ClinVar Miner

Submissions for variant NM_007272.3(CTRC):c.533A>G (p.Gln178Arg) (rs200678111)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234026 SCV000289732 benign Hereditary pancreatitis 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000521019 SCV000617860 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing This variant is denoted CTRC c.533A>G at the cDNA level, p.Gln178Arg (Q178R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has been observed in multiple individuals with acute recurrent or chronic pancreatitis (Beer 2013, Giefer 2017). Functional studies have demonstrated that CTRC Gln178Arg is associated with a significant reduction in CTRC catalytic activity (Beer 2013). CTRC Gln178Arg was observed at an allele frequency of 0.57% (192/34420) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located within the Peptidase S1 domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CTRC Gln178Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000234026 SCV000781307 uncertain significance Hereditary pancreatitis 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000234026 SCV000883689 uncertain significance Hereditary pancreatitis 2019-01-30 criteria provided, single submitter clinical testing The CTRC c.533A>G; p.Gln178Arg variant (rs200678111) is reported in patients with chronic pancreatitis (Beer 2013, Giefer 2017). However, it has also been found with two mild CFTR pathogenic variants in a pancreatitis patient tested at ARUP Laboratories, and classified as benign and uncertain in the ClinVar database (Variation ID: 240765). Functional characterizations indicate that the p.Gln178Arg has strongly reduced catalytic activity (25 percent of wildtype) (Beer 2013). The variant is found in the general population with an overall allele frequency of 0.07% (208/282802 alleles, including two homozygotes) in the Genome Aggregation Database, with an increased frequency of 0.55% in Latinos. The glutamine at codon 178 is weakly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Due to the conflicting information regarding this variant, its clinical significance is uncertain at this time. 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. 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.

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