ClinVar Genomic variation as it relates to human health

CBL: BP4, BS1

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, http://exac.broadinstitute.org; 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.

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.

The c.2312A>T (p.D771V) alteration is located in exon 15 (coding exon 15) of the CBL gene. This alteration results from a A to T substitution at nucleotide position 2312, causing the aspartic acid (D) at amino acid position 771 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).