This variant, formerly titled HEREDITARY PANCREATITIS, has been reclassified based on the findings of Szmola and Sahin-Toth (2010).
In affected members of a family with hereditary pancreatitis (167800), Felderbauer et al. (2008) identified a heterozygous G-to-A transition in exon 3 of the PRSS1 gene, resulting in an ala121-to-thr (A121T) substitution. The proband had relatively late disease onset in his thirties, and family history indicated reduced penetrance. In vitro functional expression studies showed that the mutant protein resulted in increased digestion by trypsin (more than 80% compared to wildtype PRSS1) that was calcium-dependent. The findings were consistent with a increased autodegradation and a loss of function mechanism, which was opposite to that observed with the common R122H mutation (276000.0001).
Szmola and Sahin-Toth (2010) presented evidence that the A121T variant is functionally innocuous and not a cause of pancreatitis. The authors noted that only the index patient in the report of Felderbauer et al. (2008) carried the A121T variant and suffered from chronic pancreatitis. The patient's brother and first cousin, who both carried the variant, had cholelithiasis, and his niece and her mother were asymptomatic carriers. Functional expression studies by Szmola and Sahin-Toth (2010) indicated that autoactivation of trypsinogens by the A121T variant was similar to wildtype with equal enzyme kinetics. Szmola and Sahin-Toth (2010) suggested that the variant may have been assigned clinical relevance based on a perceived analogy with the neighboring disease-causing R122H mutations (276000.0001 and 276000.0008).