ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

The CTRC c.703G>A; p.Val235Ile variant (rs140993290) is reported in the medical literature in several individuals with chronic pancreatitis, with several carrying additional pathogenic variants (Koziel 2015, Masson 2008, Paliwal 2013, Rosendahl 2008, Rosenhdahl 2014, Tomaiuolo 2015, Wang 2013, Werlin 2015, Zou 2018). This variant is reported in the ClinVar database (Variation ID: 292914), and is found in the general population with an overall allele frequency of 0.10% (293/282822 alleles, including 3 homozygotes) in the Genome Aggregation Database. The valine at this position is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this variant is reported to cause reduced protein activity (Beer 2013, Rosendahl 2008). Although there are indications this variant may be pathogenic, the evidence is conflicting, so the variant is classified as uncertain significance. 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. Koziel D et al. Genetic mutations in SPINK1, CFTR, CTRC genes in acute pancreatitis. BMC Gastroenterol. 2015 Jun 23;15:70. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. Paliwal S et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2013 Nov;62(11):1602-6 Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008 Jan;40(1):78-82. 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. Tomaiuolo AC et al. Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis. J Mol Diagn. 2015 Mar;17(2):171-8. Wang W et al. Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ Open. 2013 Sep 3;3(9):e003150. Werlin S et al. Genetic and electrophysiological characteristics of recurrent acute pancreatitis. J Pediatr Gastroenterol Nutr. 2015 May;60(5):675-9. 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.

The missense c.703G>A (p.Val235Ile) variant in CTRC gene has been reported previously as a risk factor in individuals affected Pancreatitis (Koziel et al. 2015; Nabi et al. 2020; Girodon et al. 2020). Experimental studies show that this variant showed CTRC secretion close to the wild-type levels (~86% of wild type), is resistant to trypsin degradation, and confers a moderate-to-low risk towards pancreatitis (Beer et al. 2013). The p.Val235Ile variant is reported with an allele frequency of 0.11% (287/251446 alleles, including 3 homozygotes) in the gnomAD exomes database. This variant has been reported to the ClinVar database as Benign / Pathogenic / Uncertain Significance. The amino acid change p.Val235Ile in CTRC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 235 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

The p.V235I pathogenic mutation (also known as c.703G>A), located in coding exon 7 of the CTRC gene, results from a G to A substitution at nucleotide position 703. The valine at codon 235 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with pancreatitis, some of which had additional pathogenic variants in pancreatitis-associated genes (Koziel D et al. BMC Gastroenterol, 2015 Jun;15:70; Werlin S et al. J Pediatr Gastroenterol Nutr, 2015 May;60:675-9; Gaitch N et al. Pancreatology 2016 Apr;16:515-22; Sofia VM et al. Mol Med, 2018 07;24:38). Multiple studies have examined association between this variant and pancreatitis (Masson E et al. Hum Genet, 2008 Feb;123:83-91; Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Derikx MH et al. Eur J Gastroenterol Hepatol, 2009 Aug;21:889-94; Paliwal S et al. Gut, 2013 Nov;62:1602-6; Beer S et al. Gut, 2013 Nov;62:1616-24; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204; Nabi Z et al. Dig Dis Sci, 2020 10;65:3000-3005). In one study, p.V235I was significantly associated with pancreatitis (Paliwal S et al. Gut, 2013 Nov;62:1602-6). Furthermore, in vitro studies showed that this variant does not result in complete loss of function, but slightly reduces CTRC secretion and activity (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Beer S et al. Gut, 2013 Nov;62:1616-24). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.