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Anibal Godoy's 54th-minute goal has delivered Panama a historic 1-0 victory and ended the US men's national team's unbeaten run in CONCACAF World Cup qualifying.
Panama were winless in their previous eight qualifiers against the United States and came close on a pair of dangerous corner kicks before finally finishing the task for the deciding goal in Panama City on Sunday.
Eric Davis sent the cross to the near post where Godoy got a flick past goalkeeper Matt Turner.
The US and Panama each have eight points, three behind Mexico who sit atop the group after they defeated Honduras 3-0 in the fifth round of the 14-match phase.
Elsewhere, Canada dropped to fourth with a 0-0 draw at bottom-placed Jamaica while Costa Rica moved up to fifth following their 2-1 home win over El Salvador.
The top three teams qualify for the 2022 World Cup in Qatar with the fourth-placed finisher going into an intercontinental playoff for another spot.
The US were without injured forwards Christian Pulisic (ankle) and Gio Reyna (hamstring) and midfielder Weston McKinnie (quadriceps) and they will not be available for Wednesday's match against Costa Rica in Columbus, Ohio.
And the lack of firepower showed in Panama with the US having just five shots at goal, their fewest in a qualifier since 2015, and none on target. Panama again proved to be tough at home in these qualifiers, after earlier draws against Costa Rica and Mexico.
"It was clear we didn't have our best stuff," US coach Gregg Berhalter told reporters.
"I think we came up short in a number of areas.
"Overall, we performed below the expectations we have for ourselves."
The match took place four years to the day since the US suffered a humiliating 2-1 defeat to Trinidad & Tobago that caused them to miss the 2018 World Cup in Russia, the first time they failed to reach the tournament since 1986.