Submissions for variant NM_007272.3(CTRC):c.674A>C (p.Glu225Ala)

gnomAD frequency: 0.00020  dbSNP: rs201486613

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001000068	SCV000289733	benign	Hereditary pancreatitis	2023-12-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000068	SCV000883691	uncertain significance	Hereditary pancreatitis	2020-08-14	criteria provided, single submitter	clinical testing	The CTRC c.674A>C; p.Glu225Ala variant (rs201486613) is described in the medical literature in individuals with pancreatitis (Beer 2013, Koziel 2015), but also described in unaffected individuals (Koziel 2015, Rosendahl 2008, Zhou 2011). This variant is reported in ClinVar (Variation ID: 240766). It is found in the general population with an overall allele frequency of 0.04% (115/282830 alleles, including 1 homozygote) in the Genome Aggregation Database. The glutamic acid at codon 225 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, experiments in cell culture show this variant does not affect protein stability or activity (Beer 2013). Considering available information, there is insufficient evidence to classify this variant with certainty. 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. 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. Zhou J et al. Chymotrypsin C mutations in chronic pancreatitis. J Gastroenterol Hepatol. 2011 Aug;26(8):1238-46.
Ambry Genetics	RCV001000068	SCV001187831	uncertain significance	Hereditary pancreatitis	2023-10-25	criteria provided, single submitter	clinical testing	The p.E225A variant (also known as c.674A>C), located in coding exon 7 of the CTRC gene, results from an A to C substitution at nucleotide position 674. The glutamic acid at codon 225 is replaced by alanine, an amino acid with dissimilar properties. This variant has been identified in individuals with pancreatitis and healthy controls (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Koziel D et al. BMC Gastroenterol, 2015 Jun;15:70; Sofia VM et al. Mol. Med., 2016 Sep;22:300-309; Beer S et al. Gut, 2013 Nov;62:1616-24; Cordero-Vázquez E et al. Endocrinol Diabetes Nutr (Engl Ed), 2022 Feb;69:155-156). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001000068	SCV001256380	uncertain significance	Hereditary pancreatitis	2017-04-27	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.
Sema4, Sema4	RCV001000068	SCV002537669	likely benign	Hereditary pancreatitis	2021-05-10	criteria provided, single submitter	curation
GeneDx	RCV002277591	SCV002567285	likely benign	not provided	2018-06-28	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.