The PRSS1 NM_002769.5:c.365G>A (NP_002760.1:p.(Arg122His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV104604888, n = 3 times). Experimental evidence: R122H produced 4.8-fold higher trypsin activity than wild type with 25 nM CTRC and degraded 11-fold more slowly in biochemical assays. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PRSS1 encodes trypsinogen, a digestive enzyme precursor made by the pancreas and activated in the small intestine to help break down proteins. Changes in PRSS1 are associated with hereditary pancreatitis and can increase the risk of pancreatic cancer; the gene is not established as an oncogene or tumor suppressor.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: R122H produced 4.8-fold higher trypsin activity than wild type with 25 nM CTRC and degraded 11-fold more slowly in biochemical assays.
Met at Supporting: gnomAD v4.1 grpmax FAF is 4.613e-05, below the supplied PM2 threshold of 0.0001, with 29 alleles observed.
Met at moderate strength: PRSS1 p.Arg122Cys, a different missense at residue 122, was reported to cause segregating autosomal-dominant hereditary pancreatitis.
Met at supporting strength: the variant segregated with hereditary pancreatitis in five kindreds, including affected individuals and obligate carriers.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 (strong), PM5 (moderate), PM2 (supporting), and PP1 (supporting) satisfy the generic ACMG/AMP fallback combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 29 / 1,573,650 alleles. Recorded AF 1.84285e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.06216e-05; MAF= 0.00106%, 3/282442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.32717e-05; MAF= 0.00233%, 3/128912 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.511. Refer to the recorded PP3/BP4 rationale for interpretation.
21 Pathogenic · 3 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PRSS1 encodes the digestive pro-enzyme trypsinogen, which is activated in the small intestine. Mutations in PRSS1 are associated with pancreatitis and
This variant has previously been reported in somatic cancers (COSMIC; COSV104604888, n = 3 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 8 not met · 11 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 is not assessed because the literature documents enrichment but lacks the exact affected-case denominator and complete quantitative data needed for OR and 95% CI evaluation.
PP4 is not assessed because the case phenotype and family history are not available for specificity assessment.
PP5 and BP6 are not met because the exact-variant ClinVar record has zero expert-panel submissions.
BP5 is not met because no alternate molecular basis is documented.
Both criteria are evaluated on the missense REVEL path only; the REVEL score of 0.511 is below the PP3 supporting cutoff and above the BP4 supporting cutoff.
SpliceAI and BayesDel are not counted for PP3 or BP4 in this missense situation, and no paper provides relevant computational evidence that changes either result.
No criteria match.
PS3 is met at strong strength. Multiple variant-specific functional studies evaluated PRSS1 R122H (NM_002769.5:c.365G>A; NP_002760.1:p.(R122H)) using purified recombinant human cationic trypsinogen, biochemical autoactivation and degradation assays, and an in-vivo transgenic mouse model. In the presence of chymotrypsin C, R122H produced markedly higher active trypsin than wild type, with a 3.5-fold higher activity-curve area at 5 nM CTRC and a 4.8-fold higher area at 25 nM CTRC; degradation of activated trypsin was 11-fold slower than wild type. Independent biochemical work also found significantly enhanced autoactivation at pH 8.0 and pH 5.0, and transgenic mice expressing PRSS1 R122H developed increased susceptibility to experimentally induced pancreatitis. These results are biologically relevant to PRSS1-associated hereditary pancreatitis and consistently demonstrate a damaging gain-of-function effect rather than merely a computational or clinical-association signal.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Under the supplied generic SVI calibration, PM2 Supporting is met when the allele frequency is <=0.0001. The default all-comers gnomAD v4.1 record has filtering grpmax FAF 4.613e-05, which is below 0.0001, and the gnomAD v2.1 record has grpmax FAF 7.01e-06. The variant is therefore extremely rare rather than completely absent. Non-cancer subsets corroborate rarity: gnomAD v2.1 non-cancer exomes grpmax FAF 3.23e-06 and gnomAD v3.1 non-cancer genomes grpmax FAF 6.818e-05. PM2 is assigned at Supporting strength as specified by the supplied calibration.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The observed variant is p.Arg122His. A different missense change at the same residue, PRSS1 p.Arg122Cys (R122C), was reported in independent hereditary-pancreatitis families, segregated with disease in an autosomal-dominant pattern, and the report's title identifies it as causing autosomal dominant hereditary pancreatitis. This is a pathogenic same-residue comparator for PM5; the paper uses the mature-protein numbering convention in some contexts, but the residue correspondence is explicit.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PRSS1 c.365G>A (p.R122H) was reported in all affected individuals and obligate carriers from five hereditary-pancreatitis kindreds. A separate review likewise reports segregation of R122H with hereditary pancreatitis in five American families. This is co-segregation in multiple affected family members for an established PRSS1 hereditary-pancreatitis association; no supplied generic threshold supports upgrading beyond supporting strength.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The variant is a missense change, so the governing generic rule selects the REVEL path only; SpliceAI is not used for missense PP3/BP4 and BayesDel has no established generic ACMG-strength calibration. REVEL is 0.511, below the PP3 supporting threshold of >= 0.644, so PP3 is not met. The ClinGen SVI REVEL calibration is Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
ClinVar contains exact-variant Pathogenic and Likely pathogenic laboratory submissions, but the ClinVar audit records zero expert-panel submissions. PMID:16791840 is a literature report of the variant's association with hereditary pancreatitis, not an exact-variant ClinVar expert-panel classification. Under the required generic PP5 rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger PP5.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
Generic BA1 requires allele frequency above 5%. The default all-comers gnomAD v4.1 record reports grpmax FAF 4.613e-05 (0.004613%), based on a population with 70,548 observed alleles; this is far below 0.05 and therefore does not meet BA1. The gnomAD v2.1 all-comers grpmax FAF is also only 7.01e-06. The non-cancer subsets are concordant: gnomAD v2.1 non-cancer exomes grpmax FAF 3.23e-06 and gnomAD v3.1 non-cancer genomes grpmax FAF 6.818e-05. The pathogenic ClinVar consensus does not create a BA1 frequency finding, and the frequency is not high enough to require resolving a high-frequency pathogenic-allele exception.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Generic BS1 requires an allele frequency greater than expected for the disorder; the supplied generic default is 1%, but disease prevalence, penetrance and allelic heterogeneity must be considered. The default all-comers gnomAD v4.1 filtering grpmax FAF is 4.613e-05 (0.004613%), based on 70,548 observed alleles, which is below 0.01 by more than two orders of magnitude. The gnomAD v2.1 all-comers grpmax FAF is 7.01e-06, and non-cancer estimates are similarly low (v2.1 exomes 3.23e-06; v3.1 genomes 6.818e-05). Although hereditary pancreatitis is autosomal dominant with incomplete penetrance, no maximum-credible-frequency calculation is needed to reject BS1 here because the conservative filtering FAF is already far below the generic threshold and does not indicate an excess frequency.
Allele frequency is greater than expected for the disorder.
BS3 is not met. The criterion requires well-established functional studies showing no damaging effect on protein function or splicing, but the variant-specific biochemical evidence instead demonstrates increased PRSS1 autoactivation, increased active trypsin generation, resistance to CTRC-mediated degradation, and disruption of the R122 primary lysis site. One cellular study found that R122H was secreted normally and did not produce the ER-stress pattern observed for a different misfolding mutant, but normal secretion and absence of that stress response do not establish preserved PRSS1 enzymatic regulation or absence of a damaging effect. The available functional evidence therefore contradicts, rather than satisfies, BS3.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense change, so the governing generic rule selects the REVEL path only; SpliceAI is not used for missense PP3/BP4 and BayesDel has no established generic ACMG-strength calibration. REVEL is 0.511, which is above the BP4 supporting threshold of <= 0.29 and therefore does not support BP4. The ClinGen SVI REVEL calibration is Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
No evidence in the reviewed case materials shows this variant in a case with an alternate molecular basis for hereditary pancreatitis or another disease diagnosis. The available observations concern PRSS1-associated hereditary pancreatitis and do not establish an alternate molecular cause.
Variant found in a case with an alternate molecular basis for disease.
The exact-variant ClinVar record contains no Benign or Likely benign expert-panel classification and records zero expert-panel submissions. Laboratory submissions and the aggregate ClinVar label are Pathogenic/Likely pathogenic, so the required generic BP6 trigger is absent.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
The variant is PRSS1 p.Arg122His (p.R122H). The available literature establishes this same amino-acid change, including the older R117H mature-protein numbering, but does not provide a previously established pathogenic variant with a different nucleotide change producing Arg122His. Therefore the required alternate-nucleotide same-amino-acid comparison is not available.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No case-level evidence documents a de novo occurrence of PRSS1 c.365G>A in a patient with hereditary pancreatitis, and there is no documented confirmation of both maternity and paternity or absence of family history. The available evidence concerns familial hereditary-pancreatitis kindreds rather than a de novo proband.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PMID:16791840 reports the exact PRSS1 c.365G>A (p.R122H) variant in all affected individuals and obligate carriers from five hereditary-pancreatitis kindreds and in none of the individuals who married into the families or 140 unrelated individuals. This is case-control-style enrichment evidence, but the paper extract does not provide the exact number of affected individuals or a complete 2x2 table, so an odds ratio and 95% confidence interval cannot be computed. The generic PS4 requirement is OR or RR >5.0 with a confidence interval that does not include 1.0; therefore PS4 cannot be adjudicated from the available quantitative data.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PRSS1 Arg122 is described as the primary lysis site and a functionally important site, but the available evidence does not establish that residue 122 lies within a formally defined mutational hotspot or critical functional domain that lacks benign variation. Cancer Hotspots returned no statistically significant hotspot, and no VCEP domain table or gene-specific PM1 specification is available. The COSMIC somatic count is not sufficient to establish the generic PM1 requirement.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
No case-level evidence documents an assumed de novo occurrence of PRSS1 c.365G>A. The available reports describe familial hereditary-pancreatitis kindreds and do not identify a proband as de novo, regardless of whether parental maternity or paternity was tested.
Assumed de novo, but without confirmation of paternity and maternity.
The evidence supports that pathogenic PRSS1 missense variants can cause hereditary pancreatitis through gain-of-function effects, but it does not provide a gene-wide assessment demonstrating both a low rate of benign missense variation and that missense variants are a common disease mechanism under the PP2 rule. The observed variant's rarity and pathogenic reports cannot substitute for those gene-level requirements.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available literature describes hereditary pancreatitis as the disease associated with PRSS1 p.R122H, but the case evidence does not provide the patient's phenotype or family history. Without case-specific phenotype information, it cannot be determined whether the phenotype is highly specific for a disease with a single genetic etiology.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 requires observation in a healthy adult for a dominant disorder with full penetrance expected at an early age. gnomAD shows no homozygotes, but its aggregate population record does not establish that any individual carrier was a healthy adult with adequate age and phenotype assessment. In addition, hereditary pancreatitis is described as autosomal dominant with incomplete penetrance, so the required full-penetrance early-age assumption is not established. No individual-level healthy-adult carrier observation with age and clinical ascertainment was identified; BS2 therefore cannot be adjudicated.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No supplied evidence documents affected family members who lack PRSS1 c.365G>A. The available familial reports instead describe co-segregation, so lack of segregation cannot be established; no BS4 evidence is present to weigh against the reported segregation.
Lack of segregation in affected members of a family.
The available PRSS1 evidence instead documents recurrent disease-causing missense variants and a gain-of-function missense mechanism, including p.Arg122His. However, it does not provide a systematic gene-level comparison establishing that PRSS1 disease is caused primarily by truncating variants. Therefore the BP1 applicability requirement cannot be confirmed or excluded from the supplied evidence alone.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires observation either in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or in cis with a pathogenic variant in any inheritance pattern. PRSS1 hereditary pancreatitis is described as autosomal dominant with incomplete penetrance, so the fully penetrant-dominant trans branch is not satisfied. The reviewed evidence does not document a second pathogenic variant, parental testing, offspring testing, or a cis/trans phase result for NM_002769.5:c.365G>A (p.Arg122His). The cis branch therefore cannot be evaluated from the available evidence, so BP2 is not assessed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002769.5:c.365G>A in PRSS1 is a missense substitution predicted to produce NP_002760.1:p.(Arg122His). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for PRSS1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is restricted to recessive disorders and requires the variant to be detected in trans with a pathogenic variant, with parental or offspring testing to establish phase. PRSS1-associated hereditary pancreatitis is described as an autosomal dominant disorder with incomplete penetrance, and the available case evidence does not establish a recessive inheritance context. Therefore PM3 is not applicable to this variant-disease context.
For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002769.5:c.365G>A in PRSS1 is a missense substitution predicted to produce NP_002760.1:p.(Arg122His). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for PRSS1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002769.5:c.365G>A in PRSS1 is a missense substitution predicted to produce NP_002760.1:p.(Arg122His). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for PRSS1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002769.5:c.365G>A in PRSS1 is a missense substitution predicted to produce NP_002760.1:p.(Arg122His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PRSS1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in PRSS1, mapped onto the exon structure of NM_002769.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American7 / 70,548 | 9.9e-05 |
| Remaining individuals2 / 61,288 | 3.3e-05 |
| European (non-Finnish)20 / 1,150,642 | 1.7e-05 |
| European (non-Finnish)3 / 128,912 | 2.3e-05 |
This variant is present in gnomAD v4.1 (AF= 1.84285e-05; MAF= 0.00184%, 29/1573650 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 9.92232e-05; MAF= 0.00992%, 7/70548 alleles, homozygotes = 0); grpmax FAF= 4.613e-05.
This variant is present in gnomAD v2.1 (AF= 1.06216e-05; MAF= 0.00106%, 3/282442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.32717e-05; MAF= 0.00233%, 3/128912 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
Not available in gnomAD-Canada v1.0.
The variant is a missense change, so the governing generic rule selects the REVEL path only; SpliceAI is not used for missense PP3/BP4 and BayesDel has no established generic ACMG-strength calibration. REVEL is 0.511, below the PP3 supporting threshold of >= 0.644, so PP3 is not met. The ClinGen SVI REVEL calibration is Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense change, so the governing generic rule selects the REVEL path only; SpliceAI is not used for missense PP3/BP4 and BayesDel has no established generic ACMG-strength calibration. REVEL is 0.511, which is above the BP4 supporting threshold of <= 0.29 and therefore does not support BP4. The ClinGen SVI REVEL calibration is Pejaver et al. 2022 (PMID:36413997).
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002769.5:c.365G>A in PRSS1 is a missense substitution predicted to produce NP_002760.1:p.(Arg122His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PRSS1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.511. BayesDel score = -0.0325382.
8 paper records listed. 5 cited in the classification.
Comparison of autoactivation kinetics of wild-type and mutant zymogens revealed that both HP mutations enhanced autocatalytic trypsin generation significantly at pH 8.0 and pH 5.0.
Location Results, “Autoactivation of zymogens”; Discussion
Context Purified recombinant human cationic trypsinogen and trypsin; in-vitro autoactivation assays at pH 8.0 and pH 5.0 with calcium or EDTA; autolysis and catalytic-activity assays.
Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion.
Location Abstract
Context Clinical sequencing and family segregation analysis in hereditary-pancreatitis families; the available case record contains the PubMed abstract but not a fetched full-text text file.
the c.365G4A mutation (p.R122H; p.R117H in the chymotrypsin numbering system)
Location Section “The R122H and N29I Mutations in PRSS1 Are Commonly Associated With Hereditary Pancreatitis”; Table 1, entry 21
Context Review of hereditary-pancreatitis kindreds, unrelated individuals, clinical cohorts, and published in-vitro biochemical studies of recombinant PRSS1 trypsinogen/trypsin mutants.
R122H, which results from a c.365G>A (CGC>CAC) single-nucleotide change in exon 3 of PRSS1, is the most frequent mutation causing HP.
Location Section “Missense mutations occurring in the R122 primary lysis site increase trypsin stability”
Context Review of hereditary-pancreatitis families and biochemical and transgenic-mouse studies of PRSS1 mutants.
In the presence of CTRC, trypsinogen mutants associated with classic hereditary pancreatitis (N29I, N29T, V39A, R122C, and R122H) autoactivated at increased rates and reached markedly higher active trypsin levels compared with wild-type cationic trypsinogen.
Location Abstract; Results, “Autoactivation of Cationic Trypsinogen Mutants in Presence of CTRC”; Results, “Mechanistic Basis of Increased Autoactivation in Presence of CTRC”; Results, “Effect of Pancreatitis-associated Mutations on Trypsin Stability”
Context In-vitro biochemical assays using recombinant human wild-type and mutant cationic trypsinogens, with trypsin-mediated autoactivation measured without or with human chymotrypsin C; SDS-PAGE and densitometry assessed CTRC cleavage, trypsin cleavage at Arg-122, and activated-trypsin degradation.
The mode of inheritance suggests an autosomal dominant trait with incomplete penetrance.
Abstract
mutants p.A16V, p.N29I, p.N29T, p.E79K, p.R122C, and p.R122H were secreted normally.
Introduction; Results, “Secretion of p.R116C Cationic Trypsinogen From Transiently Transfected HEK 293T Cells”; Results, “Secretion of p.R116C Cationic Trypsinogen From Transiently Transfected Paca44 Cells”
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.84285e-05; MAF= 0.00184%, 29/1573650 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 9.92232e-05; MAF= 0.00992%, 7/70548 alleles, homozygotes = 0); grpmax FAF= 4.613e-05.
This variant is present in gnomAD v2.1 (AF= 1.06216e-05; MAF= 0.00106%, 3/282442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.32717e-05; MAF= 0.00233%, 3/128912 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (21 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 11876)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.511. BayesDel score = -0.0325382.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PRSS1 encodes the digestive pro-enzyme trypsinogen, which is activated in the small intestine. Mutations in PRSS1 are associated with pancreatitis and
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104604888, n = 3 times).
This variant does not lie in a statistically significant hotspot.