ClinVar Miner

Submissions for variant NM_002769.5(PRSS1):c.47C>T (p.Ala16Val) (rs202003805)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000031920 SCV000287691 pathogenic Hereditary pancreatitis 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 16 of the PRSS1 protein (p.Ala16Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs202003805, ExAC 5%). This variant co-segregates with disease in families with hereditary pancreatitis (HP) (PMID: 19951905, 20502448, 22749696, 19453252, 21907651), is one of the most frequently identified PRSS1 variants in individuals with idiopathic chronic pancreatitis (ICP) (PMID: 10381903, 11260229), and has been reported in individuals with pancreatic cancer (PMID: 19951905, 15017610). The penetrance of this variant in HP families has been shown to be ~40-50% (PMID: 19951905, 20502448). ClinVar contains an entry for this variant (Variation ID: 38363). Experimental studies have shown that this missense change accelerates autoactivation of the PRSS1 protein, resulting in ~2-fold higher activity of trypsinogen (PMID: 16505482, 22539344). In summary, this is a relatively common missense variant that increases the activity of cationic trypsinogen in the pancreas and is associated with an elevated risk for pancreatitis and pancreatic cancer. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999826 SCV000604925 pathogenic not specified 2018-07-16 criteria provided, single submitter clinical testing 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. Howes N et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004 2(3):252-61. 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. Nemoda Z et al. Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen. J Biol Chem. 2006 281(17):11879-86. Rebours V et al. An overview of hereditary pancreatitis. Dig Liver Dis. 2012 44(1):8-15. 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. 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.
Integrated Genetics/Laboratory Corporation of America RCV000586935 SCV000698048 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing Variant summary: The PRSS1 c.47C>T (p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. Ala16 is the first residue of mature trypsinogen, as the secretory signal peptide (amino acids 115) is cleaved off during endoplasmic reticulum entry. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1935/124158 control chromosomes (including ExAC) at a frequency of 0.015585, which is approximately 3117 times the estimated maximal expected allele frequency of a pathogenic PRSS1 variant (0.000005), suggesting this variant is likely a benign polymorphism. However, the variant is located within the region oc segmental duplication and the possibility of it being derived from the pseudogene cannot be completely ruled out. This is in line with the fact that this variant is absent in 1758 control individuals in the Rosendahl _2012 study and in 6503 individuals from NHLBI ESP and is only reported in non-pass filter in gnomAD. Per published data, this variant is the third most commonly inherited mutation in the PRSS1 gene (Moran_2016) and has been reported in numerous affected individuals in dominant or compound recessive inheritance with a reported penetrance of ~50% (Grocock_2010, Rosendahl_2012), however, none of the reports confirmed that pseudogene has been ruled out. The variant has been identified in patients who also carried a pathogenic variants in other genes (SPINK1 N34S and CFTR TG11-5T) that are known causal variants liked to pancreatitis. Transheterozygosity for this variant with other pathogenic variants in SPINK1 and CFTR genes and especially in the context of risk factors such as smoking could increase the risk for pancreatitis (Moran _2016). In functional studies, in the absence of CTRC, mutation A16V had no effect on trypsinogen autoactivation and normal concentration levels (Kereszturi_2009). In presence of chymotrypsin C, A16V increased rates of autoactivation and higher active trypsin levels compared with wild-type cationic trypsinogen by increasing N-terminal processing albeit the magnitude of the increase is much smaller than other common PRSS1 pathogenic variants (R122H, V39A; Szabo_2012). At least one clinical diagnostic laboratory/reputable database have classified this variant as pathogenic. Due to contradicting evidence for pathogenicity, high frequency in controls, low penetrance, co-occurrence with a known pancreatitis causative variants, and a possibility the variant being derived from a pseudogene the variant has been classified as a variant of uncertain significance (VUS).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626826 SCV000747529 uncertain significance Recurrent pancreatitis 2017-01-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000031920 SCV000782238 pathogenic Hereditary pancreatitis 2016-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000031920 SCV001137525 likely benign Hereditary pancreatitis 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000999826 SCV001338959 uncertain significance not specified 2020-03-03 criteria provided, single submitter clinical testing Variant summary: PRSS1 c.47C>T (p.Ala16Val) causes a missense change involving the alteration of a non-conserved nucleotide. Ala16 is the first residue of the trypsinogen activation peptide, as the secretory signal peptide (amino acids 1-15) is cleaved off during endoplasmic reticulum entry. The activation peptide is also released during the activation process, thus A16V is not present in the active trypsin and thus cannot alter trypsin function, however it might affect the processing of trypsinogen by CTRC (chymotrypsin C) (Szabo_2012). Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 265048 control chromosomes (gnomAD), which is approximately 1320 times the estimated maximal expected allele frequency of a pathogenic PRSS1 variant (5e-06), suggesting this variant is likely a benign polymorphism. However, the variant is located within a region of segmental duplication and the possibility of pseudogene contamination in this data cannot be ruled out. This is in line with the fact that this variant was absent in 1758 control individuals in the Rosendahl 2012 study and in 6503 individuals from NHLBI ESP and is mainly reported in non-pass filter in gnomAD. Per published data, this variant is the third most commonly inherited mutation in the PRSS1 gene (Moran_2016) and has been reported in numerous affected individuals in dominant or compound recessive inheritance with a reported penetrance of ~50% (Grocock_2010, Rosendahl_2012). However, none of the reports confirmed that the pseudogene had been ruled out. Co-occurrences with other variants have been reported (SPINK1 c.101A>G, (p.Asn34Ser) (Rosendahl_2012, Moran_2016); CFTR TG11-5T (Moran_2016); PRSS1 c.364C>T (p.Arg122Cys) (Giefer_2017)) that are known causal variants linked to pancreatitis. Trans-heterozygosity for this variant with other pathogenic variants in SPINK1 and CFTR genes and especially in the context of risk factors such as smoking could increase the risk for pancreatitis (Moran_2016). In functional studies, A16V had no effect on trypsinogen secretion and autoactivation in the absence of chymotrypsin C (Kereszturi_2009). In presence of chymotrypsin C, A16V increased the rate of autoactivation compared with wild-type cationic trypsinogen by increasing N-terminal processing, (Nemoda_2006, Nemeth_2017), albeit the magnitude of this increase was much smaller than in the case of the highly penetrant, common PRSS1 pathogenic variants (e.g. R122H, V39A; Szabo 2012). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x), uncertain significance (1x) and likely benign (1x). Due to contradicting evidence for pathogenicity, (potential) high frequency in controls and/or pseudogene interference, low penetrance, co-occurrences with known pancreatitis causative variants, the variant's effect on protein function, the variant has been classified as VUS-possibly pathogenic.
GeneReviews RCV000031920 SCV000054561 pathologic Hereditary pancreatitis 2012-03-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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