ACMG. Imagine the following scenario: you identify a de novo variant in SCN1A in a young child with the typical clinical features of Dravet Syndrome. However, the lab returns the variant as a variant of uncertain significance. The variant is a missense variant that has never been seen before and the lab argues that they are simply applying the current variant classification criteria. Certainly, either the lab is wrong or the variant classification criteria are deficient. Shouldn’t this variant be a pathogenic variant? Your patient clearly has the typical clinical features that are very unlikely explained by anything but the de novo SCN1A variant. In fact, both assumptions are incorrect, but it is important to know the background. Here is a blog post on why variant classification is distinct from assessing whether variants are explanatory in a clinical context. And please allow me to introduce a neologism: explanatoriness. Continue reading →