PRSS1

protein-coding

serine protease 1, the group of Serine proteases

Gene summary

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]

Previous symbols:

TRY1

MANE transcript

NM_002769.5

Inheritance

ClinVar variants

P:15U:555B:243

Top phenotype

Pancreatitis, hereditary

gnomAD constraint

pLI —, LoF o/e 1.31

Max pathogenic AF

—

Genomic locus

chr7:142,749,468-142,753,072

External References & Databases

Ensembl (ENSG00000204983)

Transcript & Mutation Effects

hg38 • Region Span ~3.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary chronic pancreatitisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: Illumina

hereditary chronic pancreatitisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: Ambry Genetics

hereditary chronic pancreatitisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: ClinGen

Hereditary pancreatitis (# 167800, HP) is an autosomal dominant disorder with estimated penetrance of up to 70-80% and variable expressivity and an estimated lifetime risk of pancreatic cancer up to 40% (PMID: 12727412). At least 300 variants are reported, most are missense, in the cationic trypsinogen gene (PRSS1 *276000). The splicing and frameshift variants, as well as triplication of the gene locus (Marechal CL et al., PMID: 17072318) are also reported to be associated with Hereditary Pancreatitis. These variants have been reported to cause 'gain-of-function' of the trypsin activity. In this curation, large segregation studies lead to the identification of the most common missense variant, NM_002769.5(PRSS1):c.365G>A (p.Arg122His) (Ferec C et al, PMID 10204851 and Whitcomb DC et al., PMID8841182). Two other common missense variants, NM_002769.5(PRSS1):c.86A>T (p.Asn29Ile) and NM_002769.5(PRSS1):c.68A>G (p.Lys23Arg) were described. Additional missense variants, in familial and sporadic cases are described (Witt H et al., PMID 10381903l; Teich N et al., PMID 10930381; Chen JM et al., PMID 11073545; Simon P et al., PMID 1179509). These variants are repetitively reported and more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. This gene-disease association is also supported by functional studies (Simon P et al., PMID 11719509; Teich N et al., PMID 10930381; Sahin-Toth M et al., PIMD 1109832) and mouse model systems (Jancso Z et al., PMID31751559; Selilg L et al., PMID 17069643) for various pathogenic variants. Taken together these studies demonstrated that most pathogenic variants significantly enhance autoactivation in vitro, whereas some mutations such as p.R122H additionally inhibit autolysis of the active enzyme. In summary, these replicated studies revealed PRSS1 is definitively associated with autosomal dominant inheritance pancreatitis. This has been repeatedly demonstrated in clinical diagnostic settings and experimental research. It has been upheld over time.

hereditary chronic pancreatitisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: PanelApp Australia

malignant pancreatic neoplasmMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009831

Submitter: Genomics England PanelApp

hereditary chronic pancreatitisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: Labcorp Genetics (formerly Invitae)

hereditary chronic pancreatitisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: Orphanet

Clinical Genomic Database (CGD)

Pancreatitis, hereditaryAD

Manifestation: Gastrointestinal; Oncologic

Intervention: Gastrointestinal; Oncologic

Rationale: To decrease attacks, dietary measures (eg, low-fat diet), hydration, and antioxidants, with avoidance of precipitants, such as alcohol and tobacco can beneficial; Medical management (including with pancreatic enzyme replacement) may be benefiical; Individuals may be at increased risk for manifestations such as pancreatic cancer, and awareness may allow prompt detection and treatment

Refs: 6023921; 8841182; 9322498; 9557894; 10204851; 18184119; 18755888; 22088471; 22094894; 22379635; 23503650; 23864476; 24236450; 24242859; 24624459

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRSS1 variants in ClinVar

8 Conditions Cataloged

Hereditary pancreatitisTotal: 863

not specifiedTotal: 96

not providedTotal: 40

PRSS1-related disorderTotal: 9

Trypsinogen deficiencyTotal: 2

Vitamin D-dependent rickets type II with alopeciaTotal: 1

Hereditary cancer-predisposing syndromeTotal: 1

Myoepithelial tumorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002769.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	209 clinvar	1 clinvar	215
missense	5 clinvar	9 clinvar	518 clinvar	29 clinvar	3 clinvar	564
nonsense			9 clinvar			9
start loss			4 clinvar			4
frameshift			8 clinvar			8
splice donor/acceptor (+/-2bp)	1 clinvar		11 clinvar	1 clinvar		13
Total	6	9	555	239	4	813

Highest pathogenic variant AF is 0.000142705

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002769.5	RefSeq	NP_002760.1	5	MANE Select
ENST00000311737.12	Ensembl	ENSP00000308720.7	5	MANE Select
ENST00000486171.5	Ensembl	ENSP00000417854.1	6	Standard
ENST00000492062.2	Ensembl	ENSP00000419912.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Influenza A - Homo sapiens (human)
Protein digestion and absorption - Homo sapiens (human)
Pancreatic secretion - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Extracellular matrix organization

Biological Process

proteolysis
digestion
cobalamin metabolic process
extracellular matrix disassembly

Molecular Function

serine-type endopeptidase activity
serine-type peptidase activity
metal ion binding

Cellular Component

extracellular region
extracellular space
collagen-containing extracellular matrix
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311737
Coding exons: 5
Length: 3605
Individuals with no LoFs: 125642
Homozygous LoFs: 1
Heterozygous LoFs: 105
Defined: 125748
p: 0.000422

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.01	194	130	1.50	0.00000764	1561
Missense (PolyPhen)		55	37.875	1.4522		499
Synonymous	-3.10	78	50.1	1.56	0.00000307	460
Loss of Function	-0.941	14	10.7	1.31	6.38e-7	112

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0011	notable
Latino/Admixed American	0.00042	0.00038	rare
Ashkenazi Jewish	0.00090	0.00069	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00034	0.00032	rare
European (Non-Finnish)	0.00044	0.00041	rare
South Asian	0.00031	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has activity against the synthetic substrates Boc-Phe- Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val- Pro-Arg-Mec. The single-chain form is more active than the two- chain form against all of these substrates. {ECO:0000269|PubMed:7945238}.;
Disease: DISEASE: Pancreatitis, hereditary (PCTT) [MIM:167800]: A disease characterized by pancreas inflammation, permanent destruction of the pancreatic parenchyma, maldigestion, and severe abdominal pain attacks. {ECO:0000269|PubMed:10204851, ECO:0000269|PubMed:10381903, ECO:0000269|PubMed:10930381, ECO:0000269|PubMed:11073545, ECO:0000269|PubMed:11788572, ECO:0000269|PubMed:11866271, ECO:0000269|PubMed:14695529, ECO:0000269|PubMed:15776435, ECO:0000269|PubMed:8841182, ECO:0000269|PubMed:9322498, ECO:0000269|PubMed:9633818}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.781

Intolerance Scores

LoFtool: 0.125
RVIS EVS: -0.12
RVIS percentile EVS: 44.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.370

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium