VCV000011876.62 - ClinVar

NM_002769.5(PRSS1):c.365G>A (p.Arg122His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(22)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002769.5(PRSS1):c.365G>A (p.Arg122His)

Variation ID: 11876 Accession: VCV000011876.62

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q34 7: 142751938 (GRCh38) [ NCBI UCSC ] 7: 142459789 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Feb 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002769.5:c.365G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002760.1:p.Arg122His	missense
NC_000007.14:g.142751938G>A
NC_000007.13:g.142459789G>A
NG_001333.2:g.585606G>A
NG_008307.3:g.7455G>A
LRG_1013:g.7455G>A
LRG_1013t1:c.365G>A	LRG_1013p1:p.Arg122His
	P07477:p.Arg122His

... more HGVS ... less HGVS

Protein change

R122H

Other names

PRSS1, ARG122HIS, 365G-A

Canonical SPDI

NC_000007.14:142751937:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA341151 UniProtKB: P07477#VAR_006721 OMIM: 276000.0001 dbSNP: rs111033565 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PRSS1		No evidence available	No evidence available	GRCh38 GRCh38 GRCh37	2	827
TRB	-	-	-	GRCh38 GRCh38 GRCh37	1	837

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary pancreatitis	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Nov 25, 2023	RCV000012651.67
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Feb 28, 2024	RCV000487005.39
PRSS1-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 20, 2024	RCV003944816.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 20, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568661.3 First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017	Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001424479.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020
Pathogenic (Nov 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812500.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047387.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The PRSS1 (c.365G>A) variant has been reported in heterozygous state in individuals affected with Pancreatitis, hereditary (Sahin-Tóth et. al., 2000), and is the most frequent … (more) The PRSS1 (c.365G>A) variant has been reported in heterozygous state in individuals affected with Pancreatitis, hereditary (Sahin-Tóth et. al., 2000), and is the most frequent mutation found in individuals with the same disorder (Chen et. al., 2009). 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 (Kukor et. al., 2002; Sahin-Tóth et. al., 2000). A different missense substitution at this codon (p.Arg122Cys) has been determined to be pathogenic (Chen et. al., 2009), 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. The p.Arg122His variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.001% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 122 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg122His in PRSS1 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Pancreatitis (present) , Failure to thrive (present)
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary pancreatitis Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004123061.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Aug 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604930.7 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: 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). … (more) 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. PMID: 17087933. 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. PMID: 24458023. 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. PMID: 11097832. 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. PMID: 22539344. Whitcomb D et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996; 14(2):141-5. PMID: 8841182. (less)
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782240.1 First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018
Pathogenic (Mar 13, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000053050.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2020	Publications: PubMed (5) PubMed: 9557894‚ 8841182‚ 19191323‚ 11097832‚ 27264265 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 24, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534749.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The PRSS1 c.365G>A (p.R122H) variant has been reported in heterozygosity in numerous individuals with hereditary pancreatitis (PMID: 8841182, 18755888, 27264265). Functional studies have shown that … (more) The PRSS1 c.365G>A (p.R122H) variant has been reported in heterozygosity in numerous individuals with hereditary pancreatitis (PMID: 8841182, 18755888, 27264265). Functional studies have shown that this variant results in significantly increased levels of active trypsin versus wild type and is highly resistant to degradation (PMID: 22539344). This variant was identified in at least five unrelated families, where it was found to segregate with the phenotype across 20 meioses/individuals (PMID: 8841182). It is also known as R117H in the literature and is a well-established pathogenic variant associated with pancreatitis (PMID: 22379635). It was observed in 3/128912 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 11876). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (5) PubMed: 8841182‚ 18755888‚ 27264265‚ 22539344‚ 22379635
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818191.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: unknown	3billion Accession: SCV004013551.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (5) PubMed: 11748242‚ 31419436‚ 11097832‚ 11788572‚ 8841182 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11097832, 11748242, 31419436). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011876 / PMID: 8841182). A different missense change at the same codon (p.Arg122Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011883 / PMID: 11788572). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abdominal pain (present) , Abnormal facial shape (present)
Pathogenic (Nov 25, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000552151.10 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 8841182‚ 19453252‚ 11097832‚ 11748242 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 122 of the PRSS1 protein (p.Arg122His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 122 of the PRSS1 protein (p.Arg122His). 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 HP (PMID: 8841182, 19453252). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg117His or R117H. ClinVar contains an entry for this variant (Variation ID: 11876). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 11097832, 11748242). 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: 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. (less)
Pathogenic (Aug 19, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001182352.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 12508340‚ 18755888‚ 22539344‚ 31419436‚ 8841182 Comment: The p.R122H pathogenic mutation (also known as c.365G>A), located in coding exon 3 of the PRSS1 gene, results from a G to A substitution at … (more) The p.R122H pathogenic mutation (also known as c.365G>A), located in coding exon 3 of the PRSS1 gene, results from a G to A substitution at nucleotide position 365. The arginine at codon 122 is replaced by histidine, an amino acid with highly similar properties. This mutation is one of the most common mutations observed in families with hereditary pancreatitis. In one study, this mutation was detected in 105/135 (78%) PRSS1 mutation carriers from 50 unrelated families (Rebours V et al. Gut, 2009 Jan;58:97-103). In addition, an in vitro study demonstrated that this mutation results in a markedly higher active trypsin level compared to wild type and is resistant to degradation (Szabó A et al. J. Biol. Chem., 2012 Jun;287:20701-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jun 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005046503.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Other databases https://pancreasgenetics.org/prs… https://pancreasgenetics.org/prss1/ Number of individuals with the variant: 9
Pathogenic (Feb 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197283.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Mar 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247577.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Aug 01, 2006)	no assertion criteria provided Method: literature only	PANCREATITIS, HEREDITARY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032886.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 17, 2021	Publications: PubMed (6) PubMed: 8841182‚ 10204851‚ 12765848‚ 11702203‚ 12413370‚ 16791840 Audrezet, M.-P., Chen, J.-M., Le (more...) Audrezet, M.-P., Chen, J.-M., Le Marechal, C., Ruszniewski, P., Robaszkiewicz, M., Raguenes, O., Quere, I., Scotet, V., Ferec, C. Determination of the relative contribution of three genes--the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic chronic pancreatitis. Europ. J. Hum. Genet. 10: 100-106, 2002. Comment on evidence: The arg122-to-his mutation (R122H; previously designated ARG117HIS, or R117H, by the chymotrypsin numbering system) was a consistent finding in all cases of hereditary pancreatitis (167800) … (more) The arg122-to-his mutation (R122H; previously designated ARG117HIS, or R117H, by the chymotrypsin numbering system) was a consistent finding in all cases of hereditary pancreatitis (167800) examined by Whitcomb et al. (1996)--a total of 20 affected individuals and 6 obligate carriers in 5 kindreds. X-ray crystal structure analysis, molecular modeling, and protein digest data indicated that the arg117 residue is a trypsin-sensitive site. The authors suggested that cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis. Ferec et al. (1999) detected this mutation in 4 of 8 families with hereditary pancreatitis caused by mutation in the PRSS1 gene. In most cases the R122H mutation results from a G-to-A (CGC to CAC) transition (365G-A), which most probably occurred as a spontaneous deamination of 5-methylcytosine to give thymine in the CpG dinucleotides on the opposite strand (Chen and Ferec, 2000). Chen et al. (2000) identified a GC-to-AT (CGC to CAT) substitution (276000.0008), which also resulted in an R122H mutation but clearly arose via a different genetic mechanism, namely, gene conversion. This theory was strongly supported by the presence of AT in the corresponding position of 2 homologous genes and a Chi-like sequence in the 3-prime vicinity of the mutation. This mutation would not be detected by the generally used screening method based on a specific restriction site. Audrezet et al. (2002) analyzed the entire coding sequence and exon/intron junctions of the PRSS1 gene by denaturing gradient gel electrophoresis (DGGE) analysis and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. The R122H missense mutation was found in a 42-year-old male patient who had suffered the disease from the age of 6 years, and with no family members reported to have pancreatitis. Simon et al. (2002) reported the trypsinogen mutation in 5 of 50 patients (10%) with idiopathic pancreatitis; all 5 had the R122H mutation. Patients with trypsinogen mutations were significantly younger at disease onset (mean age, 14 years) than the remaining cohort (38 years) and accounted for 35% of the patients younger than 25 years. At least 1 of the 5 patients could be confidently stated to have a de novo R122H mutation. Among cases of chronic pancreatitis, mutations in arg122 and in neighboring amino acid residues have been found with unusually high frequency. Furthermore, the R122H mutation has been found worldwide and, as noted, was identified as a de novo mutation in a German patient by Simon et al. (2002). An R122C amino acid change (276000.0009) had been found by 4 groups including their own, according to Teich et al. (2006). Teich et al. (2006) proposed that the high frequency of mutations in or close to arg122 causing chronic pancreatitis suggests that 'this sequence is particularly prone to mutations.' (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740413.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957668.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980661.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Jan 20, 2024)	no assertion criteria provided Method: clinical testing	PRSS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004761756.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The PRSS1 c.365G>A variant is predicted to result in the amino acid substitution p.Arg122His. This variant, also described as p.Arg117His in earlier publications, has been … (more) The PRSS1 c.365G>A variant is predicted to result in the amino acid substitution p.Arg122His. This variant, also described as p.Arg117His in earlier publications, has been reported multiple times to be causative for chronic pancreatitis and is one of the most commonly reported causative variants (see for example Whitcomb et al. 1996. PubMed ID: 8841182; Archer et al. 2006. PubMed ID: 17087933). This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/11876/). We interpret this variant as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Hereditary pancreatitis Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000054559.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 22379635 BookShelf: NBK84399 BookShelf: NBK84399
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Citation text

Audrezet, M.-P., Chen, J.-M., Le Marechal, C., Ruszniewski, P., Robaszkiewicz, M., Raguenes, O., Quere, I., Scotet, V., Ferec, C. Determination of the relative contribution of three genes--the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic chronic pancreatitis. Europ. J. Hum. Genet. 10: 100-106, 2002.

Comment:

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.

Comment:

The PRSS1 (c.365G>A) variant has been reported in heterozygous state in individuals affected with Pancreatitis, hereditary (Sahin-Tóth et. al., 2000), and is the most frequent mutation found in individuals with the same disorder (Chen et. al., 2009). 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 (Kukor et. al., 2002; Sahin-Tóth et. al., 2000). A different missense substitution at this codon (p.Arg122Cys) has been determined to be pathogenic (Chen et. al., 2009), 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. The p.Arg122His variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.001% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 122 is changed to a His changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg122His in PRSS1 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

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. PMID: 17087933. 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. PMID: 24458023. 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. PMID: 11097832. 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. PMID: 22539344. Whitcomb D et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996; 14(2):141-5. PMID: 8841182.

Comment:

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.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11097832, 11748242, 31419436). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011876 / PMID: 8841182). A different missense change at the same codon (p.Arg122Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011883 / PMID: 11788572). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 122 of the PRSS1 protein (p.Arg122His). 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 HP (PMID: 8841182, 19453252). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg117His or R117H. ClinVar contains an entry for this variant (Variation ID: 11876). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 11097832, 11748242). 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: 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.

Comment:

The p.R122H pathogenic mutation (also known as c.365G>A), located in coding exon 3 of the PRSS1 gene, results from a G to A substitution at nucleotide position 365. The arginine at codon 122 is replaced by histidine, an amino acid with highly similar properties. This mutation is one of the most common mutations observed in families with hereditary pancreatitis. In one study, this mutation was detected in 105/135 (78%) PRSS1 mutation carriers from 50 unrelated families (Rebours V et al. Gut, 2009 Jan;58:97-103). In addition, an in vitro study demonstrated that this mutation results in a markedly higher active trypsin level compared to wild type and is resistant to degradation (Szabó A et al. J. Biol. Chem., 2012 Jun;287:20701-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The PRSS1 c.365G>A variant is predicted to result in the amino acid substitution p.Arg122His. This variant, also described as p.Arg117His in earlier publications, has been reported multiple times to be causative for chronic pancreatitis and is one of the most commonly reported causative variants (see for example Whitcomb et al. 1996. PubMed ID: 8841182; Archer et al. 2006. PubMed ID: 17087933). This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/11876/). We interpret this variant as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Transgenic Expression of PRSS1(R122H) Sensitizes Mice to Pancreatitis.	Huang H	Gastroenterology	2020	PMID: 31419436
PRSS1-Related Hereditary Pancreatitis.	Adam MP	-	2019	PMID: 22379635
Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis.	Sofia VM	Molecular medicine (Cambridge, Mass.)	2016	PMID: 27264265
Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C.	Szabó A	The Journal of biological chemistry	2012	PMID: 22539344
Chronic pancreatitis: genetics and pathogenesis.	Chen JM	Annual review of genomics and human genetics	2009	PMID: 19453252
Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism.	Kereszturi E	Human mutation	2009	PMID: 19191323
The natural history of hereditary pancreatitis: a national series.	Rebours V	Gut	2009	PMID: 18755888
Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.	Teich N	Human mutation	2006	PMID: 16791840
"Loss of function" mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis.	Chen JM	Molecular genetics and metabolism	2003	PMID: 12765848
Hereditary pancreatitis.	Charnley RM	World journal of gastroenterology	2003	PMID: 12508340
Spontaneous and sporadic trypsinogen mutations in idiopathic pancreatitis.	Simon P	JAMA	2002	PMID: 12413370
Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis.	Audrézet MP	European journal of human genetics : EJHG	2002	PMID: 11938439
Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis.	Pfützer R	Gut	2002	PMID: 11788572
Human cationic trypsinogen. Arg(117) is the reactive site of an inhibitory surface loop that controls spontaneous zymogen activation.	Kukor Z	The Journal of biological chemistry	2002	PMID: 11748242
Molecular pathology and evolutionary and physiological implications of pancreatitis-associated cationic trypsinogen mutations.	Chen JM	Human genetics	2001	PMID: 11702203
Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen.	Sahin-Tóth M	Biochemical and biophysical research communications	2000	PMID: 11097832
Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis.	Férec C	Journal of medical genetics	1999	PMID: 10204851
Heterogeneity in hereditary pancreatitis.	Dasouki MJ	American journal of medical genetics	1998	PMID: 9557894
Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.	Whitcomb DC	Nature genetics	1996	PMID: 8841182
https://pancreasgenetics.org/prss1/	-	-	-	-
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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002769.5(PRSS1):c.365G>A (p.Arg122His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111033565 ...