RM Sotheby's is to auction the first Shelby Cobra in its August 19-20 sale in Monterey, California.
The car, ref CSX 2000, was born in a garage in Santa Fe Springs in 1962.
Its creator, former racing driver Carroll Shelby, and his team shoehorned a Ford V8 engine into a modified AC Ace.
The result was one of the most powerful sports cars of all time.
It remains an icon of American engineering prowess.
Shelby Myers, car specialist at RM Sotheby's, comments: "When it comes to American sports cars, CSX 2000 is without peers. Its historical significance and impact on the global sports car scene cannot be overstated.
"In the automotive world, CSX 2000 was the shot heard 'round the world; it revolutionized not only American racing, but the greater auto industry as a whole.
"Had Carroll Shelby never decided to squeeze that high performance V-8 into its engine bay, there would be no Cobra and certainly no Shelby American, nor GT40, nor the others that followed.
"The automotive landscape and sports cars as we know them would be very different."
No estimate is available for the lot, but it looks likely to beat the record for a Cobra - set at $5.5m for a 1966 427 Super Snake made especially for Carroll Shelby himself. It may well also break the auction record for a US car, held by the Ford GTO driven by Steve McQueen in 1968 film Le Mans, which sold for $11m in 2012.
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