Variants of Uncertain Significance
Genetics are complicated and tricky! When there is a mutation in one of our genes, it is like changing an ingredient in a recipe book. Swapping T for a G changes a lot. Let's say T is Turmeric and G is Garlic - it's going to significantly change the taste of the end product - It doesn't mean that you'll die eating it, you might not even notice the difference, but it might also make you sick.
VUS cannot be categorised as potentially disease causing or harmless because the meaning of this type of genetic change is not yet known. The genetics underlying familial long QT syndrome (LQTS) are among the best characterised of all of the inherited heart conditions.
DNA changes can affect how stable a cell membrane is.
Imagine building a wall, and instead of using big concrete blocks to make your wall big and strong, you only have large pebbles. Your wall isn't going to be as strong as you need it to be.
When that wall serves a significant purpose, like a wall for your house, that can be pretty disastrous. Having a flexible wall instead of a nice solid wall in your house... isn't ideal. It is going to cause all sorts of structural issues.
Think of the 3 Little Pigs. A house of sticks didn't hold up so well.
If it's just a wall to look pretty in the garden, rather than a wall for the side of the house, it doesn't really matter too much.
Improved sequencing techniques along with more accurate variant classification criteria means there is doubt as to whether some of the previously identified genes actually cause LQTS.
New scientific discoveries make all genes and variants subject to a continuous process of re-classification. For example, it is argued that the gene for LQT5 (KCNE1) could be considered just disease modifier so it alters the effect of other genes (like KCNQ1 or KCNH2), potentially influencing the severity or presentation of a genetic condition. (HCL 2020). This means that while the KCNE1 gene variants associated with LQT5 can predispose individuals to QT prolongation, they often do not always manifest clinically in the majority of carriers.
The picture is forever changing! Some variants that were considered benign or not disease causing may have been in fact now found to cause Long QT Syndrome. It is recommended that if you are clinically symptomatic but had a genetic test over 10 years ago that produced negative or a VUS result, you should be retested.
A genetic result of VUS doesn’t necessarily mean that you do not have a gene mutation which causes Long QT Syndrome. There is still a lot to learn about genetics and how variants in genes relate to clinical expressions.