ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.2345C>T (p.Pro782Leu) (rs2229073)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000680286 SCV000057274 likely benign not provided 2018-02-15 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038358 SCV000062030 uncertain significance not specified 2013-06-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Pro782Leu varia nt in CBL has been identified by our laboratory in this patient's son, however i t has not been seen in the literature. This variant has been identified in 0.7% (30/4398) of African American chromosomes from a large population study by the N HLBI Exome Sequencing Project (; dbSNP rs222907 3). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) suggest that the Pro782Leu variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. In summary, additional information is needed to fully assess the clinical s ignificance of the Pro782Leu variant.
Invitae RCV001088335 SCV000260563 benign Rasopathy 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000106328 SCV000367779 benign Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038358 SCV001426998 benign not specified 2020-07-27 criteria provided, single submitter clinical testing Variant summary: CBL c.2345C>T (p.Pro782Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251460 control chromosomes, predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3280 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. c.2345C>T has been reported in the literature in at least one individual affected with Noonan Syndrome (Justino_2015). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285521 SCV001471960 benign none provided 2020-05-22 criteria provided, single submitter clinical testing
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000106328 SCV000143826 not provided Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia no assertion provided not provided

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