Stefan Amaris is perhaps the only person in-universe who has been directly compared to Adolf Hitler... in fact it wouldn't be surprising if a 3025 version of Godwin's Law actually named Amaris. His crossing of the horizon came when he executed the entirety of the Cameron family, and then left their bodies to rot in the throne room where they were executed.
Another MEH was crossed by Jinjiro Kurita when he massacred almost the entire population of Kentares IV.
During the Clan Invasion, Clan Smoke Jaguar ordered an orbital bombardment over a city full of civilians, this act enraged the Inner Sphere and the other Clans call it needlessly cruel.
Exalted: Being a loyalist Abyssal or an Infernal counts as — or requires — crossing the Moral Event Horizon. Signing up with the Neverborn and the Deathlords means voluntarily killing absolutely everything; your family, crush, dreams and hope included. Hopping on the Reclamation wagon means that you will devote your godlike powers to freeing infinitely hateful demon-gods upon the world, who might as well rewrite reality so that nothing can die and everything suffers eternally. Still, this being Exalted, this doesn't describe all of them, or even most, particularly in the case of the latter. The Abyssals may repent and reclaim their original nature of the Solar Exalted. A possibility is convincing their good nature to the Unconquered Sun, who is now sadly addicted to Celstial Crack and has not paid attention to Creation in a thousand years. Another is reaching Autochthon (who is hiding in a different plane of reality) and talking him into rewriting the corrupted Exaltation. Nobody has achieved either of this... yet (although, to be fair, the first Abyssals were created only a few years back at the time of the setting's default chronological campaign starting point). For an Infernal, stealing away the powers of the Yozis, subverting their control and becoming a proto-Primordial on their own can allow them to pursue their own heroic, not-necessarily-sadistic goals. This is about as difficult as inventing a new type of reality. Which is to say, "not the most". These are people meant to remake reality, not destroy it, after all.
In the New World of Darkness, every person is subject to a zero-to-ten Karma Meter, with an average person falling in somewhere around seven. For normal humans, falling to a low Morality only gives a penalty in that getting to that level requires committing acts that would get you tried under the Geneva Conventions, if not thrown in prison for life (though one is unlikely to drop very low without going at least a little insane). For supernaturals, however, falling down on their respective morality scales often imposes supernatural penalties, and for both regular humans and all supernaturals, falling to 0 irreversibly corrupts you in some manner and you're turned into an NPC. The "irreversible corruption" works in different ways:
Sin-Eaters have their minds and souls shattered, with their Geist as much or more in control than they are of the pitiful wreck they've become.
Changelings with Clarity 0 have a bad habit of disappearing into the Hedge and never coming back. Why? Because they become True Fae themselves.
Mages become The Mad and are, as the name implies, completely insane. They range from "merely" insane mages, the equivalent of autistic savants of magic, to utterly transformed beings — bizarre and twisted constructs of flesh, minds freed from their bodies, forces of nature, or supernatural phenomena. That's at best.
Geniuses, from the fanmade Genius The Transgression, have to essentially be Mengele to reach these lower points. When they hit zero, their individual personality largely disintegrates, and they become monsters that won't give a damn how many people they have to hurt in order to complete their experiments.
Mortals and Hunters are the only groups who actually follows what anyone would really call morals, even if there's noticeable overlap, because the supernaturals have already shed their human viewpoints, and different acts ding different numbers on different meters. Vampires are essentially fighting off mindless, bestial gluttony, while Mages have to resist succumbing to their own egotism, for instance. The books tend to recommend varying levels of harshness from storytellers if a particular act doesn't hit a listed threshold, but illustrates a noticeable move toward the lower end of the scale. The scales aren't balanced across each other, either. Sin-Eaters, for instance, can lose permanent ranks of Synergy, while a Changeling is never permanently barred from reaching Clarity 10, but a Changeling's clarity nevermakes exceptions for motivation or extenuating circumstances when considering dings on the meter; it might mean penalties or bonuses if the ST feels it's appropriate, but a degeneration roll is always made regardless.
In the Old World of Darkness system, vampires who wanted to start down an alternate path of morality instead of the default humanity had to commit some atrocity in order to shed their humanity forever. Once this was done, they became true monsters who couldn't even pass for human. However, whatever atrocity the vampire commits isn't what pushes them over the MEH; it's the resulting rejection of humanity that the atrocity symbolized.
Likewise, in Mage: The Ascension, you have the Nephandi, mages who have sold out their souls to dark and terrible masters in the name of universal destruction. To do so requires the mage go through a Caul and turn their Avatar (the representation of their higher magical beliefs) inside out. This is something few mages do accidentally; to truly become a Nephandus requires knowingly desecrating everything you hold dear, from your faith to your relationships to your morals.
Count Strahd Von Zarovich murdered his brother Sergei over Tatyana, the woman both men loved, on their wedding day, leading to Tatyana throwing herself off the wall of Ravenloft as Strahd pursued her. Every generation, Tatyana is reincarnated and Strahd pursues her to her death, never learning his lesson.
Lord Soth committed several major acts that would qualify as Acts of Ultimate Darkness:
He and his first wife, Lady Korrine of Gladria, had been trying to produce a son to be his heir, and Korrine had consulted a witch about the problem, who had agreed to help them, but had warned her that the child would be a representation of Soth's soul. Unfortunately, Korrine didn't know about the evil deeds that her husband had done, including ordering the murders of his half-brother and sister by his seneschal Caradoc, else she would have known what would eventually transpire of the birth and would be of a mind to curse the witch. When she gave birth to the son in question, it had a face similar to that of dragon-kin with two arms on one side and a leg on the other, with the last leg placed at the bottom of the buttocks as if it were a tail. To say that Soth was pissed about this was a massive understatement and, thinking that she had cheated on him with some kind of demon, murdered both Korrine and the monstrous child.
After marrying a second wife named Isolde, he set out on a quest to stop the Kingpriest from unleashing the Cataclysm upon Krynn by forcing the Rod of Omniscient Wisdom into his hands (according to Isolde's vision, it would take many tries, and each time he was killed, he'd rise with greater power) in return for redemption. When Soth and the thirteen knights with him found the Rod, he left his soul due to the curse on the coffer, becoming a type of Lich, with his soul residing in the coffer like a phylactery, astrally projecting into his body, and unaware of this new state. On his way to Istar, he came across three elf-maids who proceeded to poison him against Isolde, telling him lies about her infidelity and saying that she had sent him on this quest to die in order to get rid of him. Soth got pissed again, returned home, and confronted his wife just as the Cataclysm began. A chandelier fell on Isolde and their newborn son, and she begged for him to save their son, but Soth stopped himself from doing so, so as to prevent his own son from growing up as he himself had. With her final breath, Isolde cursed him to live the lifetime of every soul that he had caused death on that day, and as Soth's keep burned down, Soth became a death knight and his retainers became undead.
Azalin Rex executed his own son after catching him freeing political prisoners.
Lord Wilfred Godefroy murdered his wife and daughter with his walking stick because his wife hadn't given him the son he wanted.
Harkon Lukas abused his position as "Grandfather Wolf" in order to bring civilization to his homelands, driving out his own people in the process. Interestingly, the Act wasn't enough to catapult him to Darklord-dom; rather, it was using the colonists as a food source, which isn't normally a powers-check-worthy act for wolfweres, as well as the betrayal of trust.
In Shadowrun, the Horizon Mega Corp. in Columbian Subterfuge reveals they killed POWs rescued by the players' Shadowrunners and made it look like Atzlan did it.
Horus went over the line when he destroyed Isstvan III in an attempt to eliminate the loyalist elements of several Legions. This included members of his own Legion, who looked up to him like a father. When some of them dug in and survived the virus-bombing, Horus ordered the forces loyal to him to go down to the surface and kill them, making them complicit in his treachery and betrayal. For the Emperor, however, it was flaying Ollanius Pius (who is either an Adeptus Custodes, an Imperial Fists Terminator, or an ordinary Guardsman: Games Workshop can't decide which) alive with mind bullets that was what finally convinced him Horus was beyond saving.
In Dark Heresy, you can spend experience to remove corruption, but you can't reduce your corruption level (which goes up every 10 corruption points) and thus can never remove malignancies. At the highest level of Corruption — 100 points — a character is "Damned" and is functionally killed off... unless, of course, you bring in Black Crusade, which makes 100 Corruption just the beginning.
The murder of the beautiful cleric Aleena with a Magic Missile by Bargle the Infamous from the introductory adventure of Basic D&D would make the evil magic user an enemy for life for many a player back in the 80s. (Of course, as far as villains go in the big scheme of things, Bargle was rather tame... But he had the potential to become a rather vile villain; it all depended on just how far the DM was willing to take the character.)