There's an interesting Star Trek TNG episode called Parallels in which Worf gets shunted into progressively more foreign parallel universes. In one, he finds himself at his post while the ship is under attack, and he is unable to raise the shields in time because in that universe, the control console is laid out differently.
In a later DS9 episode, while in command on the Defiant, Worf chides a junior officer for rearranging his console for greater efficiency and orders him to change it back. If someone ever needed to take over that officer's post while using the custom layout, they'd be stuck just as Worf once was, though he doesn't mention his dimension-hopping experience at the time.
I haven't yet done any experiments with trying to use a DVORAK layout long-term, but I do remember my custom-UI experiences from my days playing WoW.
Everyone who plays WoW at any kind of serious level has something custom about their interface. At the very least, they tend to do things like replace the standard HUD with one that uses fewer visual frills (borders, etc.) and puts information they need exactly where it's easy to see. Rather than make lots of action bars visible on screen, advanced players memorize all their custom bindings and hide them so they won't clutter the interface.
There are some key setups that are very class-specific. I generally played as a hunter, and when spammy shot rotations were the norm in BC, I bound the rotation macro to my scroll wheel. I had "send pet to attack" and "bring pet back" bound to the "back" and "forward" buttons on my mouse almost from level 10 (which was when hunters got their pets back then). Mouse movement was usually the norm among hunters, and I adopted this at some point (though I did my Rhok'delar quest using WASD), but I heard that healers often preferred WASD at high levels so that the mouse would be free to click on teammates as they needed healing.
My screen layout actually had rather a lot of visible keys--several rows' worth--but they were mostly stacked right at the center-bottom of the screen, where they were relatively out of the way.
A little guidance: this picture was taken during the WotLK era (the level cap was 80). The large top row of buttons is my main action bar, with the shots on the left side lined up in a priority order in accordance with the theorycrafting of the time. Pet skills are the small buttons. The "Wrath" button is my main "click these stackable abilities and trinkets all at once" macro, which wouldn't actually include Bestial Wrath in a survival build. From the cooldown timers on the right--mine on top, my pet's on the bottom--I can see that this macro is about to be ready again. On the bottom I have three Hearthstone-equivalent items lined up for easy clicking. On the far left are three labeled gearsets--I was an avid fisher and had several items to boost the ability. The cloak near those is a parachute. That "Focus" button is a macro that determines who appears in the special frame above my chat log; I would have usually set that as the main tank, for Misdirection. The really scary thing is that I can still remember all of this fluently after 6 years of not playing the game.
This setup made standard, day-to-day play relatively pleasant. But every time I had to turn the mods off for any reason, my screen would suddenly become an absolute mess. The only reason my custom setup worked at all was that I was able to always play on the same computer that I never had to share with anyone. If I'd ever had to play on anyone else's computer, I'd have had a rough time. In fact, that aforementioned Rhok'delar quest was somewhat slowed by my mouse breaking that week, which required me to hike down to Best Buy and get a new one...and I had to be picky about it, because those back and forward thumb buttons were critical. I ran at least a couple dungeons using a trackpad; I'm just thankful I was with friends and not having to prove myself to strangers (and was still using WASD to move).
Thus we see the conundrum of UI efficiency: the most efficient solution for your own situation is probably a custom setup, but if there's any chance you won't be able to use your own equipment, you'll need to maintain the ability to manage, at least reasonably, without the custom gear.
My preference for laptops makes it a little more cumbersome than usual to swap in any kind of alternative layout, but I may see if I can find a cheap DVORAK at some point.
...Honestly, even a standalone QUERTY might be nice to have. The "feel" of my current laptop's keys is a little odd, and I've never quite gotten used to it. Either MSI blew their keyboard budget on making them light up, or I'm just not a fan of this "flat square tile" key shape (they look kind of like the keys on a MacBook).