chr7-142751937-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PM1PM5PP3_ModeratePP5_Very_StrongBS2_Supporting

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 Pathogenic.

Frequency

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

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0680

Publications

63 publications found

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]

PRSS1 Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

PRSS1 links:

TRB (HGNC:12155):

TRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 35 uncertain in NM_002769.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-142751938-GC-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 11882.Status of the report is no_assertion_criteria_provided, 0 stars.

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 VariationId is 11883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5 link	c.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
PRSS1	ENST00000311737.12 link	c.364C>T	p.Arg122Cys	missense_variant	Exon 3 of 5	1	NM_002769.5	ENSP00000308720.7		P07477

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152052

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251452

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41382

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000885

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

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

Aug 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 18, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R122C pathogenic mutation (also known as c.364C>T), located in coding exon 3 of the PRSS1 gene, 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 variant 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 variant results in increased autoactivation and impaired autolysis 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 with this variant developed pancreatitis (de las Heras-Castaño et al. JOP. 2009; 10(3): 249-55). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. PfÃ¼tzer 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. -

Dec 11, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Pathogenic:4

Mar 27, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_moderate, PM5, PS3, PS4_moderate -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 12, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PRSS1-related disorder

Pathogenic:1

Apr 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;.;D;D

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.027

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.73

.;.;N;.

PhyloP100

0.068

PrimateAI

Benign

0.25

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

GERP RS

1.3

Varity_R

0.42

gMVP

0.65

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over