ClinVar Genomic variation as it relates to human health

The G217S variant in the CTRC gene has previously been reported in association with chronic pancreatitis (Masson et al., 2008; Beer et al., 2013; Rosendahl et al., 2013). However, G217S has also been observed in unaffected control individuals, suggesting incomplete penetrance (Beer et al., 2013; Rosendahl et al., 2013). Functional studies show G217S leads to catalytic deficiency, as well as trypsin degradation (Rosendahl et al., 2008; Beer et al., 2013). The G217S variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. A missense variant at the same residue (G217R), as well as nearby residues (G214R, L220R) have been reported in the Human Gene Mutation Database in association with CTRC-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, G217S is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.

The CTRC c.649G>A; p.Gly217Ser variant (rs202058123) is reported in the literature in individuals affected with idiopathic chronic pancreatitis (Masson 2008, Rosendahl 2008, Zou 2018), including an individual with a pathogenic CTRC variant presumed to be on the opposite chromosome. However, this variant is also reported in a pancreatitis patient with a pathogenic CTRC and CFTR variant, and in healthy controls (Beer 2013, Rosendahl 2008, Rosendahl 2013). This variant is reported in ClinVar (Variation ID: 430258), and is found in the general population with an overall allele frequency of 0.0057% (16/282714 alleles) in the Genome Aggregation Database. The glycine at codon 217 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the p.Gly217Ser protein indicate significant impairment of catalytic activity (Rosendahl 2008, Beer 2013), with the variant protein showing increased sensitivity to trypsin degradation (Beer 2013). Additionally, another variant at this codon (c.649G>C; p.Gly217Arg) has been reported in individuals with chronic pancreatitis (Beer 2013, Rosendahl 2008). Based on available information, the p.Gly217Ser variant is considered to be likely pathogenic.

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 217 of the CTRC protein (p.Gly217Ser). This variant is present in population databases (rs202058123, gnomAD 0.02%). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 18059268, 18172691, 22427236, 22942235, 23951356, 33101984). ClinVar contains an entry for this variant (Variation ID: 430258). 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, 22942235). 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.

The p.G217S variant (also known as c.649G>A), located in coding exon 7 of the CTRC gene, results from a G to A substitution at nucleotide position 649. The glycine at codon 217 is replaced by serine, an amino acid with similar properties. This variant has been reported in multiple individuals with chronic pancreatitis, as well as in one control subject (Rosendahl J et al. Nat Genet, 2008 Jan;40:78-82; Masson E et al. Hum Genet, 2008 Feb;123:83-91; Rosendahl J et al. Gut, 2013 Apr;62:582-92; Beer S et al. Gut, 2013 Nov;62:1616-24; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204). In some individuals, the alteration was detected in conjunction with a second alteration in CTRC and/or alterations in other genes implicated in the development of pancreatitis, including CFTR and PRSS1 (Rosendahl J et al. Nat Genet, 2008 Jan;40:78-82; Masson E et al. Hum Genet, 2008 Feb;123:83-91; Masson E et al. PLoS One, 2013 Aug;8:e73522; Rosendahl J et al. Gut, 2013 Apr;62:582-92; Sofia VM et al. Mol Med, 2018 07;24:38; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204). In vitro studies showed that the amino acid substitution results in reduced catalytic activity and increased trypsin-mediated degradation of the CTRC protein (Rosendahl J et al. Nat Genet, 2008 Jan;40:78-82; Beer S et al. Gut, 2013 Nov;62:1616-24). Internal structural analysis revealed that this variant destabilizes the protein structure (Pignol D et al. EMBO J, 1994 Apr;13:1763-71). 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 majority of available evidence to date, this variant is likely to be pathogenic, but may represent a risk factor.