In all primary arrhythmia syndromes, and more general, in probably all inherited diseases, it is well known that disease penetrance and expressivity is markedly variable between individuals hosting identical mutations. It has been established that a number of clinical variables impact on disease penetrance. These variables include gender, age and external factors like concomitant disease, drug use etc. In addition, genetic factors are also most likely to contribute. In the Long QT Syndrome (LQTS) known genetic factors include pathogenic variants in other LQT-related genes and modifying single nucleotide polymorphisms (SNP’s) in LQT-related and other genes. Indeed, it is well known that patients with double mutations have a more severe phenotype. SNP’s seem to impact, in gross terms, on repolarization reserve by several mechanisms including an effect on the ion currents involved. Several of these SNP’s have been identified in the general population (with impact on the QTc interval). Among others, functional SNP’s have been identified in KCNH2 for example and in NOS1AP. The LQT phenotype can also be influenced by altered transcriptional regulation, for example by genetic variants (SNP’s) in the promotor elements or by SNP’s in the 3′ untranslated region (3’UTR). The latter mechanism has been shown to be very robust for LQT1. The effect depends on the KCNQ1 allele on which they reside. QTc intervals are almost normal when the SNPs are on the allele that contains the mutation. Oppositely, when they reside on the healthy allele (i.e. the allel without the LQT1-causing mutation), QTc intervals are longer and symptoms more frequent. The allele-specific effects of these 3’UTR SNPs on disease severity strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside. As such, the balance between proteins stemming from either the normal or the mutant KCNQ1 allele is disturbed. In conclusion, phenotypic heterogeneity is arrhythmia syndromes is well known and we are starting to the understand the underlying causes. These include a number of clinical and genetic factors, among which genetic variants that alter protein expression.