ClinVar Miner

Submissions for variant NM_002769.5(PRSS1):c.365G>A (p.Arg122His) (rs111033565)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000012651 SCV000053050 pathogenic Hereditary pancreatitis 2019-03-13 criteria provided, single submitter clinical testing Variant summary: PRSS1 c.365G>A (p.Arg122His) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246622 control chromosomes (gnomAD). c.365G>A has been reported in the literature in multiple individuals affected with Chronic Pancreatitis (Sofia_2016, Dasouki_1998, Whitcomb_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to increase autolytic stability of trypsin and enhance autocatalytic trypsin generation (Sahin-Toth_2000), resulting in a gain of function effect. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000012651 SCV000552151 pathogenic Hereditary pancreatitis 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 122 of the PRSS1 protein (p.Arg122His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant (rs111033565) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This missense variant has been reported to segregate with hereditary pancreatitis (HP) in several large families (PMID: 8841182), and is the most frequent mutation found in individuals with HP (PMID: 19453252). This variant is also known as Arg117His or R117H in the literature. ClinVar contains an entry for this variant (Variation ID: 11876). Experimental studies have shown that this missense change leads to an increase in both PRSS1 stability and trypsinogen activity, due to an inhibition of autolysis (PMID: 11748242, 11097832). A different missense substitution at this codon (p.Arg122Cys) has been determined to be pathogenic (PMID: 19453252), further demonstrating that the arginine residue is critical for normal inactivation of trypsinogen in the pancreas, and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000487005 SCV000568661 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing The R122H variant in the PRSS1 gene has been reported previously in association with hereditary pancreatitis in multiple unrelated individuals from diverse ethnic backgrounds (Whitcomb et al., 1996; Nishimori et al., 1999; Saito et al., 2016). The R122H variant is the most common pathogenic variant associated with hereditary pancreatitis (Nemeth and Sahin-Toth, 2014). The R122H variant is is not observed in large population cohorts (Lek et al., 2016). The R122H variant is a conservative amino acid substitution and occurs at a position that is not conserved. Functional studies demonstrated that the R122H variant significantly enhanced autoactivation of cationic trypsinogen in vitro and inhibited autocatalytic inactivation of trypsin (Sahin-Toth et al., 2000). Therefore, we interpret R122H as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000034 SCV000604930 pathogenic not specified 2018-07-13 criteria provided, single submitter clinical testing The PRSS1 c.365G>A; p.Arg122His variant (rs111033565) is reported in the literature as the most common pathogenic variant associated with hereditary pancreatitis (Nemeth and Sahin-Toth 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11876). This variant increases the auto-activation and stability of trypsin, even in the presence of inhibitory factors such as chymotrypsin C (Sahin-Toth 2000, Szabo 2012, Whitcomb 1996), and leads to chronic pancreatic inflammation and acinar cell necrosis in a mouse model (Archer 2006). Based on available information, this variant is considered pathogenic for the development of pancreatitis. References: Archer H et al. A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology. 2006; 131(6):1844-55. Nemeth BC and Sahin-Toth M. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2014 Mar;306(6):G466-73. Sahin-Toth M et al. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun. 2000; 278(2):286-9. Szabo A et al. Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. J Biol Chem. 2012; 287(24):20701-10. Whitcomb D et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996; 14(2):141-5.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000012651 SCV000782240 pathogenic Hereditary pancreatitis 2016-11-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001020821 SCV001182352 pathogenic Inborn genetic diseases 2018-08-09 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487005 SCV001247577 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
OMIM RCV000012651 SCV000032886 pathogenic Hereditary pancreatitis 2006-08-01 no assertion criteria provided literature only
GeneReviews RCV000012651 SCV000054559 pathologic Hereditary pancreatitis 2012-03-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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