Many sibling comments dismiss this as a non-issue if you've ever actually tried an alternative layout.
As a Dvorak user on macOS for ~12 years, I do believe it's an issue. I use "Dvorak - QWERTY ⌘" as my daily driver and while it works for most applications, it's infuriating for those it doesn't. Sometimes keyboard shortcuts are control/option based without using command, so it's still in Dvorak mode.
In Gimp, the New Image shortcut is ⌘-N, which doesn't work. I have to press physical L, which is the key for N in Dvorak. This is common. The apps seem to do some lower-level key detection. https://gitlab.gnome.org/GNOME/gimp/-/issues/3352 I think Fusion 360 does similar, though I don't have it installed at the moment. I have also had trouble with remove desktop applications, which is kind of to be expected but another downside.