Never, since you've excluded optional systems in the DMG. I've run sessions and campaigns that experimented with slower healing mechanics, variant initiatives, lingering injuries and things like that. Sometimes these have been tweaked to my specific desires, but that's part of the point of the variant rules. For instance, I ran a short campaign where players could choose to roll on the injury table instead of going unconscious. Sort of leaning into combat with potential long-term consequences. That's not exactly the way the rule is presented in the DMG, but it was more of an experiment than an attempt to completely rewire the game.
Likewise, there are places where a particular ruling was made and I codified that ruling for consistency in a document that players could reference on Roll20.
5e encourages DMs to tweak certain systems to achieve different goals. That's part of how it was designed. Apart from that, I don't feel like I have modified the game because of a fundamental disagreement on design choices made by the 5e team.