Maro Itoje has conceded defeat in his battle to be fit for the climax to England's Guinness Six Nations against Scotland on Saturday.
Itoje last week suffered a setback in his recovery from the knee injury sustained against Ireland on the opening weekend of the tournament and has now been omitted from a 31-man training squad for the final-round fixture at Twickenham.
"Maro Itoje has returned to his club Saracens to continue to rehabilitation," the Rugby Football Union has announced.
Eddie Jones was non committal when asked about Itoje's condition in the wake of Saturday's rout of Italy, declaring "we'll just wait and see", but the second row's Championship is now definitively over with only 53 minutes played.
It was hoped he would return to face the Azzurri only to injure the same right knee that was hurt in Dublin when taking part in a forwards drill at the squad's Surrey base.
Bizarrely, Jones raised the prospect of the British and Irish Lion being propelled back into the matchday 23 against Italy soon after he had been left out, stating that he could make a rapid recovery.
While the loss of Itoje is a blow, England can at least take heart from the performance of George Kruis at Twickenham on Saturday.
Jones singled out Kruis as his man of the match on the grounds of his work-rate and the 29-year-old is set to continue his second-row partnership with Joe Launchbury against the Scots.
Fly-half Marcus Smith has been called into title-chasing England's training squad for the first time in this Six Nations in a snub to Danny Cipriani, who does not appear to be in Jones' World Cup plans.