rs202003805
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PM1PP5_Very_StrongBP4BS2
The NM_002769.5(PRSS1):c.47C>T(p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A16A) has been classified as Likely benign.
Frequency
Consequence
NM_002769.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRSS1 | NM_002769.5 | c.47C>T | p.Ala16Val | missense_variant | 2/5 | ENST00000311737.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRSS1 | ENST00000311737.12 | c.47C>T | p.Ala16Val | missense_variant | 2/5 | 1 | NM_002769.5 | P1 | |
PRSS1 | ENST00000486171.5 | c.47C>T | p.Ala16Val | missense_variant | 2/6 | 5 | |||
PRSS1 | ENST00000497041.1 | n.51C>T | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
PRSS1 | ENST00000485223.1 | n.54-68C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 45782AN: 118562Hom.: 0 Cov.: 36 FAILED QC
GnomAD3 exomes AF: 0.0000901 AC: 22AN: 244118Hom.: 0 AF XY: 0.0000679 AC XY: 9AN XY: 132610
GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.202 AC: 162367AN: 803306Hom.: 0 Cov.: 90 AF XY: 0.205 AC XY: 82190AN XY: 401142
GnomAD4 genome ? Data not reliable, filtered out with message: InbreedingCoeff AF: 0.386 AC: 45818AN: 118638Hom.: 0 Cov.: 36 AF XY: 0.381 AC XY: 22029AN XY: 57794
ClinVar
Submissions by phenotype
Hereditary pancreatitis Pathogenic:7Uncertain:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jun 19, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 16 of the PRSS1 protein (p.Ala16Val). 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 pancreatic cancer (PMID: 10381903, 11260229, 15017610, 19453252, 19951905, 20502448, 21907651, 22749696). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38363). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PRSS1 function (PMID: 16505482, 22539344). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 03, 2021 | The p.A16V pathogenic mutation (also known as c.47C>T), located in coding exon 2 of the PRSS1 gene, results from a C to T substitution at nucleotide position 47. The alanine at codon 16 is replaced by valine, an amino acid with similar properties. In pediatric individuals, heterozygosity for this mutation was associated with chronic pancreatitis (Witt H et al. Gastroenterology, 1999 Jul;117:7-10). Subsequent studies also observed this mutation in affected individuals of all ages, but suggested a reduced penetrance given the presence of asymptomatic family members (Grocock CJ et al. Gut, 2010 Mar;59:357-63; Joergensen MT et al. Am. J. Gastroenterol., 2010 Aug;105:1876-83). In addition, two functional studies demonstrated increased trypsinogen activation in vitro due to a 4- and 5.8-fold increased rate of chymotrypsin C-mediated N-terminal processing relative to wild type, respectively (Nemoda Z et al. J. Biol. Chem., 2006 Apr;281:11879-86; 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. - |
Uncertain significance, flagged submission | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The variant PRSS1:c.47C>T (p.Ala16Val) was identified in dbSNP (ID: rs202003805) and Clinvar (classified as pathogenic). The PRSS1 p.Ala16Val variant is the third most common PRSS1 mutation and is significantly associated with pancreatitis. The variant was identified in 22 individuals across 10 different families, with 15 individuals across 6 families reporting symptoms of pancreatitis. Of these, two individuals confirmed as being PRSS1 p.Ala16Val carriers had pancreatic cancer (Grocock_2009_ PMID:19951905). In another study, the variant was detected in 4 out of 44 patients. Three of these patients had no family history of chronic pancreatitis, although the mutation was inherited in all cases by one parent. Only 1 of 7 first-degree relatives with p.Ala16Val was affected, indicating a low penetrance of this mutation (Witt_2001_PMID:12120220). The variant was identified in control databases in 22 of 244,118 chromosomes (0 homozygous) at a frequency of 0.009%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 1800 of 110,396 chromosomes (freq: 0.0163%) (Genome Aggregation Database March 6, 2019, v2.1.1. The p.Ala16Val 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, 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. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 22, 2023 | The PRSS1 c.47C>T; p.Ala16Val variant (rs202003805) is one of the most common pathogenic PRSS1 variants (Rebours 2012), has been reported to co-segregate with disease in families with hereditary pancreatitis (Grocock 2010, Joergensen 2010, Rebours 2012), and is reported in the literature in individuals affected with idiopathic chronic pancreatitis (Grocock 2010, Howes 2004, Witt 1999). This variant is reported in ClinVar (Variation ID: 38363), and is found in the general population with an overall allele frequency of 0.65% (1680/256738 alleles) in the Genome Aggregation Database, but is considered a low confidence variant in the database. This variant has been described to have variable penetrance (Grocock 2010, Joergensen 2010), and in vitro assays have shown p.Ala16Val to increase cationic trypsinogen activity (Nemoda 2006, Szabo 2012). Based on functional assays and this variant's strong association with pancreatitis, the p.Ala16Val variant is considered to be pathogenic. References: Grocock CJ et al. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. 2010 Gut. 59(3):357-63. PMID: 19951905. Howes N et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004 2(3):252-61. PMID: 15017610. Joergensen MT et al. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. Am J Gastroenterol. 2010 105(8):1876-83. PMID: 20502448. Nemoda Z et al. Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen. J Biol Chem. 2006 281(17):11879-86. PMID: 16505482. Rebours V et al. An overview of hereditary pancreatitis. Dig Liver Dis. 2012 44(1):8-15. PMID: 21907651. 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. Witt H et al. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology. 1999 117(1):7-10. PMID: 10381903. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2022 | One of the most common PRSS1 pathogenic variants observed in families with pancreatitis and suggested to have a reduced penetrance compared to other pathogenic PRSS1 variants given unaffected carriers in some families (Witt 1999, Howes 2004, Grocock 2010, Joergensen 2010, Chen 2012); Published functional studies demonstrate a damaging effect: increased rate of chymotrypsin C (CTRC)-mediated trypsinogen activation (Nemoda 2006); Case control studies suggest this variant is associated with pancreatitis (Rosendahl 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17204147, 24002981, 15082592, 19453252, 19191323, 22539344, 23143602, 27535533, 19951905, 10381903, 26658045, 25546417, 22749696, 15017610, 11788572, 16791840, 16542853, 24458023, 21907651, 11260229, 22427236, 20502448, 32547704, 32268488, 27555793, 34065437, 33504001, 34036232, 16505482) - |
Recurrent pancreatitis Uncertain:1
Uncertain significance, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at