ClinVar Miner

Submissions for variant NM_007272.3(CTRC):c.703G>A (p.Val235Ile) (rs140993290)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000347906 SCV000349089 benign Hereditary pancreatitis 2018-03-06 criteria provided, single submitter clinical testing 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.
Invitae RCV000347906 SCV000562018 benign Hereditary pancreatitis 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000347906 SCV000603257 uncertain significance Hereditary pancreatitis 2019-06-02 criteria provided, single submitter clinical testing The CTRC c.703G>A; p.Val235Ile variant (rs140993290) is reported in the medical literature in several individuals with chronic pancreatitis, with several carrying additional pathogenic variants (Koziel 2015, Masson 2008, Paliwal 2013, Rosendahl 2008, Rosenhdahl 2014, Tomaiuolo 2015, Wang 2013, Werlin 2015). The variant is described as benign or likely benign in the ClinVar database (Variation ID: 292914). This variant is found in the general population with an overall allele frequency of 0.1% (293/282822 alleles, including 3 homozygotes) in the Genome Aggregation Database. The valine at this position is conserved across species and computational algorithms predict this variant is deleterious. Additionally, this variant is reported to cause reduced protein activity (Beer 2013, Rosendahl 2008). Although there are indications this variant may be pathogenic, the evidence is conflicting, so the variant is classified as uncertain significance. 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. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. Paliwal S et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2013 Nov;62(11):1602-6 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. 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. Tomaiuolo AC et al. Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis. J Mol Diagn. 2015 Mar;17(2):171-8. Wang W et al. Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ Open. 2013 Sep 3;3(9):e003150. Werlin S et al. Genetic and electrophysiological characteristics of recurrent acute pancreatitis. J Pediatr Gastroenterol Nutr. 2015 May;60(5):675-9.
Ambry Genetics RCV001025959 SCV001188248 pathogenic Inborn genetic diseases 2018-07-11 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification;Significant disease association in appropriately sized case-control study(ies)

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