL c.125_127dupACC (p.His42dup) results in a in-frame duplication which adds an additional histidine residue to a short repeat of 7 histidines. The variant allele was found at a frequency of 0.002 in 151840 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4400 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. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813226	SCV002060486	benign	Noonan syndrome and Noonan-related syndrome	2020-12-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408491	SCV002674655	benign	Cardiovascular phenotype	2021-12-20	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.
Fulgent Genetics, Fulgent Genetics	RCV002490443	SCV002803544	benign	Juvenile myelomonocytic leukemia; CBL-related disorder	2021-12-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514229	SCV004033171	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CBL: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004532481	SCV004742156	benign	CBL-related disorder	2019-05-17	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514229	SCV001797653	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000514229	SCV001923137	likely benign	not provided		no assertion criteria provided	clinical testing