Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000119044 | SCV000958881 | uncertain significance | Hereditary pancreatitis | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the CTRC protein (p.Ala73Thr). This variant is present in population databases (rs515726209, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 18059268, 18172691, 22580415, 25569187). ClinVar contains an entry for this variant (Variation ID: 132149). 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 expected to disrupt CTRC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTRC function (PMID: 18059268, 22942235, 26022124). 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, |
RCV000119044 | SCV001473550 | pathogenic | Hereditary pancreatitis | 2023-11-28 | criteria provided, single submitter | clinical testing | The CTRC c.217G>A; p.Ala73Thr variant (rs515726209) is reported in the literature in multiple individuals affected with chronic pancreatitis (Beer 2013, LaRusch 2015, Masson 2008, Paliwal 2013, Rosendahl 2008). While this variant has also been observed in healthy controls, case-control studies reproducibly demonstrate enrichment in affected individuals with odds ratios >8.0 (Beer 2013, Paliwal 2013, Rosendahl 2008). This variant is found in the South Asian population with an overall allele frequency of 0.53% (163/30556 alleles, including one homozygote) in the Genome Aggregation Database; however, most affected individuals with this variant are reported to be of South Asian descent (Beer 2013, Paliwal 2013, Rosendahl 2008). Functional studies of the p.Ala73Thr variant suggest that the variant protein has normal enzymatic activity but is poorly secreted from cells, resulting in retention, degradation, and increased activation of endoplasmic reticulum stress and apoptotic cascades (Beer 2013, Rosendahl 2008, Szmola 2010). Based on available information, this variant is considered to be pathogenic. References: Beer S et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut. 2013 Nov;62(11):1616-24. PMID: 22942235. LaRusch J et al. The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol. 2015 Jan 8;6:e68. PMID: 25569187. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. PMID: 18172691. Paliwal S et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2013 Nov;62(11):1602-6. PMID: 22580415. Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008 Jan;40(1):78-82. PMID: 18059268. Szmola R and Sahin-Toth M. Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells. Gut. 2010 Mar;59(3):365-72. PMID: 19951900. |
| Mendelics | RCV000119044 | SCV002519462 | pathogenic | Hereditary pancreatitis | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000119044 | SCV002730106 | likely pathogenic | Hereditary pancreatitis | 2023-07-01 | criteria provided, single submitter | clinical testing | The p.A73T variant (also known as c.217G>A), located in coding exon 3 of the CTRC gene, results from a G to A substitution at nucleotide position 217. The alanine at codon 73 is replaced by threonine, an amino acid with similar properties. In one study, this variant was identified in 5/71 individuals with tropical pancreatitis and 0/84 healthy controls; expression of this variant in HEK293T cells showed diminished secretion relative to wild type (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82). In another study, this variant was associated with a significant odds ratio (OR 8.2, CI 2.5-27.5) for pancreatitis in the Indian population. In addition, functional studies in HEK293T cells demonstrated a defect in secretion of protein bearing this alteration, a small decrease in catalytic efficiency, and that the protein was resistant to degradation (Beer S et al. Gut, 2013 Nov;62:1616-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Neuberg Centre For Genomic Medicine, |
RCV000119044 | SCV005382331 | pathogenic | Hereditary pancreatitis | 2023-05-20 | criteria provided, single submitter | clinical testing | The observed missense c.217G>A(p.Ala73Thr) variant in CTRC gene has been reported previously in multiple individuals affected with pancreatitis (Beer S, et al., 2013; Paliwal S, et al., 2013; Rosendahl J, et al., 2008). Functional studies demonstrate that this variant poorly secretes from cells, resulting in retention, degradation, and increased activation of endoplasmic reticulum stress and apoptotic cascades, suggesting a deleterious effect (Binker MG, et al., 2015; Szmola R & Sahin-Tóth M., 2010). The p.Ala73Thr variant has been reported with allele frequency of 0.05% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 73 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000119044 | SCV000153750 | pathogenic | Hereditary pancreatitis | 2014-03-13 | no assertion criteria provided | literature only |