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

gnomAD frequency: 0.00009  dbSNP: rs200678111

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234026	SCV000289732	benign	Hereditary pancreatitis	2024-01-18	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	2023-10-23	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 is classified as benign and uncertain in the ClinVar database (Variation ID: 240765). Functional characterizations indicate that the p.Gln178Arg variant has reduced catalytic activity (Beer 2013). The variant is found in the general population with an overall allele frequency of 0.07% (202/282802 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 analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.423). 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. 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.
Ambry Genetics	RCV000234026	SCV002643253	uncertain significance	Hereditary pancreatitis	2023-07-21	criteria provided, single submitter	clinical testing	The p.Q178R variant (also known as c.533A>G), located in coding exon 6 of the CTRC gene, results from an A to G substitution at nucleotide position 533. The glutamine at codon 178 is replaced by arginine, an amino acid with highly similar properties. This variant has been identified in multiple individuals with acute recurrent or chronic pancreatitis (Beer S et al. Gut, 2013 Nov;62:1616-24; Giefer MJ et al. J. Pediatr., 2017 Jul;186:95-100); in vitro studies showed that the catalytic efficiency of this variant was significantly reduced from wild type (Beer S et al. Gut, 2013 Nov;62:1616-24). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003417831	SCV004117191	uncertain significance	CTRC-related condition	2023-08-04	criteria provided, single submitter	clinical testing	The CTRC c.533A>G variant is predicted to result in the amino acid substitution p.Gln178Arg. This variant has been reported in multiple individuals with acute recurrent or chronic pancreatitis and functional studies suggested that this variant results in reduced enzyme activity (Beer et al. 2012. PubMed ID: 22942235; Giefer et al. 2017. PubMed ID: 28502372). However, this variant is also reported in 0.55% of alleles in individuals of Latino descent in gnomAD, including two homozygotes (http://gnomad.broadinstitute.org/variant/1-15771140-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.