ClinVar Miner

Submissions for variant NM_002769.5(PRSS1):c.364C>T (p.Arg122Cys) (rs111033568)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012658 SCV000552153 pathogenic Hereditary pancreatitis 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 122 of the PRSS1 protein (p.Arg122Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs111033568, ExAC 0.001%). This variant has been reported to segregate with hereditary pancreatitis (HP) and/or pancreatic cancer in several families (PMID: 11788572, 19454815, 11719509), and is one of the most common variants identified in individuals with HP (PMID: 24458023). ClinVar contains an entry for this variant (Variation ID: 11883). Experimental studies have shown that this missense change results in increased PRSS1 stability and activity due to inhibition of protein autolysis (PMID: 22539344, 11719509). A different missense substitution at this codon (p.Arg122His, also known as p.Arg117His) has been determined to be pathogenic (PMID: 8841182), and is the most frequent variant found in individuals with HP (PMID: 19453252). This suggests that the arginine residue is critical for PRSS1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508091 SCV000604931 pathogenic not specified 2018-08-17 criteria provided, single submitter clinical testing The PRSS1 p.Arg122Cys variant has been reported in multiple individuals diagnosed with pancreatitis (Le Marechal 2001, Pfutzer 2002). However, the variant shows incomplete penetrance; with approximately 40-50 percent of carriers develop pancreatic disease (de las Heras-Castano 2009, Simon 2002). Functional characterization indicates that the variant protein has increased auto-activation and enzymatic activity, and shows greater resistance to autolysis and inhibition (Simon 2002, Szabo 2012), consistent with the established disease mechanisms. Based on the above information, the variant is classified as pathogenic for the development of pancreatitis. REFERENCES de las Heras-Castano G et al. Hereditary pancreatitis: clinical features and inheritance characteristics of the R122C mutation in the cationic trypsinogen gene (PRSS1) in six Spanish families. JOP. 2009; 10(3):249-55. Le Marechal C et al. Discrimination of three mutational events that result in a disruption of the R122 primary autolysis site of the human cationic trypsinogen (PRSS1) by denaturing high performance liquid chromatography. BMC Genet. 2001; 2:19. Pfutzer R et al. Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis. Gut. 2002; 50(2):271-2. Simon P et al. Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 --> Cys) that alters autoactivation and autodegradation of cationic trypsinogen. J Biol Chem. 2002; 277(7):5404-10.
Integrated Genetics/Laboratory Corporation of America RCV000012658 SCV000698045 pathogenic Hereditary pancreatitis 2019-07-16 criteria provided, single submitter clinical testing Variant summary: PRSS1 c.364C>T (p.Arg122Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 254704 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.364C>T has been reported in the literature in individuals affected with Chronic Pancreatitis (e.g. Pfutzer_2002, LeMarechal_2001, Simon_2002, Teich_2006, Sobczynska-Tomaszewska_2006, Wang_2013, Zou_2018), however with reduced penetrance. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant slightly increased autoactivation and severely reduced chymotrypsin C (CTRC)-dependent degradation that is consistent with the mechanism of disease (Szabo_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both laboratories classified the variant as pathogenic. In this region other missense variants (p.A121T, p.R122H, and p.V123M) have also been reported in association with pancreatitis, suggesting importance of this region in PRSS1 function. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000012658 SCV000032893 pathogenic Hereditary pancreatitis 2006-08-01 no assertion criteria provided literature only
GeneReviews RCV000012658 SCV000054558 pathologic Hereditary pancreatitis 2012-03-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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