ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.2312A>T (p.Asp771Val) (rs199788586)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000038356 SCV000057273 likely benign not specified 2012-08-21 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 RCV000038356 SCV000062028 uncertain significance not specified 2016-08-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp771Val var iant in CBL has been identified by our laboratory in 2 Caucasian individuals wit h clinical features of a RASopathy disorder, both of whom also carried a disease -causing variant in another gene sufficient to explain their disease. This varia nt has been identified in 13/66740 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs199788586). Computati onal prediction tools and conservation analysis suggest that this variant may no t impact the protein, though this information is not predictive enough to rule o ut pathogenicity. In summary, while the clinical significance of the p.Asp771Val variant is uncertain, the presence of this variant in combination with a report ed pathogenic variant suggests that it is more likely to be benign.
Invitae RCV000552056 SCV000659111 likely benign Rasopathy 2020-08-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038356 SCV001362202 likely benign not specified 2021-06-14 criteria provided, single submitter clinical testing Variant summary: CBL c.2312A>T (p.Asp771Val) 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 9.1e-05 in 251462 control chromosomes. The observed variant frequency is approximately 37 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 benign. To our knowledge, no occurrence of c.2312A>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has re-classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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