Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000012655 | SCV000630744 | uncertain significance | Hereditary pancreatitis | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 79 of the PRSS1 protein (p.Glu79Lys). 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 individuals with hereditary pancreatitis, idiopathic chronic pancreatitis, and alcohol-related chronic pancreatitis (PMID: 11260229, 14526128, 14695529, 18184119, 23751316, 23951356, 24458023, 27179762). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11880). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 14695529, 19191323). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| ARUP Laboratories, |
RCV000757691 | SCV000886012 | uncertain significance | not provided | 2017-05-09 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192438 | SCV001360555 | uncertain significance | not specified | 2024-01-16 | criteria provided, single submitter | clinical testing | Variant summary: PRSS1 c.235G>A (p.Glu79Lys) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. 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 4.5e-05 in 1615650 control chromosomes, predominantly at a frequency of 0.00024 within the African or African-American subpopulation in the gnomAD v4 database. This frequency is close to the estimated maximal expected allele frequency of a pathogenic PRSS1 causing Chronic Pancreatitis (0.00024 vs 0.00025), suggesting this may be a benign polymorphism. Co-occurrence with a pathogenic variant has been reported following internal testing (SPINK1 c.101A>G, p.Asn34Ser) while, there are at least four reported chronic pancreatitis patients in literature that carry CFTR pathogenic variants (5T allele or p.F508del) along with this variant (Keiles_2006, Masson_2013, Oracz_2016, Sultan_2012). c.235G>A has been reported in the literature in multiple individuals/families affected with chronic pancreatitis, idiopathic chronic pancreatitis, hereditary pancreatitis and alcohol-related chronic pancreatitis as well as in unaffected controls and unaffected family members (e.g. Chen_2001, Bernardino_2003, Teich_2004, Derikx_2009, Rousseau_2012, Hamoir_2013, Oracz_2016, Masson_2023). Functional studies (Teich_2004, Kereszturi_2009) of E79K trypsin revealed unaltered secretion, catalytic activity, autolysis, and inhibition by pancreatic secretory trypsin inhibitor; however, the variant was found to cause increased trypsinogen activation following transactivation of PRSS2. The following publications have been ascertained in the context of this evaluation (PMID: 14526128, 25543846, 11260229, 19857283, 23751316, 17003641, 19191323, 36517351, 23951356, 27179762, 18755888, 22094894, 20452997, 14695529). ClinVar contains an entry for this variant (Variation ID: 11880). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Gene |
RCV000757691 | SCV002015699 | uncertain significance | not provided | 2021-05-14 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed alone and with variants in CFTR in individuals with idiopathic and familial pancreatitis, as well as unaffected controls (Chen 2001, Bernardino 2003, Rebours 2008, Sultan 2012, Hamoir 2013, Masson 2013, Oracz 2016); Published functional studies are inconclusive: catalytic activity and inhibition by pancreatic secretory trypsin inhibitor similar to wild type and differing results regarding the autoactivation of trypsinogen (Teich 2004, Buettner 2014); This variant is associated with the following publications: (PMID: 27673710, 23474566, 16791840, 14695529, 19191323, 11260229, 23951356, 14526128, 20676769, 24458023, 17003641, 18184119, 22094894, 23751316, 27179762, 25543846) |
| Ambry Genetics | RCV000012655 | SCV002735740 | uncertain significance | Hereditary pancreatitis | 2023-10-04 | criteria provided, single submitter | clinical testing | The p.E79K variant (also known as c.235G>A), located in coding exon 3 of the PRSS1 gene, results from a G to A substitution at nucleotide position 235. The glutamic acid at codon 79 is replaced by lysine, an amino acid with similar properties. This variant has been reported in individuals with chronic and recurrent acute pancreatitis, some of whom have variants in other genes that may contribute to their disease; in addition, the variant has been identified in unaffected family members and healthy controls (Teich N et al. Hum. Mutat., 2004 Jan;23:22-31; Chen JM et al. Clin. Genet., 2001 Mar;59:189-93; Oracz G et al. Pancreatology Apr;16:535-41; Bernardino AL et al. JOP, 2003 Sep;4:169-77; Keiles S et al. Pancreas, 2006 Oct;33:221-7; Hamoir C et al. Digestion, 2013 Jun;87:229-39; Masson E et al. PLoS One, 2013 Aug;8:e73522; Wejnarska K et al. J Pediatr Gastroenterol Nutr, 2016 12;63:665-670). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. |
| OMIM | RCV000012655 | SCV000032890 | pathogenic | Hereditary pancreatitis | 2004-01-01 | no assertion criteria provided | literature only |