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

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense

Scores

3
7
8

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 0.0680
Variant links:
Genes affected
PRSS1 (HGNC:9475): (serine protease 1) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved to its active form in the small intestine. It is active on peptide linkages involving the carboxyl group of lysine or arginine. Mutations in this gene are associated with hereditary pancreatitis. This gene and several other trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a strand (size 2) in uniprot entity TRY1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_002769.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-142751938-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.87
PP5
Variant 7-142751937-C-T is Pathogenic according to our data. Variant chr7-142751937-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142751937-C-T is described in UniProt as null. Variant chr7-142751937-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-142751937-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRSS1NM_002769.5 linkc.364C>T p.Arg122Cys missense_variant Exon 3 of 5 ENST00000311737.12 NP_002760.1 P07477

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRSS1ENST00000311737.12 linkc.364C>T p.Arg122Cys missense_variant Exon 3 of 5 1 NM_002769.5 ENSP00000308720.7 P07477

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152052
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251452
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461878
Hom.:
0
Cov.:
61
AF XY:
0.0000220
AC XY:
16
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152052
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74270
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000957
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary pancreatitis Pathogenic:5Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2006- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 08, 2021The 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 providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 12, 2024The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 11, 2020Variant 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2024This 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 submitterclinical testingGeneDxFeb 12, 2025In 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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMar 27, 2024PM2_moderate, PM5, PS3, PS4_moderate -
PRSS1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 16, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
.;.;D;D
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.027
N
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Benign
0.73
.;.;N;.
PrimateAI
Benign
0.25
T
PROVEAN
Uncertain
-3.4
D;.;D;D
REVEL
Uncertain
0.52
Sift
Benign
0.12
T;.;T;T
Sift4G
Benign
0.12
T;T;T;T
Polyphen
0.99
D;.;D;.
Vest4
0.49
MVP
0.94
MPC
0.57
ClinPred
0.59
D
GERP RS
1.3
Varity_R
0.42
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111033568; hg19: chr7-142459788; COSMIC: COSV61197190; COSMIC: COSV61197190; API