ClinVar Genomic variation as it relates to human health

The CTRC c.181G>A; p.Gly61Arg variant (rs769482036) is reported in individuals with chronic pancreatitis (Beer 2013, Derikx 2009, Zou 2018) and functional analysis shows this variant causes complete loss of CTRC secretion (Beer 2013, Derikx 2009). This variant is found in the general population with a low overall allele frequency of 0.002% (5/282788 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 61 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.942). 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 Nov;62(11):1616-24. Derikx MH et al. Tropical calcific pancreatitis and its association with CTRC and SPINK1 (p.N34S) variants. Eur J Gastroenterol Hepatol. 2009 Aug;21(8):889-94. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204.

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. Studies have shown that this missense change alters CTRC gene expression (PMID: 19404200, 22942235, 26022124). 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. ClinVar contains an entry for this variant (Variation ID: 1330384). This missense change has been observed in individual(s) with autosomal dominant hereditary pancreatitis (PMID: 19404200, 30420730). This variant is present in population databases (rs769482036, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 61 of the CTRC protein (p.Gly61Arg).

The p.G61R variant (also known as c.181G>A), located in coding exon 3 of the CTRC gene, results from a G to A substitution at nucleotide position 181. The glycine at codon 61 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in two individuals with pancreatitis; one individual was also heterozygous for SPINK1 p.N34S (Derikx MH et al. Eur J Gastroenterol Hepatol, 2009 Aug;21:889-94; Zou WB et al. Clin Transl Gastroenterol, 2018 Nov;9:204). In multiple assays testing CTRC function, this variant showed functionally abnormal results (Derikx MH et al. Eur J Gastroenterol Hepatol, 2009 Aug;21:889-94; Beer S et al. Gut, 2013 Nov;62:1616-24; Binker MG et al. Biochem Biophys Res Commun, 2015 Jul;463:329-35). 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 available evidence, the clinical significance of this alteration remains unclear.