ClinVar

Description

Variant summary: PRSS1 c.235G>A (p.Glu79Lys) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 1615650 control chromosomes, predominantly at a frequency of 0.00024 within the African or African-American subpopulation in the gnomAD v4 database. This frequency is close to the estimated maximal expected allele frequency of a pathogenic PRSS1 causing Chronic Pancreatitis (0.00024 vs 0.00025), suggesting this may be a benign polymorphism. Co-occurrence with a pathogenic variant has been reported following internal testing (SPINK1 c.101A>G, p.Asn34Ser) while, there are at least four reported chronic pancreatitis patients in literature that carry CFTR pathogenic variants (5T allele or p.F508del) along with this variant (Keiles_2006, Masson_2013, Oracz_2016, Sultan_2012). c.235G>A has been reported in the literature in multiple individuals/families affected with chronic pancreatitis, idiopathic chronic pancreatitis, hereditary pancreatitis and alcohol-related chronic pancreatitis as well as in unaffected controls and unaffected family members (e.g. Chen_2001, Bernardino_2003, Teich_2004, Derikx_2009, Rousseau_2012, Hamoir_2013, Oracz_2016, Masson_2023). Functional studies (Teich_2004, Kereszturi_2009) of E79K trypsin revealed unaltered secretion, catalytic activity, autolysis, and inhibition by pancreatic secretory trypsin inhibitor; however, the variant was found to cause increased trypsinogen activation following transactivation of PRSS2. The following publications have been ascertained in the context of this evaluation (PMID: 14526128, 25543846, 11260229, 19857283, 23751316, 17003641, 19191323, 36517351, 23951356, 27179762, 18755888, 22094894, 20452997, 14695529). ClinVar contains an entry for this variant (Variation ID: 11880). Based on the evidence outlined above, the variant was classified as uncertain significance.