Finding out that Nicole was Dead All Along in Dead Space. Despite being a Heroic Mime, You can help but feel sorry for Isaac at the part.
Nicole: I didn't want it to end like this. I really wanted to see you again...just once. I loved you. I've always loved you.
- The animation Isaac goes through during the revelation - even though you never see his face, his body language speaks volumes for just how badly it hits him. Even worse if you read his in-game diary: he knew Nicole was dead, but kept himself in denial up until that point. Ouch.