Elliot Daly will miss all of England's Six Nations campaign after the full-back suffered a hamstring injury playing for Saracens.
The 30-year-old, who has won 57 international caps, is expected to be out of action for around 12 weeks.
He was forced off during the second half of Saracens' European Champions Cup defeat at Edinburgh on Sunday.
Former Wasps man Daly, who can also play at centre and on the wing, made his England debut in 2016.
On Tuesday Daly had withdrawn from the England training squad which is preparing for the Six Nations opener against Scotland on 4 February.
New head coach Steve Borthwick has already had to deal with a number of injuries as he prepares for his first match in charge, having taken over from Eddie Jones in December.
Forward Courtney Lawes and hooker George McGuigan pulled out of the squad on Monday with calf and knee injuries respectively, while Exeter forward Luke Cowan-Dickie will miss at least the start of the tournament with an ankle problem.
After their opener against Scotland at Twickenham, England host Italy on 12 February.
A trip to Wales follows on 25 February before a home game against defending champions France on 11 March precedes their final game against Ireland on 18 March in Dublin.
A 12-week absence could see Daly back in action for Saracens in the Premiership leaders' final game of the regular campaign at Bath on the first weekend in May.
This season's Premiership final is on Saturday, 27 May at Twickenham, with the European Champions Cup final seven days beforehand in Dublin.