12:14 PM PT -- The San Diego County Sheriff's Dept. tells TMZ that a call came in for medical aid around 1:30 PM PT Monday -- and that when deputies arrived, fire officials were already providing lifesaving measures for Karen Houghton ... who sadly passed away.

Unclear what medical incident precipitated the call.

Kris Jenner's sister, Karen Houghton, has died ... TMZ has learned.

Law enforcement sources tell us Karen was reported as deceased to San Diego County officials Monday in San Marcos, CA. The exact circumstances of her passing are unclear, but we're told county officials are attributing her death to natural causes for now.

Karen was Kris' only sister -- sharing parents MJ and Robert Houghton -- and was born three years after the famed momager. Karen and Kris grew up in San Diego together, living predominantly with MJ after her divorce from the girls' father.

Sources with direct knowledge tell TMZ Kris is very upset over the passing of her sibling -- and is also concerned about Karen's mother and niece. This is MJ's first loss of a child, so obviously it's devastating. We're told the family at large is rallying around each other.

Kris addressed Karen's death on social media as well, with a sweet tribute that touched on their history and relationship ... remembering Karen fondly.

Despite the Kardashians' very public life, Karen has not played a major role in their reality TV fame ... as the sisters have had a somewhat complicated relationship over the years.

Karen went public with their issues back in 2014, alleging in an interview that Kris had changed since skyrocketing to A-list status. She also infamously weighed in on Kris' high-profile divorce from Olympian Caitlyn Jenner ... seemingly siding with her ex-in-law.

Then, in 2016, Karen made headlines for undergoing a five-hour facelift in order to look more like the Kardashian-Jenner matriarch -- ultimately pleased with the results, at the time.

A family truce seemed to be confirmed in 2019 -- when Karen and Kris posed for a photo with their mom MJ and their respective daughters, Natalie Zettel and Kylie Jenner, at Christmastime.

However, Karen hasn't been spotted with the family in recent years, having kept a low profile out of the limelight. She worked as a part-time nurse and an author before her death.

Karen is survived by her daughter -- who she welcomed with ex-husband Mark Zettel -- mother, sister and several nieces and a nephew. She was 65.

RIP