7-142751937-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_002769.5(PRSS1):c.364C>T(p.Arg122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002769.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152052Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251452Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461878Hom.: 0 Cov.: 61 AF XY: 0.0000220 AC XY: 16AN XY: 727240
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152052Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74270
ClinVar
Submissions by phenotype
Hereditary pancreatitis Pathogenic:5Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 08, 2021 | The p.R122C pathogenic mutation (also known as c.364C>T) is located in coding exon 3 of the PRSS1 gene. This alteration results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first identified in two families with hereditary pancreatitis and was seen to have incomplete penetrance (Pfutzer R et al. Gut. 2002;50:271-272). One in vitro studied determined that this mutation results in increased autoactivation and impaired autoloysis of trypsinogen at a basic pH in the absence of calcium (Simon et al. J Biol Chem. 2002;277(7):5404-10). In addition, a study of 6 families with hereditary pancreatitis found that approximately 40% of the 22 carriers of this mutation developed pancreatitis (de las Heras-Castaño et al. JOP. 2009; 10(3): 249-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 12, 2024 | The PRSS1 c.364C>T; p.Arg122Cys variant (rs111033568) is 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 developing pancreatic disease (de las Heras-Castano 2009, Simon 2002). This variant is also reported in ClinVar (Variation ID: 11883), and is found in the general population with an overall allele frequency of 0.0020% (5/251452 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). 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 available information, the variant is considered to be pathogenic. 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 May 18;10(3):249-55. PMID: 19454815. 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. PMID: 11734061. Pfützer R et al. Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis. Gut. 2002 Feb;50(2):271-2. PMID: 11788572. 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 Feb 15;277(7):5404-10. PMID: 11719509. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2020 | Variant summary: PRSS1 c.364C>T (p.Arg122Cys) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain of 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. 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). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the PRSS1 protein (p.Arg122Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hereditary pancreatitis (HP) and/or pancreatic cancer (PMID: 11719509, 11788572, 19454815, 24458023). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11883). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRSS1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRSS1 function (PMID: 11719509, 22539344). This variant disrupts the p.Arg122 amino acid residue in PRSS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8841182, 19453252). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2025 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28502372, 24624459, 19686634, 11788572, 19454815, 27179762, 22539344, 16791840, 17568390, 11719509, 19191323, 12120221, 11734061, 17003641, 18755888, 20452997, 24458023, 24002981, 19453252, 8841182, 22427236, 23951356, 25010710, 18511571, 16954950, 27673710, 31589614, 33257277, 34224489, 30420730, 36369231) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 27, 2024 | PM2_moderate, PM5, PS3, PS4_moderate - |
PRSS1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 16, 2024 | The PRSS1 c.364C>T variant is predicted to result in the amino acid substitution p.Arg122Cys. This variant, as well as an alternative substitution at the same amino acid position (p.Arg122His), has been reported to be causative for autosomal dominant hereditary chronic pancreatitis with penetrance of ~40-70% (Le Maréchal et al. 2001. PubMed ID:11734061; Simon et al. 2002 PubMed ID: 11719509; Pfützer et al. 2002 PubMed ID: 11788572; de las Heras-Castaño et al. 2009. PubMed ID: 19454815). A different substitution at the same amino acid position (p.Arg122His) has also been reported as pathogenic. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at