“Splicing it all together”: Discovery of a novel likely pathogenic CDH1 variant using RNA analysis

Take home points: 

1. Based on expert panel guidelines, pathogenic missense variants in CDH1 are rarely pathogenic. In this case, RNA evidence clarified that the c.944A>G (p.Asn315Ser) variant has a deleterious impact on splicing resulting in a predicted frameshift and alternate stop codon.   

2. RNA’s Role in improving Variant interpretation and diagnostic yield: CDH1 variant found via RNA analysis in DGC patient. RNA assessment aids VUS resolution in CDH1 and improves genetic testing accuracy. 

3. Including RNA analysis as part of DNA genetic testing can provide clinically actionable results that would be missed by DNA testing alone.