The combination of genetic variants may explain the variability in the manifestation of symptoms in C1-INH-HAE, in which nonpathogenic variants in diverse genes may confer susceptibility to a more severe phenotype when associated to pathogenic mutations in SERPING1. Within SERPING1, the c.-21T>C variant has been recognized as a disease modifier (Sections Homozygous and Compound Heterozygous Probands Carrying SERPING1 Variants and Variants at Intron/Exon Boundaries). The gene discussed is SERPING1; the disease is hereditary angioedema.