My vote is on the Tyrells, even if they are one of my favorite houses. But they have been too influential, too powerful, and they are still more unscathed than other houses. They're in for a fall and their absence from the game would be a big game changer, I think.
In second place, I think House Baratheon will fall if Stannis and Shireen die. Yeah, someone could legitimize the bastards, but losing Stannis would be a huge blow for the Baratheon cause. Not to mention the likely demise of Storm's End and the stormlands.
Edited by Jon of the Dead, 17 September 2013 - 01:59 PM.