Submissions for variant NM_007272.3(CTRC):c.760C>T (p.Arg254Trp)

gnomAD frequency: 0.00374  dbSNP: rs121909293

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119045	SCV000551759	association	Hereditary pancreatitis	2025-01-28	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CTRC protein function with a positive predictive value of 95%. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119045	SCV000603259	likely pathogenic	Hereditary pancreatitis	2024-11-12	criteria provided, single submitter	clinical testing	The CTRC c.760C>T; p.Arg254Trp variant (rs121909293, ClinVar Variation ID: 8178) 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, Felderbauer 2010, Giefer 2017, Grabarczyk 2017, LaRusch 2015, 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 found in the general population with an overall allele frequency of 0.46% (1305/282668 alleles, including 12 homozygotes) in the Genome Aggregation Database (v2.1.1). 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 Felderbauer P et al. Multifactorial genesis of pancreatitis in primary hyperparathyroidism: evidence for "protective" (PRSS2) and "destructive" (CTRC) genetic factors. Exp Clin Endocrinol Diabetes. 2011 Jan;119(1):26-9. doi: 10.1055/s-0030-1255106. Epub 2010 Jul 12. PMID: 20625975. 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 Grabarczyk AM, et al. Chymotrypsinogen C Genetic Variants, Including c.180TT, Are Strongly Associated With Chronic Pancreatitis in Pediatric Patients. J Pediatr Gastroenterol Nutr. 2017 Dec;65(6):652-657. PMID: 28968289. 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
Ambry Genetics	RCV000119045	SCV001189039	pathogenic	Hereditary pancreatitis	2022-03-17	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV002247276	SCV002519074	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV000119045	SCV003935032	likely pathogenic	Hereditary pancreatitis	2022-12-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003421912	SCV004128570	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CTRC: BS1, BS2
Institute of Human Genetics, University of Leipzig Medical Center	RCV000119045	SCV005368178	uncertain significance	Hereditary pancreatitis	2022-05-18	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM1,PP3,BA1
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000008657	SCV005902165	likely pathogenic	Pancreatitis, chronic, susceptibility to	2025-03-31	criteria provided, single submitter	clinical testing	Risk factor for chronic pancreatitis, associated with approximately 3-fold increased risk.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000119045	SCV005914393	uncertain significance	Hereditary pancreatitis	2023-05-09	criteria provided, single submitter	research
OMIM	RCV000008657	SCV000028866	risk factor	Pancreatitis, chronic, susceptibility to	2008-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000119045	SCV000153751	not provided	Hereditary pancreatitis		no assertion provided	literature only