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. ClinVar contains an entry for this variant (Variation ID: 29923). This missense change has been observed in individual(s) with pancreatitis (PMID: 11708864, 11842279, 15786540, 19191323, 19433603, 20502448, 24909264, 30420730). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 116 of the PRSS1 protein (p.Arg116Cys). Experimental studies have shown that this missense change affects PRSS1 function (PMID: 19191323, 31521106). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_002769.5(PRSS1):c.346C>T (p.Arg116Cys)
Germline
Classification
Help
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.
(7)
Help
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/Likely pathogenic
7
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.346C>T (p.Arg116Cys)
Variation ID: 29923 Accession: VCV000029923.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 142751919 (GRCh38) [ NCBI UCSC ] 7: 142459770 (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 Jun 2, 2024 May 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002769.5:c.346C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002760.1:p.Arg116Cys missense NC_000007.14:g.142751919C>T NC_000007.13:g.142459770C>T NG_001333.2:g.585587C>T NG_008307.3:g.7436C>T LRG_1013:g.7436C>T LRG_1013t1:c.346C>T LRG_1013p1:p.Arg116Cys P07477:p.Arg116Cys - Protein change
- R116C
- Other names
- -
- Canonical SPDI
- NC_000007.14:142751918:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00010
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2023 | RCV000022814.44 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 9, 2023 | RCV004557257.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001218550.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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. ClinVar contains an entry for this variant (Variation ID: 29923). This missense change has been observed in individual(s) with pancreatitis (PMID: 11708864, 11842279, 15786540, 19191323, 19433603, 20502448, 24909264, 30420730). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 116 of the PRSS1 protein (p.Arg116Cys). Experimental studies have shown that this missense change affects PRSS1 function (PMID: 19191323, 31521106). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(Mar 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158034.3
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The PRSS1 c.346C>T; p.Arg116Cys variant (rs387906698), is reported in the literature in multiple individuals and families affected with pancreatitis (Kereszturi 2009, Kurian 2014, see link … (more)
The PRSS1 c.346C>T; p.Arg116Cys variant (rs387906698), is reported in the literature in multiple individuals and families affected with pancreatitis (Kereszturi 2009, Kurian 2014, see link to Chronic Pancreatitis database and references therein). This variant is also reported in ClinVar (Variation ID: 29923). It is observed in the East Asian population with an allele frequency of 0.07% (14/19950 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.597). However, functional analyses of the variant protein show misfolding and intracellular retention, leading to endoplasmic reticular stress (Kereszturi 2009). Based on available information, the p.Arg116Cys variant is considered to be pathogenic. References: Link to Genetic Risk Factors in Chronic Pancreatitis database: http://pancreasgenetics.org/e107_plugins/aacgc_itemlist/Item_List.php?det.1 Kereszturi E et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009 Apr;30(4):575-82. PMID: 19191323. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9. PMID: 24733792. (less)
|
|
|
Pathogenic
(May 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002613930.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R116C pathogenic mutation (also known as c.346C>T), located in coding exon 3 of the PRSS1 gene, results from a C to T substitution at … (more)
The p.R116C pathogenic mutation (also known as c.346C>T), located in coding exon 3 of the PRSS1 gene, results from a C to T substitution at nucleotide position 346. The arginine at codon 116 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several unrelated families with hereditary pancreatitis. Furthermore, this mutation was shown to promote misfolding of the enzyme, leading to abnormal retention within cells (Kereszturi E et al. Hum Mutat. 2009; 30(4):575-582). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005046502.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001571365.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Family history: no
Secondary finding: no
|
|
|
Likely pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003815666.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Apr 01, 2009)
|
no assertion criteria provided
Method: literature only
|
PANCREATITIS, HEREDITARY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044103.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 17, 2021 |
Comment on evidence:
Teich et al. (2006) reported that the 346C-T transition in exon 3 of the PRSS1 gene, resulting in an arg116-to-cys (R116C) substitution, had been identified … (more)
Teich et al. (2006) reported that the 346C-T transition in exon 3 of the PRSS1 gene, resulting in an arg116-to-cys (R116C) substitution, had been identified by 4 independent groups in Turkish, German, and Thai families with hereditary pancreatitis (167800) and in 2 unrelated French patients with pancreatitis. In an 11-year-old German girl with hereditary pancreatitis, originally reported by Teich et al. (2002), Kereszturi et al. (2009) showed that trypsinogen misfolding is the likely disease mechanism. The R116C substitution occurs in a surface loop that is highly sensitive to autolytic cleavage. In vitro functional expression studies showed that the R116C mutation resulted in misfolding of the protein, but residual amounts of properly folded protein showed normal activation, catalytic properties, and degradation. Expression of the mutant protein in HEK 293T cells showed decreased secretion compared to wildtype, suggesting that the unpaired cysteine residue at codon 116 interferes with proper protein folding, resulting in the mutant protein being retained inside the cell. Biochemical evidence indicated activation of the unfolded protein response, although there was no evidence of increased caspase-3 (CASP3; 600636) activity. The R116C mutation was also found in the girl's 57-year-old affected maternal grandfather and her 38-year-old unaffected mother, indicating incomplete penetrance. (less)
|
Comment:
Comment:
The PRSS1 c.346C>T; p.Arg116Cys variant (rs387906698), is reported in the literature in multiple individuals and families affected with pancreatitis (Kereszturi 2009, Kurian 2014, see link to Chronic Pancreatitis database and references therein). This variant is also reported in ClinVar (Variation ID: 29923). It is observed in the East Asian population with an allele frequency of 0.07% (14/19950 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.597). However, functional analyses of the variant protein show misfolding and intracellular retention, leading to endoplasmic reticular stress (Kereszturi 2009). Based on available information, the p.Arg116Cys variant is considered to be pathogenic. References: Link to Genetic Risk Factors in Chronic Pancreatitis database: http://pancreasgenetics.org/e107_plugins/aacgc_itemlist/Item_List.php?det.1 Kereszturi E et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009 Apr;30(4):575-82. PMID: 19191323. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9. PMID: 24733792.
Comment:
The p.R116C pathogenic mutation (also known as c.346C>T), located in coding exon 3 of the PRSS1 gene, results from a C to T substitution at nucleotide position 346. The arginine at codon 116 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several unrelated families with hereditary pancreatitis. Furthermore, this mutation was shown to promote misfolding of the enzyme, leading to abnormal retention within cells (Kereszturi E et al. Hum Mutat. 2009; 30(4):575-582). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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:
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. ClinVar contains an entry for this variant (Variation ID: 29923). This missense change has been observed in individual(s) with pancreatitis (PMID: 11708864, 11842279, 15786540, 19191323, 19433603, 20502448, 24909264, 30420730). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 116 of the PRSS1 protein (p.Arg116Cys). Experimental studies have shown that this missense change affects PRSS1 function (PMID: 19191323, 31521106). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The PRSS1 c.346C>T; p.Arg116Cys variant (rs387906698), is reported in the literature in multiple individuals and families affected with pancreatitis (Kereszturi 2009, Kurian 2014, see link to Chronic Pancreatitis database and references therein). This variant is also reported in ClinVar (Variation ID: 29923). It is observed in the East Asian population with an allele frequency of 0.07% (14/19950 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.597). However, functional analyses of the variant protein show misfolding and intracellular retention, leading to endoplasmic reticular stress (Kereszturi 2009). Based on available information, the p.Arg116Cys variant is considered to be pathogenic. References: Link to Genetic Risk Factors in Chronic Pancreatitis database: http://pancreasgenetics.org/e107_plugins/aacgc_itemlist/Item_List.php?det.1 Kereszturi E et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009 Apr;30(4):575-82. PMID: 19191323. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9. PMID: 24733792.
Comment:
The p.R116C pathogenic mutation (also known as c.346C>T), located in coding exon 3 of the PRSS1 gene, results from a C to T substitution at nucleotide position 346. The arginine at codon 116 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several unrelated families with hereditary pancreatitis. Furthermore, this mutation was shown to promote misfolding of the enzyme, leading to abnormal retention within cells (Kereszturi E et al. Hum Mutat. 2009; 30(4):575-582). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Expanding ACMG variant classification guidelines into a general framework. | Masson E | Human genomics | 2022 | PMID: 35974416 |
| Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
| Clinical interpretation of PRSS1 variants in patients with pancreatitis. | Girodon E | Clinics and research in hepatology and gastroenterology | 2021 | PMID: 33257277 |
| PRSS1 mutation: a possible pathomechanism of pancreatic carcinogenesis and pancreatic cancer. | Liu Q | Molecular medicine (Cambridge, Mass.) | 2019 | PMID: 31521106 |
| SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. | Zou WB | Clinical and translational gastroenterology | 2018 | PMID: 30420730 |
| Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis. | Chang MC | Journal of gastroenterology and hepatology | 2014 | PMID: 24909264 |
| Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. | Joergensen MT | The American journal of gastroenterology | 2010 | PMID: 20502448 |
| Association and differential role of PRSS1 and SPINK1 mutation in early-onset and late-onset idiopathic chronic pancreatitis in Chinese subjects. | Chang YT | Gut | 2009 | PMID: 19433603 |
| Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. | Kereszturi E | Human mutation | 2009 | PMID: 19191323 |
| Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. | Teich N | Human mutation | 2006 | PMID: 16791840 |
| A Thai family with hereditary pancreatitis and increased cancer risk due to a mutation in PRSS1 gene. | Pho-Iam T | World journal of gastroenterology | 2005 | PMID: 15786540 |
| Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants. | Teich N | The American journal of gastroenterology | 2002 | PMID: 11866271 |
| R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis. | Tautermann G | Digestion | 2001 | PMID: 11842279 |
| Identification of a novel pancreatitis-associated missense mutation, R116C, in the human cationic trypsinogen gene (PRSS1). | Le Maréchal C | Molecular genetics and metabolism | 2001 | PMID: 11708864 |
| https://pancreasgenetics.org/prss1/ | - | - | - | - |
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Text-mined citations for rs387906698 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.