The big one for me is the deities. If WotC never bothers fleshing out and updating the non-Sword-Coast parts of the realms, fine. I hate it, but it doesn't affect a game on the sword coast if we never hear about what's going on in Cormyr or Turmish or Unther or Myth Drannor or whatever. But the Gods are everywhere, and a lot of the 4e metaplot turned their lore inside out and upside down, and that directly affects what a PC (cleric, or paladin, or just worshipper) knows or thinks of their (or someone else's) god, church, religion, etc.
I mean, Tyr killed Helm and then gave up his godhood and disappeared and came back. Tyr is the lawful Good god of justice, for pete's sake, and so that's a very big deal. What impact did that episode have on Tyr's church, on Tyr's clergy, on Tyr's doctrine, on how Tyr is perceived in the Realms? SCAG just airily assumes the Tyr/Torm/Ilmater triad took up where it left off once Tyr came back, but that ... strains credibility to the breaking point. Or what about Hoar-Assuran? The god of revenge - he became the minion of Bane for what, a hundred years or so? Bane is the sort of god that many, many people want to take revenge AGAINST, so what did that do for Hoar-Assuran's credibility, or clergy, to be his flunky for so long? What does Hoar-Assuran have to say for himself? What's the official line from the church of Hoar-Assuran when asked 'hey, X years ago my family were murdered in cold blood by Bane-worshippers and Hoar-Assuran denied me help and sided with the Baneites when i asked for revenge, what's up with that?'
Strong feeling is that modern WotC fervently wished that the Spellplague era had never been written, and just wish the whole issue would go away so they never talk about it much. And frankly, the Spellplague lore wrote realmlore into such an messy place that there's probably no plausible way to fix it. It looks to me like WotC has chosen to deal with by simply advancing the timeline, returning to something kinda-sorta similar to the status quo ante and never talking about details ever again.