Hereditary pancreatitis (# 167800, HP) is an autosomal dominant disorder with estimated penetrance of up to 70-80% and variable expressivity and an estimated lifetime risk of pancreatic cancer up to 40% (PMID: 12727412). At least 300 variants are reported, most are missense, in the cationic trypsinogen gene (PRSS1 *276000). The splicing and frameshift variants, as well as triplication of the gene locus (Marechal CL et al., PMID: 17072318) are also reported to be associated with Hereditary Pancreatitis. These variants have been reported to cause 'gain-of-function' of the trypsin activity. In this curation, large segregation studies lead to the identification of the most common missense variant, NM_002769.5(PRSS1):c.365G>A (p.Arg122His) (Ferec C et al, PMID 10204851 and Whitcomb DC et al., PMID8841182). Two other common missense variants, NM_002769.5(PRSS1):c.86A>T (p.Asn29Ile) and NM_002769.5(PRSS1):c.68A>G (p.Lys23Arg) were described. Additional missense variants, in familial and sporadic cases are described (Witt H et al., PMID 10381903l; Teich N et al., PMID 10930381; Chen JM et al., PMID 11073545; Simon P et al., PMID 1179509). These variants are repetitively reported and more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. This gene-disease association is also supported by functional studies (Simon P et al., PMID 11719509; Teich N et al., PMID 10930381; Sahin-Toth M et al., PIMD 1109832) and mouse model systems (Jancso Z et al., PMID31751559; Selilg L et al., PMID 17069643) for various pathogenic variants. Taken together these studies demonstrated that most pathogenic variants significantly enhance autoactivation in vitro, whereas some mutations such as p.R122H additionally inhibit autolysis of the active enzyme. In summary, these replicated studies revealed PRSS1 is definitively associated with autosomal dominant inheritance pancreatitis. This has been repeatedly demonstrated in clinical diagnostic settings and experimental research. It has been upheld over time.
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