NM_007272.3(CTRC):c.760C>T (p.Arg254Trp) AND Hereditary pancreatitis

Clinical significance:Conflicting interpretations of pathogenicity, association, Benign(1);Likely pathogenic(1) (Last evaluated: Oct 6, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000119045.12

Allele description [Variation Report for NM_007272.3(CTRC):c.760C>T (p.Arg254Trp)]

NM_007272.3(CTRC):c.760C>T (p.Arg254Trp)

Gene:
CTRC:chymotrypsin C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p36.21
Genomic location:
Preferred name:
NM_007272.3(CTRC):c.760C>T (p.Arg254Trp)
HGVS:
  • NC_000001.11:g.15445717C>T
  • NG_009253.1:g.12275C>T
  • NM_007272.3:c.760C>TMANE SELECT
  • NP_009203.2:p.Arg254Trp
  • NP_009203.2:p.Arg254Trp
  • NC_000001.10:g.15772212C>T
  • NM_007272.2:c.760C>T
  • Q99895:p.Arg254Trp
Protein change:
R254W; ARG254TRP
Links:
UniProtKB: Q99895#VAR_043529; OMIM: 601405.0001; dbSNP: rs121909293
NCBI 1000 Genomes Browser:
rs121909293
Molecular consequence:
  • NM_007272.3:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary pancreatitis (PCTT)
Synonyms:
Hereditary chronic pancreatitis; PRSS1-Related Hereditary Pancreatitis
Identifiers:
MONDO: MONDO:0008185; MedGen: C0238339; Orphanet: 676; OMIM: 167800

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000153751GeneReviewsno assertion criteria providedPathogenic
(Mar 13, 2014)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000349091Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Mar 6, 2018)
germlineclinical testing

Citation Link,

SCV000551759Invitaecriteria provided, single submitter
association
(Oct 6, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000603259ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Aug 27, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk.

Beer S, Zhou J, Szabó A, Keiles S, Chandak GR, Witt H, Sahin-Tóth M.

Gut. 2013 Nov;62(11):1616-24. doi: 10.1136/gutjnl-2012-303090. Epub 2012 Sep 1.

PubMed [citation]
PMID:
22942235
PMCID:
PMC3660471

CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?

Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H.

Gut. 2013 Apr;62(4):582-92. doi: 10.1136/gutjnl-2011-300645. Epub 2012 Mar 17.

PubMed [citation]
PMID:
22427236
See all PubMed Citations (7)

Details of each submission

From GeneReviews, SCV000153751.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000349091.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000551759.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with tryptophan at codon 254 of the CTRC protein (p.Arg254Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121909293, ExAC 2.3%). This variant is reported as heterozygous in ~2% of patients with chronic pancreatitis and in ~0.7% of unaffected controls; overall it has been reported to confer ~3-fold increased risk for chronic pancreatitis in heterozygous carriers (PMID: 18059268, 22942235, 22427236, 18172691, 25569187). ClinVar contains an entry for this variant (Variation ID: 8178). Experimental studies demonstrate that this missense change reduces the activity of CTRC by ~50% (PMID: 18059268). This result is consistent with increased trypsinogen activity in the pancreas and an increased risk for pancreatitis (PMID: 19453252). In summary, this missense variant affects protein function and is associated with a statistically significant risk for developing chronic pancreatitis. Therefore, it has been classified as an Increased Risk Allele.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000603259.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The CTRC c.760C>T; p.Arg254Trp variant (rs121909293) has been reported in multiple individuals with chronic, hereditary, or recurrent acute pancreatitis, both in the homozygous state and in individuals carrying a second pathogenic variant (Beer 2013, Giefer 2017, Masamune 2013, Masson 2008, Rosendahl 2008, Rosendahl 2013). Functional characterization of p.Arg254Trp indicates a moderate reduction in the level of secreted CTRC protein, but no impact on enzymatic activity (Beer 2013, Rosendahl 2008), leading to its designation as a moderate-to-low-risk variant (Beer 2013). The variant is reported in ClinVar (Variation ID: 8178) and is found in the general population with an overall allele frequency of 0.46% (1305/282668 alleles, including 12 homozygotes) in the Genome Aggregation Database. However, it is reported to be at a higher frequency in affected European individuals compared to controls (Beer 2013, Masson 2008, Rosendahl 2008, Rosendahl 2013), and to co-occur at increased frequency with the SPINK1 p.Asn34Ser variant in affected individuals (Rosendahl 2008). The arginine at residue 254 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.809). Based on available information, this variant is considered to be 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; 62(11):1616-24. 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. 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. Masamune A et al. Identification of novel missense CTRC variants in Japanese patients with chronic pancreatitis. Gut. 2013; 62(4):653-4. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008; 123(1):83-91. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92. Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008; 40(1):78-82.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 16, 2021

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