Witt et al: Sequencing of CPA1 in 944 individuals with nonalcoholic chronic pancreatitis and in 3,938 control subjects of German origin found functionally impaired (<20% activity) variants were in 29/944 (3.1%) German patients and in 5/3,938 (0.1%) controls (odds ratio [OR] = 24.9; P = 1.5 ×10-16). The association was strongest in subjects aged ≤10 years (9.7%; OR = 84.0; P = 4.1 ×10-24). In 3 additional replication cohorts, defective CPA1 variants were observed in 8/600 (1.3%) patients and in 9/2,432 (0.4%) controls from Europe (P = 0.01), in 5/230 (2.2%) patients and 0/264 controls from India (P = 0.02), and in 5/247 (2.0%) patients but 0/341 controls from Japan (P =0.013). 3 variants p.N256K and p.R382W and the splice-site variant c.1073-2A>G were more common in the cases. Mechanism thought to involve misfolding induced endoplasmic reticulum stress. No information provided on family history.
Kujko et al - found 2 Polish families with p.(Ser282Pro) missense variant. Functional studies showed ER stress (similar to p.(N256K). Showed segregation in 3 affected family members (age of onset 17, 51 and 31 years) and 1 unaffected grandfather (age 83) in 1 family. In 2nd family found in affected mother and child (note Dad has CRTC variant also inherited by child who had onset age 12). Affected Mum had onset at 32 years.
Due to age-of-onset/non-penetrance in 83 year old unaffected grandfather, keep as amber
Created: 1 Feb 2019, 2:49 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CPA1 will remain amber until further evidence can be provided before this will be promoted to green gene status.
Created: 4 Sep 2019, 9:38 a.m. | Last Modified: 4 Sep 2019, 9:38 a.m.
Panel Version: 1.12
Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: CPA1; Suggested intial gene rating: Amber; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given
Created: 7 Jan 2019, 4:15 p.m.
Comment on list classification: Rating Amber on advice from Genomics England clinical team.
Created: 23 Sep 2018, 11:19 a.m.
Waiting on advice from Genomics England clinical team about the appropriate rating for this gene.
Created: 13 Sep 2018, 10:45 a.m.
Comment on publications: 28650851 is a review
Created: 13 Sep 2018, 10:41 a.m.
CPA1 is not associated with any disorder in OMIM (entry last updated in 2014). OMIM reports that Witt et al. (2013)(PMID: 23955596) analyzed CPA1 in 944 subjects with nonalcoholic chronic pancreatitis (cases) and 3,938 controls in a German discovery set and 3 replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10(-16)) but only 3 variants were significantly enriched in patients (p.Asn256Lys, p.Tyr358fs (splice site variant), p.Arg382Trp) (heterozygous). In replication sets defective CPA1 variants were present in 1.3% of 600 cases and 0.4% of 2,432 controls from Europe (p = 0.01, 2.2% of 230 cases and 0 of 264 controls from India (p = 0.02), and 2.0% of 247 cases and 0 of 341 controls from Japan (p = 0.013.).
Witt et al. (2013) proposed that the mechanism by which CPA1 variants confer increased pancreatitis risk might involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.
However, Wu et al. (2017) (PMID: 28497564) found no significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort (1,112 Han Chinese idiopathic chronic pancreatitis patients-the 1,580 control).
Kujko et al. (2017)(PMID: 28258133) report two Polish families with hereditary chronic pancreatitis carrying a novel heterozygous c.844T>C (p.Ser282Pro) CPA1 variant. In both families the diagnosis of CP was confirmed by imaging methods. Chronic pancreatitis risk factors such as alcohol abuse, smoking, injury, anatomical defects, metabolic and bile duct disorders were excluded. Functional studies with HEK 293T cells transfected with wild-type and mutant CPA1 constructs showed only wild type proenzyme was secreted. p.Ser282Pro mutant protein was retained intracellularly and suffered degradation, indicative of misfolding, as did the p.Asn256Lys mutant (identified by Witt et al, previously shown to cause misfolding and ER stress).
No information in Gene2Phenotype for this gene.
Created: 13 Sep 2018, 10:23 a.m.
Mode of inheritance for gene: CPA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Source NHS GMS was added to CPA1.
Eleanor Williams: CPA1 is not associated with an
Phenotypes for gene: CPA1 were changed from chronic pancreatitis; hereditary chronic pancreatitis to Chronic pancreatitis; Hereditary chronic pancreatitis
Tag watchlist tag was added to gene: CPA1.
Gene: cpa1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CPA1 were changed from to chronic pancreatitis; hereditary chronic pancreatitis
Publications for gene: CPA1 were set to
CPA1 was added to Pancreatitis panel. Sources: EUROPAC
CPA1 was created by Ellen McDonagh