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NM_002769.5(PRSS1):c.86A>T (p.Asn29Ile)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(1);Pathogenic(6)

Review status:
criteria provided, conflicting interpretations
Submissions:
9 (Most recent: Oct 22, 2019)
Last evaluated:
May 28, 2019
Accession:
VCV000011877.2
Variation ID:
11877
Description:
single nucleotide variant
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NM_002769.5(PRSS1):c.86A>T (p.Asn29Ile)

Allele ID
26916
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7q34
Genomic location
7: 142750600 (GRCh38) GRCh38 UCSC
7: 142458451 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.14:g.142750600A>T
NC_000007.13:g.142458451A>T
NM_002769.5:c.86A>T NP_002760.1:p.Asn29Ile missense
... more HGVS
Protein change
N29I
Other names
-
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.47511
Links
ClinGen: CA341152
UniProtKB: P07477#VAR_006720
OMIM: 276000.0002
dbSNP: rs111033566
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 1 criteria provided, single submitter Jan 11, 2018 RCV000506924.2
Pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763166.1
Conflicting interpretations of pathogenicity 7 criteria provided, conflicting interpretations May 28, 2019 RCV000012652.27
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PRSS1 No evidence available No evidence available GRCh38
GRCh38
GRCh37
3 216
TRB - - - GRCh38
GRCh38
GRCh37
4 226

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Nov 01, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary pancreatitis
Allele origin: germline
Center for Human Genetics, Inc
Accession: SCV000782239.1
Submitted: (Dec 20, 2017)
Evidence details
Pathogenic
(Jan 11, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604933.2
Submitted: (Oct 10, 2018)
Evidence details
Comment:
The PRSS1 c.86A>T; p.Asn29Ile variant (rs111033566) has been reported as a common PRSS1 pathogenic variant in hereditary pancreatitis (Rebours 2009, Rosendahl 2013), and co-segregates with ... (more)
pathogenic
(Aug 18, 2011)
criteria provided, single submitter
Method: curation, clinical testing
heritable chronic pancreatitis
(autosomal dominant)
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000053054.1
Submitted: (Aug 18, 2011)
Evidence details
Publications
PubMed (4)
Comment:
Converted during submission to Pathogenic.
Pathogenic
(Jun 14, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary Pancreatitis
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000467092.2
Submitted: (Oct 18, 2016)
Evidence details
Publications
PubMed (8)
Comment:
Across a selection of available literature, the c.86A>T (p.Asn29Ile) variant, also referred to as p.Asn21Ile, has been reported in at least 160 hereditary pancreatitis (HP) ... (more)
Pathogenic
(Jul 01, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary pancreatitis
Allele origin: germline
Invitae
Accession: SCV000552149.4
Submitted: (Aug 29, 2018)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change replaces asparagine with isoleucine at codon 29 of the PRSS1 protein (p.Asn29Ile). The asparagine residue is weakly conserved and there is a ... (more)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary pancreatitis
Trypsinogen deficiency
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893753.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Benign
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary pancreatitis
Allele origin: unknown
Mendelics
Accession: SCV001137527.1
Submitted: (Oct 22, 2019)
Evidence details
Pathogenic
(Jan 01, 2000)
no assertion criteria provided
Method: literature only
PANCREATITIS, HEREDITARY
Allele origin: germline
OMIM
Accession: SCV000032887.1
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (4)
Pathologic
(Mar 01, 2012)
no assertion criteria provided
Method: curation
PRSS1-Related Hereditary Pancreatitis
Allele origin: not provided
GeneReviews
Accession: SCV000054566.1
Submitted: (Nov 29, 2012)
Evidence details
Comment:
Converted during submission to Pathogenic.

Citations for this variant

Title Author Journal Year Link
<i>PRSS1</i>-Related Hereditary Pancreatitis Shelton C - 2019 PMID: 22379635
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Pancreatitis Overview LaRusch J - 2014 PMID: 24624459
Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. Wang W BMJ open 2013 PMID: 24002981
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
High incidence of PRSS1 and SPINK1 mutations in Korean children with acute recurrent and chronic pancreatitis. Lee YJ Journal of pediatric gastroenterology and nutrition 2011 PMID: 21415673
Chronic pancreatitis: genetics and pathogenesis. Chen JM Annual review of genomics and human genetics 2009 PMID: 19453252
The natural history of hereditary pancreatitis: a national series. Rebours V Gut 2009 PMID: 18755888
A novel A121T mutation in human cationic trypsinogen associated with hereditary pancreatitis: functional data indicating a loss-of-function mutation influencing the R122 trypsin cleavage site. Felderbauer P Journal of medical genetics 2008 PMID: 18511571
Role of genetic disorders in acute recurrent pancreatitis. Keim V World journal of gastroenterology 2008 PMID: 18286680
Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene. Boulling A European journal of human genetics : EJHG 2007 PMID: 17568390
Hereditary chronic pancreatitis. Rosendahl J Orphanet journal of rare diseases 2007 PMID: 17204147
Biochemical models of hereditary pancreatitis. Sahin-Tóth M Endocrinology and metabolism clinics of North America 2006 PMID: 16632094
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
Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl. Teich N Human mutation 2005 PMID: 15776435
Hereditary pancreatitis: clinical characteristics and diagnostic criteria in Japan. Otsuki M Pancreas 2004 PMID: 15028953
The course of genetically determined chronic pancreatitis. Keim V JOP : Journal of the pancreas 2003 PMID: 12853682
Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis. Chandak GR Journal of medical genetics 2002 PMID: 12011155
Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Drenth JP Gut 2002 PMID: 11950817
Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis. Kukor Z The Journal of biological chemistry 2002 PMID: 11932257
Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis. Pfützer R Gut 2002 PMID: 11788572
Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 --&gt; Cys) that alters autoactivation and autodegradation of cationic trypsinogen. Simon P The Journal of biological chemistry 2002 PMID: 11719509
R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis. Tautermann G Digestion 2001 PMID: 11842279
Comparative in vitro studies on native and recombinant human cationic trypsins. Cathepsin B is a possible pathological activator of trypsinogen in pancreatitis. Szilágyi L The Journal of biological chemistry 2001 PMID: 11312265
Expression and penetrance of the hereditary pancreatitis phenotype in monozygotic twins. Amann ST Gut 2001 PMID: 11247900
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
SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Pfützer RH Gastroenterology 2000 PMID: 10982753
Origin and implication of the hereditary pancreatitis-associated N21I mutation in the cationic trypsinogen gene. Chen JM Human genetics 2000 PMID: 10982192
Risk factors for cancer in hereditary pancreatitis. International Hereditary Pancreatitis Study Group. Lowenfels AB The Medical clinics of North America 2000 PMID: 10872414
Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Witt H Nature genetics 2000 PMID: 10835640
Human cationic trypsinogen. Role of Asn-21 in zymogen activation and implications in hereditary pancreatitis. Sahin-Tóth M The Journal of biological chemistry 2000 PMID: 10801865
Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis. Chen JM Journal of medical genetics 2000 PMID: 10691414
Hereditary pancreatitis-associated mutation asn(21) --&gt; ile stabilizes rat trypsinogen in vitro. Sahin-Tóth M The Journal of biological chemistry 1999 PMID: 10514442
Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. Férec C Journal of medical genetics 1999 PMID: 10204851
Mutations of the cationic trypsinogen in hereditary pancreatitis. Teich N Human mutation 1998 PMID: 9633818
Heterogeneity in hereditary pancreatitis. Dasouki MJ American journal of medical genetics 1998 PMID: 9557894
Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gorry MC Gastroenterology 1997 PMID: 9322498
Hereditary chronic relapsing pancreatitis. A clue to pancreatitis in general? Robechek PJ American journal of surgery 1967 PMID: 6023921

Record last updated Jan 09, 2020