ClinVar Miner

Submissions for variant NM_007272.3(CTRC):c.746C>T (p.Pro249Leu) (rs142560329)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685719 SCV000813211 uncertain significance Hereditary pancreatitis 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 249 of the CTRC protein (p.Pro249Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs142560329, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuasl affected with pancreatitis (PMID: 18059268, 22942235, 21631589). Experimental studies have shown that this missense change produces low enzyme activity in vitro (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, Molecular Genetics and Genomics, ARUP Laboratories RCV000757145 SCV000885270 likely pathogenic not provided 2018-04-22 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 a low frequency of 0.01% (31/277074 alleles) in the Genome Aggregation Database. The proline at codon 249 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is damaging. 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. 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. 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.

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