ClinVar Genomic variation as it relates to human health

The CTRC c.640-12G>A variant (rs183053579) is reported in the literature in multiple individuals affected with pancreatitis (Giefer 2017, LaRusch 2015, Masson 2015). Functional characterization of patient mRNA indicates that the variant leads to the inclusion of 10 nucleotides from intron 6, potentially introducing a frameshift in the translated protein (Masson 2015). This variant is reported in ClinVar (Variation ID: 439575), and is found in the African population with an allele frequency of 0.65% (162/24,920 alleles, including a single homozygote) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site, consistent with the functional studies. Based on available information, the c.640-12G>A variant is considered to be likely pathogenic. References: 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. LaRusch J et al. The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol. 2015 Jan 8;6:e68. PMID: 25569187. Masson E et al. Report of 2 CTRC Intronic Mutations Associated With Acute or Chronic Pancreatitis and Delineation of Their Pathogenic Molecular Mechanisms. Pancreas. 2015; 44(6):999-1001. PMID: 26166474.

The c.640-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 7 in the CTRC gene. This variant was identified in several individuals with pancreatitis, including three from different African countries (LaRusch J et al. Clin Transl Gastroenterol, 2015 Jan;6:e68; Masson E et al. Pancreas, 2015 Aug;44:999-1001). In one individual, RT-PCR and sequencing of cultured fibroblasts demonstrated aberrant splicing leading to the creation of a novel splice acceptor, resulting in inclusion of the last 10 bp of the intron, and leading to a protein elongation (Masson E et al. Pancreas, 2015 Aug;44:999-1001). Based on data from gnomAD, the A allele has an overall frequency of 0.0698% (197/282392) total alleles studied, including 1 homozygote. The highest observed frequency was 0.6501% (162/24920) of African alleles. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The CTRC c.640-12G>A variant is predicted to interfere with splicing. This variant has been reported in association with chronic pancreatitis (Masson et al. 2015. PubMed ID: 26166474; Giefer et al. 2017. PubMed ID: 28502372). Sequencing of RT-PCR products derived from patients harboring the c.640-12G>A variant revealed an aberrant mRNA transcript incorporating the last 10bp of intron 6 into exon 7, which is predicted to result in a frameshift and protein extension (Masson et al. 2015. PubMed ID: 26166474). This variant occurs relatively frequently in the gnomAD general population database, with a subpopulation allele frequency as high as 0.63% in Africans, including one homozygote, which is likely too common to be a highly penetrant cause of disease. While it is possible that this variant may contribute to chronic pancreatitis phenotypes with incomplete penetrance, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.