Table 6 Illustrative examples of additions to the main classification categories in the context of PRSS1 variants
From: Expanding ACMG variant classification guidelines into a general framework
Variant | Classification |
|---|---|
Trypsinogen gene triplication | Pathogenic (causes HCP; has also been noted in cases with FCP and ICP; causes the disease via a gene dosage effect) [39] |
p.Ala16Val | Pathogenic (highly variable penetrance [38]; causes disease via the trypsin-dependent pathway) [77] |
p.Arg122His | Pathogenic (the most frequent variant found in HCP families [38]; causes disease via the trypsin-dependent pathway) [41, 91] |
p.Gly208Ala | Predisposing (Asian population-specific variant, with an allele frequency of 0.009873 in East Asians; odds ratio for ICP, 4.92 [36]; may predispose to CP through the misfolding pathway [42] since it causes a moderate effect on secretion [61]) |
c.-204A > C | Predisposing (a common promoter polymorphism whose pathological authenticity is supported by both in silico and functional data; exerts a moderate genetic effect; odds ratio for ICP, 1.28) [64] |
c.200 + 1G > A | Benign (a loss-of-function mutation that was found in normal controls; protective against CP) |