The format is simple: Lady Dimitrescu—a menacing, nine-foot-six vampire in an enormous hat—is pictured scowling into the phone. A perfect reaction image for an unrelated photo of a different character on the other end of the line.
Canonically, the phone scene involves Lady Dimitrescu angrily talking to a character named Mother Miranda, reporting that the game’s protagonist Ethan Winters has broken into her castle. Lady Dimitrescu is clearly pissed off, but restrains herself until the call is over, at which point she flings her desk across the room.
But none of that is really relevant to the meme. Lady Dimitrescu’s face represents the universal experience of taking an annoying phone call—and provides a perfect format for relatable Twitter jokes.