Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000685719 | SCV000813211 | uncertain significance | Hereditary pancreatitis | 2025-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 249 of the CTRC protein (p.Pro249Leu). This variant is present in population databases (rs142560329, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pancreatitis (PMID: 18059268, 21631589, 22942235). ClinVar contains an entry for this variant (Variation ID: 566014). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CTRC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CTRC function (PMID: 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. |
| ARUP Laboratories, |
RCV000685719 | SCV000885270 | likely pathogenic | Hereditary pancreatitis | 2024-10-09 | criteria provided, single submitter | clinical testing | The CTRC c.746C>T; p.Pro249Leu variant (rs142560329) has been described in individuals with pancreatitis (Cho 2016, Rosendahl 2008) and is observed in the general population at an overall frequency of 0.011% (32/282744 alleles) in the Genome Aggregation Database. The proline at codon 249 is highly conserved and computational algorithms predict that this variant is deleterious (REVEL: 0.949). Additionally, in vitro functional studies of this variant protein demonstrate reduced expression and severe catalytic deficiency (Beer 2013). Based on available information, this variant is considered 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. PMID: 22942235 Cho S et al. PRSS1, SPINK1, CFTR, and CTRC Pathogenic Variants in Korean Patients With Idiopathic Pancreatitis. Ann Lab Med. 2016 Nov;36(6):555-60. PMID: 27578509 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. PMID: 18059268 |
| Ambry Genetics | RCV000685719 | SCV002671730 | uncertain significance | Hereditary pancreatitis | 2024-11-08 | criteria provided, single submitter | clinical testing | The p.P249L variant (also known as c.746C>T), located in coding exon 7 of the CTRC gene, results from a C to T substitution at nucleotide position 746. The proline at codon 249 is replaced by leucine, an amino acid with some similar properties. In a functional study, this variant was reported in 1 of 1708 affected individuals with chronic pancreatitis. This study also reported this variant showed very little enzyme activity and reduced protein levels (Beer et al. Gut. 2013; 62(11): 1616-24). In addition, this alteration results in substantial disruption of the core structure of CTRC (Ambry internal data). 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 variant remains unclear. |