New technologies allow rapid discovery of novel sequence variants among which those involving complex structural rearrangements. The description of such complex variants challenges the existing standard sequence variation nomenclature of the Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen), because this mainly focuses on simple variants. Here, we suggest several extensions of the HGVS nomenclature guidelines to facilitate unambiguous description of complex sequence variants at the DNA level. These include: (1) nesting to support description of changes within inversions and duplications, and (2) composite changes to support concatenation of inserted sequences. The advantage of these additions is that inversions and duplications with small differences and more complex variants can be described without reverting to the less informative indel description. In addition, they should provide sufficient flexibility and consistency, thereby limiting alternative interpretations and ambiguous descriptions. The specifications should allow easy implementation in sequence variant nomenclature checkers (e.g., Mutalyzer, http://www.mutalyzer.nl/). We are extending the functionality of Mutalyzer to incorporate the latest version of the HGVS sequence variation nomenclature guidelines. Hum Mutat 32:1–5, 2011. © 2011 Wiley-Liss, Inc.