7-142750600-A-T
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4
The NM_002769.5(PRSS1):c.86A>T(p.Asn29Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,417,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N29K) has been classified as Uncertain significance.
Frequency
Consequence
NM_002769.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.283 AC: 44150AN: 155926 AF XY: 0.304 show subpopulations
GnomAD4 exome AF: 0.00000635 AC: 9AN: 1417370Hom.: 0 Cov.: 85 AF XY: 0.00000567 AC XY: 4AN XY: 705934 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary pancreatitis Pathogenic:10Uncertain:1Other:1
The PRSS1 c.86A>T; p.Asn29Ile variant (rs111033566), also known as Asn21Ile, has been reported as a common PRSS1 pathogenic variant in hereditary pancreatitis (Rebours 2009, Rosendahl 2013), and co-segregates with affected individuals in multiple unrelated families (Ferec 1999, Gorry 1997, Teich 1998). Functional analyses reveal that the variant protein has enhanced auto-activation activity in acidic environments, which is predicted to be the pathogenic mechanism (Sahin-Toth 2000a, Sahin-Toth 2000b). This variant is also reported in ClinVar (Variation ID: 11877). The asparagine at codon 29 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.269). Based on available information, this variant is considered to be pathogenic. References: Ferec C et al. Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. J Med Genet. 1999 Mar;36(3):228-32. PMID: 10204851. Gorry MC et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology. 1997 Oct;113(4):1063-8. PMID: 9322498. Rebours V et al. The natural history of hereditary pancreatitis: a national series. Gut. 2009 Jan;58(1):97-103. PMID: 18755888. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92. PMID: 22427236. Sahin-Toth M et al. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun. 2000a Nov 19;278(2):286-9. PMID: 11097832. Sahin-Toth M. Human cationic trypsinogen. Role of Asn-21 in zymogen activation and implications in hereditary pancreatitis. J Biol Chem. 2000b Jul 28;275(30):22750-5. PMID: 10801865. Teich N et al. Mutations of the cationic trypsinogen in hereditary pancreatitis. Hum Mutat. 1998;12(1):39-43. PMID: 9633818. -
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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) patients (Gorry et al. 1997; Ferec et al. 1997; Otsuki et al. 2004; Sahin-Toth et al. 2006; Lee et al. 2011; Wang et al. 2013). Gorry et al. (1997) first reported the p.Asn29Ile variant in two unrelated pedigrees. Both had an extensive history of HP with one pedigree with 15 affected family members who all shared the p.Asn29Ile variant. In addition, in a review of a variant database maintained by Leipzig University in Germany, Sahin-Toth et al. (2006) observed that the p.Asn29Ile variant was the second most common PRSS1 variant associated with HP, accounting for approximately 25% of all identified pathogenic alleles in PRSS1. The p.Asn29Ile variant was absent from 382 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. To evaluate the functional impact of the p.Asn29Ile variant, wild-type and variant trypsinogen were expressed in either E. coli or HEK293T cells. Presence of the p.Asn29Ile variant resulted in an increased rate of trypsinogen autoactivation compared to wild type, thereby also increasing trypsin levels (Szabo et al. 2012). Based on the collective evidence, the p.Asn29Ile variant is classified as pathogenic for hereditary pancreatitis. -
The p.N29I pathogenic mutation (also known as c.86A>T), located in coding exon 2 of the PRSS1 gene, results from an A to T substitution at nucleotide position 86. The asparagine at codon 29 is replaced by isoleucine, an amino acid with dissimilar properties. This mutation (referred to as p.N21I) was first described in a hereditary pancreatitis (HP) family (Gorry MC et al. Gastroenterology, 1997 Oct;113:1063-8) and was subsequently observed to segregate with disease in 2 additional unrelated HP families (Férec C et al. J. Med. Genet., 1999 Mar;36:228-32). In another study, this mutation accounted for 12% of all PRSS1 mutations in a cohort of French individuals with HP (Rebours V et al. Gut, 2009 Jan;58:97-103). In one functional study, this mutation was observed to result in an increase in auto-activation of cationic trypsinogen (Sahin-Tóth M et al. Biochem. Biophys. Res. Commun., 2000 Nov;278:286-9). The p.N29I mutation accounts for approximately 25% of HP families; it increases trypsinogen activation and reduces CTRC-dependent degradation (Németh BC et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2014 Mar;306:G466-73). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 29 of the PRSS1 protein (p.Asn29Ile). 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 hereditary pancreatitis (PMID: 2539344, 18755888, 19453252). It has also been observed to segregate with disease in related individuals. This variant is also known as Asn21Ile. ClinVar contains an entry for this variant (Variation ID: 11877). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 10801865, 11097832, 22539344). For these reasons, this variant has been classified as Pathogenic. -
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The PRSS1 p.Asn29Ile variant was identified in the literature associated with chronic and acute recurrent pancreatitis (Howes_2004_15017610). In a European cohort of 418 individuals with either chronic or acute recurrent pancreatitis, 94 were heterozygous for the p.Asn29Ile variant, 7 of which developed pancreatic cancer (Howes_2004_15017610). The p.Asn29Ile variant was associated with a 4-5 year delayed onset of disease presentation  compared to individuals with the common R122H variant in PRSS1(Howes_2004_15017610). Moreover, women and patients with the p.Asn29Ile variant underwent pancreatic resection for pain much earlier than males and those with wild-type or different PRSS1 mutations, respectively(Howes_2004_15017610). The p.Asn29Ile variant was also identified in 1 of 92 unrelated Mexican children (Sanchez-Ramirez_2012_22699143) and 2 of 92 unrelated Polish children (Sobczyńska-Tomaszewska_2006_16954950) with chronic or acute recurrent pancreatitis, however the number of subjects with chronic or acute recurrent pancreatitis bearing the PRSS1 p.Asn29Ile variant was not significantly different from controls. In a cohort of 71 Korean patients with chronic pancreatitis (alcoholic: 47, idiopathic: 22, and familial: 2), 0 carried the  p.Asn29Ile variant (Lee_2004_15329520).  The PRSS1 p.Asn29Ile variant was identified in dbSNP (rs111033566) and ClinVar (conflicting predictions; 6 pathogenic and 1 benign). In vitro studies suggest that the p.Asn29Ile variant increases autoactivation of human cationic trypsinogen (Tg-1) under acidic conditions, which might be relevant to the pathomechanism of the p.Asn21Ile mutation in hereditary pancreatitis (Sahin-Toth_2000_10801865). The variant was identified in the ExAC control database in 57,066 of 121,412 chromosomes (0 homozygous) at a frequency of 47%, and was observed at the highest frequency in the South Asian (SAS) population in 16,362 alleles (freq:49.1077%). The variant was not identified in the Gnomad database. The p.Asn29Ile residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, It is possible that the p.Asn29Ile variant acts as a risk allele for hereditary pancreatitis. However, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.PRSS1 is associated with autosomal dominant hereditary pancreatitis (Phenotype MIM number: 167800). Pancreatitis is characterized by inflammation of the pancreas. In some individuals it may progress from acute (sudden onset; duration <6 months) to recurrent acute (>1 episode of acute pancreatitis) to chronic (duration >6 months). The range of symptoms and disease course vary from person to person. -
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The observed missense c.86A>Tp.Asn29Ile variant in PRSS1 gene has been reported previously in heterozygous state in individuals affected with Hereditary pancreatitis Panchoo et al., 2022. Experimental studies have shown that this missense change affects PRSS1 function Szabó and Sahin-Tóth, 2012. This variant is reported with the very high allele frequency in the gnomAD Exomes. 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 variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic multiple submissions. The amino acid Asn at position 29 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn29Ile in PRSS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence Polyphen - Benign, SIFT - Tolerated, and MutationTaster - Disease causing automatic predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:3
PRSS1: PS4, PM2, PP1:Moderate, PS3:Moderate, PP4 -
Observed in many affected individuals with sporadic pancreatitis and segregates with disease in several hereditary pancreatitis families in published literature (PMID: 9322498, 18755888, 24002981, 24525505, 28861620, 30420730, 11247900, 34399810, 35899558, 35578795); Published functional studies demonstrate a damaging effect: enhances autoactivation of the PRSS1 enzyme as compared to wild-type (PMID: 11097832, 22539344, 32547704); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.Asn21Ile; This variant is associated with the following publications: (PMID: 19191323, 27578509, 11950817, 23143602, 10872414, 19453252, 10982192, 11073713, 11097832, 22539344, 10801865, 15776435, 16632094, 27884173, 15028953, 21415673, 10204851, 11842279, 29641165, 29901518, 30241646, 12853682, 9322498, 27673710, 24002981, 10835640, 24525505, 28861620, 18755888, 30420730, 32547704, 10671922, 35899558, 34570182, 34399810, 35578795, 11247900, 22379635) -
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Hereditary pancreatitis;C0268417:Trypsinogen deficiency Pathogenic:1
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PRSS1-related disorder Pathogenic:1
The PRSS1 c.86A>T variant is predicted to result in the amino acid substitution p.Asn29Ile. This variant, previously reported as p.Asn21Ile, as well as a different substitution at the same amino acid position (p.Asn29Thr) have been reported to be causative for autosomal dominant hereditary chronic pancreatitis (Gorry et al. 1997. PubMed ID: 9322498; Singhi et al. 2014. PubMed ID: 24525505; Pfützer et al. 2002. PubMed ID: 11788572). Functional studies indicate the p.Asn29Ile change leads to increased trypsinogen activation (Szabó and Sahin-Tóth. 2012. PubMed ID: 22539344). Based on the available evidence, we interpret this variant as pathogenic. -
Vitamin D-dependent rickets type II with alopecia Pathogenic:1
The missense variant p.N29I in PRSS1 (NM_002769.4) has been previously reported in multiple individuals with hereditary pancreatitis and is the second most common alllele reported with hereditary pancreatitis (Németh et al, 2014; Chen et al, 2009). Though reported in the gnomAD database with a frequency of 28.37%, this estimate is not considered to be true because of poor site quality metrics. Experimental studies have shown that this missense change leads to auto-activation of cationic trypsinogen and results in high levels of activated trypsin in the pancreas (Sahin-Tóth et al, 2000). It has been submitted to the ClinVar database as Pathogenic. There is a large physicochemical difference between asparagine and isoleucine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico predictions do not suggest a damaging effect and the residue is poorly conserved across species. For these reasons, this variant has been classified as Pathogenic -
Myoepithelial tumor Uncertain:1
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Computational scores
Source:
Splicing
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