ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

The CTRC c.760C>T; p.Arg254Trp variant (rs121909293) has been reported in multiple individuals with chronic, hereditary, or recurrent acute pancreatitis, both in the homozygous state and in individuals carrying a second pathogenic variant (Beer 2013, Giefer 2017, Masamune 2013, Masson 2008, Rosendahl 2008, Rosendahl 2013). Functional characterization of p.Arg254Trp indicates a moderate reduction in the level of secreted CTRC protein, but no impact on enzymatic activity (Beer 2013, Rosendahl 2008), leading to its designation as a moderate-to-low-risk variant (Beer 2013). The variant is reported in ClinVar (Variation ID: 8178) and is found in the general population with an overall allele frequency of 0.46% (1305/282668 alleles, including 12 homozygotes) in the Genome Aggregation Database. However, it is reported to be at a higher frequency in affected European individuals compared to controls (Beer 2013, Masson 2008, Rosendahl 2008, Rosendahl 2013), and to co-occur at increased frequency with the SPINK1 p.Asn34Ser variant in affected individuals (Rosendahl 2008). The arginine at residue 254 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.809). Based on available information, this variant is considered to be likely 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; 62(11):1616-24. PMID: 22942235 Giefer MJ et al. Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations. J Pediatr. 2017 Jul;186:95-100. PMID: 28502372 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 Masamune A et al. Identification of novel missense CTRC variants in Japanese patients with chronic pancreatitis. Gut. 2013; 62(4):653-4. PMID: 23135764 Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008; 123(1):83-91. PMID: 18172691 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 Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008; 40(1):78-82. PMID: 18059268

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the CTRC protein (p.Arg254Trp). This variant is present in population databases (rs121909293, gnomAD 2.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with chronic pancreatitis and in unaffected controls. Overall it has been reported to confer ~3-fold increased risk for chronic pancreatitis in heterozygous carriers (PMID: 18059268, 18172691, 22427236, 22942235, 25569187). ClinVar contains an entry for this variant (Variation ID: 8178). 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, 19453252). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele.

The p.R254W pathogenic mutation (also known as c.760C>T), located in coding exon 7 of the CTRC gene, results from a C to T substitution at nucleotide position 760. The arginine at codon 254 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been shown to be over-represented in individuals with idiopathic or hereditary chronic pancreatitis; it was demonstrated to cause a reduction in chymotrypsin C activity due to decreased production and/or secretion (Rosendahl J et al. Nat Genet. 2008;40(1):78-82). Another study found this mutation in 2.07% of affected individuals versus 0.57% of control individuals and in vitro studies suggest that this mutation results in slightly decreased protein secretion and increased rate of degradation by trypsin (Beer S et al. Gut. 2013 Nov;62(11):1616-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Criteria applied: PS3,PM1,PP3,BA1

CTRC: BS1, BS2