Devastated England right-back Reece James has confirmed he will not be going to the World Cup.
The 22-year-old was a shoo-in for Qatar until sustaining a knee injury in the Champions League match against AC Milan on October 11.
Chelsea announced James was facing an eight-week lay-off - a timescale that would mean a return around the World Cup quarter-final stage.
James said at the time "the race against time is on" and vowed not to give up, but he has now confirmed he will not be in England's 26-man squad on Thursday after speaking to manager Gareth Southgate.
"Devastated," 15-cap England international James posted on Twitter.
"The minute I injured my knee, I knew the turn around to make the World Cup would be tight, but I always felt it was possible.
"I've worked harder than I ever thought I could to give myself the best chance of going and truly believed I could help the team."
Earlier, French sports paper L'Equipe reported Senegal forward Sadio Mané would also miss the event with a tendon injury sustained while playing for Bayern Munich.
The report said the injury would see the African player of the year Mané sidelined for several weeks after he went off in the 20th minute of Bayern's 6-1 Bundesliga win against Bremen.
Other several high-profile players have already been forced to pull out of the ill-timed tournament with injury, including French stars Paul Pogba and N'Golo Kante, Portugal's Diogo Jota, Argentina's Pablo Dybala and Netherlands' Georginio Wijnaldum.
Elsewhere, Japan midfielder Wataru Endo was stretchered off after being knocked unconscious during VfB Stuttgart's 2-1 home win over Hertha Berlin.
"Wataru Endo was unconscious on the field but was responsive again in the ambulance," Stuttgart wrote on Twitter.
The 29-year-old defensive midfielder has 43 caps and was last week named in Japan's World Cup squad.
But there was better news for South Korea's Tottenham star Son Heung-min, who ended any lingering doubts over his participation after suffering a fracture around his left eye during a 2-1 win away to Marseille in the Champions League last week.
After undergoing surgery on Friday, Son confirmed on Wednesday he'll feature in Qatar, saying on Instagram: "I won't miss this for the world. I can't wait to represent our beautiful country, see you soon."
- With DPA