England fly-half Owen Farrell has been ruled out of the entire Six Nations with a knee injury.
Specialists have confirmed Farrell, 23, has suffered a high-grade medial ligament strain.
The Saracens player hurt his left knee in a European Champions Cup defeat by Clermont on Sunday.
England head coach Stuart Lancaster said: "It's a real shame for Owen that he sustained this injury and we wish him the best for his recovery."
Farrell is the latest addition to a list of absentees in England's squad as they prepare for their opening Six Nations match against Wales in Cardiff on 6 February.
In the absence of Farrell, Bath's George Ford - who started the final two autumn Tests - is likely to retain the number 10 jersey, with Sale's Danny Cipriani and Northampton's Stephen Myler also competing for a place in the match-day squad against Wales.
"We are fortunate to have three other number 10s in the squad in what is a very competitive position," Lancaster added.
Leicester lock Geoff Parling and Saracens centre Brad Barritt are continuing to receive treatment for knee medial ligament strains.
Northampton Saints flanker Tom Wood also has an ankle injury, while Bath centre Kyle Eastmond has a shoulder strain.
|England's injury list|
|Ben Foden (knee - out for season), Manu Tuilagi (groin - could return next month), Kyle Eastmond (shoulder - being assessed), Brad Barritt (knee - being assessed), Owen Farrell (knee - out for whole Six Nations), Dan Cole (ankle - could return in next two weeks), Joe Launchbury (neck - could be fit by April), Courtney Lawes (ankle - could return mid-late February), Geoff Parling (knee - being assessed, estimated 'two to three weeks'), Ed Slater (knee - could be fit by April), Tom Wood (ankle - being assessed), Ben Morgan (leg - out for season).|