ClinVar Miner

Submissions for variant NM_007272.3(CTRC):c.52G>A (p.Gly18Arg)

gnomAD frequency: 0.00005  dbSNP: rs200576965
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000706248 SCV000835287 uncertain significance Hereditary pancreatitis 2022-10-05 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CTRC function (PMID: 22942235). 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: 582232). This missense change has been observed in individual(s) with pancreatitis (PMID: 22942235, 25251442). This variant is present in population databases (rs200576965, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 18 of the CTRC protein (p.Gly18Arg).
Illumina Laboratory Services, Illumina RCV000706248 SCV001252553 uncertain significance Hereditary pancreatitis 2017-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000706248 SCV001472096 uncertain significance Hereditary pancreatitis 2020-08-05 criteria provided, single submitter clinical testing The CTRC c.52G>A; p.Gly18Arg variant (rs200576965) is reported in the literature in the heterozygous state individuals affected with pancreatitis (Ballard 2015, Beer 2013). This variant is reported in ClinVar (Variation ID: 582232), and is found in the non-Finnish European population with an allele frequency of 0.011% (14/124118 alleles) in the Genome Aggregation Database. The glycine at codon 18 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show no change to protein levels or activity compared to wildtype under normal conditions, but a loss of activity in the presence of trypsin (Beer 2013). Given the lack of clinical data and conflicting functional data, the clinical significance of the p.Gly18Arg variant is uncertain at this time. References: Ballard DD et al. Evaluating Adults With Idiopathic Pancreatitis for Genetic Predisposition: Higher Prevalence of Abnormal Results With Use of Complete Gene Sequencing. Pancreas. 2015;44(1):116-121. Beer S et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut. 2013;62(11):1616-1624.
Ambry Genetics RCV000706248 SCV002647192 uncertain significance Hereditary pancreatitis 2024-05-16 criteria provided, single submitter clinical testing The p.G18R variant (also known as c.52G>A), located in coding exon 2 of the CTRC gene, results from a G to A substitution at nucleotide position 52. The glycine at codon 18 is replaced by arginine, an amino acid with dissimilar properties. In HEK293 cells, this variant demonstrated similar enzyme kinetics to wild type, but showed approximately 20% loss in activity in the presence of trypsin (Beer S et al. Gut, 2013 Nov;62:1616-24). 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.

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