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Pancreatitis v2.10 TRPV6 Miranda Durkie changed review comment from: PMID: 31930989: Heterozygous variants that affected function of the TRPV6 protein statistically over represented in cases vs controls (300 cases from Japan, 470 from France, 410 from Germany & >1000 controls). Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P ¼ 2.4 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P ¼ 6.2 10–8). Homozygous mouse model given cerulein developed more severe pancreatitis than control mice (although homozygous / compound heterozygous disease in humans associated with transient neonatal hyperparathyroidism (OMIM 618188) with no reported pancreatitis). Also reported 20% had trans-heterozygous SPINK1 pathogenic variants.
PMID: 32383311: Chinese case control study of 669 cases and 609 controls showed over represented of confirmed loss of function alleles (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022).
Hypothesised treatment with Vitamin D may be beneficial.
Likely susceptibility allele therefore amber rating currently
Sources: Literature

Additional paper: PMID: 34923708 . Sequenced cohort of HCP and ICP and patients and identified 25 novel TRPV6 missense variants. Used functional Ca2+ assay to show 8 are functionally defective. Revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Therefore likely susceptibility allele as part of polygenic model. Keep at amber rating; to: PMID: 31930989: Heterozygous variants that affected function of the TRPV6 protein statistically over represented in cases vs controls (300 cases from Japan, 470 from France, 410 from Germany & >1000 controls). Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P ¼ 2.4 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P ¼ 6.2 10–8). Homozygous mouse model given cerulein developed more severe pancreatitis than control mice (although homozygous / compound heterozygous disease in humans associated with transient neonatal hyperparathyroidism (OMIM 618188) with no reported pancreatitis). Also reported 20% had trans-heterozygous SPINK1 pathogenic variants.
PMID: 32383311: Chinese case control study of 669 cases and 609 controls showed over represented of confirmed loss of function alleles (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022).
Hypothesised treatment with Vitamin D may be beneficial.
Likely susceptibility allele therefore amber rating currently
Sources: Literature

Additional paper: PMID: 34923708 added 20/01/2022. Sequenced cohort of HCP and ICP and patients and identified 25 novel TRPV6 missense variants. Used functional Ca2+ assay to show 8 are functionally defective. Revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Therefore likely susceptibility allele as part of polygenic model. Keep at amber rating 22/01/22
Pancreatitis v2.10 TRPV6 Miranda Durkie changed review comment from: PMID: 31930989: Heterozygous variants that affected function of the TRPV6 protein statistically over represented in cases vs controls (300 cases from Japan, 470 from France, 410 from Germany & >1000 controls). Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P ¼ 2.4 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P ¼ 6.2 10–8). Homozygous mouse model given cerulein developed more severe pancreatitis than control mice (although homozygous / compound heterozygous disease in humans associated with transient neonatal hyperparathyroidism (OMIM 618188) with no reported pancreatitis). Also reported 20% had trans-heterozygous SPINK1 pathogenic variants.
PMID: 32383311: Chinese case control study of 669 cases and 609 controls showed over represented of confirmed loss of function alleles (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022).
Hypothesised treatment with Vitamin D may be beneficial.
Likely susceptibility allele therefore amber rating currently
Sources: Literature; to: PMID: 31930989: Heterozygous variants that affected function of the TRPV6 protein statistically over represented in cases vs controls (300 cases from Japan, 470 from France, 410 from Germany & >1000 controls). Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P ¼ 2.4 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P ¼ 6.2 10–8). Homozygous mouse model given cerulein developed more severe pancreatitis than control mice (although homozygous / compound heterozygous disease in humans associated with transient neonatal hyperparathyroidism (OMIM 618188) with no reported pancreatitis). Also reported 20% had trans-heterozygous SPINK1 pathogenic variants.
PMID: 32383311: Chinese case control study of 669 cases and 609 controls showed over represented of confirmed loss of function alleles (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022).
Hypothesised treatment with Vitamin D may be beneficial.
Likely susceptibility allele therefore amber rating currently
Sources: Literature

Additional paper: PMID: 34923708 . Sequenced cohort of HCP and ICP and patients and identified 25 novel TRPV6 missense variants. Used functional Ca2+ assay to show 8 are functionally defective. Revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Therefore likely susceptibility allele as part of polygenic model. Keep at amber rating
Pancreatitis v2.4 TRPV6 Miranda Durkie gene: TRPV6 was added
gene: TRPV6 was added to Pancreatitis. Sources: Literature
Mode of inheritance for gene: TRPV6 was set to Unknown
Publications for gene: TRPV6 were set to PMID: 31930989; 32383311
Phenotypes for gene: TRPV6 were set to Chronic pancreatitis
Penetrance for gene: TRPV6 were set to unknown
Review for gene: TRPV6 was set to AMBER
Added comment: PMID: 31930989: Heterozygous variants that affected function of the TRPV6 protein statistically over represented in cases vs controls (300 cases from Japan, 470 from France, 410 from Germany & >1000 controls). Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P ¼ 2.4 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P ¼ 6.2 10–8). Homozygous mouse model given cerulein developed more severe pancreatitis than control mice (although homozygous / compound heterozygous disease in humans associated with transient neonatal hyperparathyroidism (OMIM 618188) with no reported pancreatitis). Also reported 20% had trans-heterozygous SPINK1 pathogenic variants.
PMID: 32383311: Chinese case control study of 669 cases and 609 controls showed over represented of confirmed loss of function alleles (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022).
Hypothesised treatment with Vitamin D may be beneficial.
Likely susceptibility allele therefore amber rating currently
Sources: Literature
Pancreatitis v1.4 SPINK1 Ivone Leong Marked gene: SPINK1 as ready
Pancreatitis v1.4 SPINK1 Ivone Leong Added comment: Comment when marking as ready: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: SPINK1 is associated with the phenotype; however, penetrance is low. The Specialist Test Group agreed that there is enough evidence to rate this gene green.
Pancreatitis v1.4 SPINK1 Ivone Leong Gene: spink1 has been classified as Green List (High Evidence).
Pancreatitis v1.4 SPINK1 Ivone Leong reviewed gene: SPINK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Pancreatitis v1.3 SPINK1 Ivone Leong Source NHS GMS was added to SPINK1.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Pancreatitis v0.43 SPINK1 Ellen McDonagh commented on gene: SPINK1
Pancreatitis v0.5 SPINK1 Eleanor Williams Phenotypes for gene: SPINK1 were changed from to Pancreatitis, hereditary 167800
Pancreatitis v0.4 SPINK1 Eleanor Williams Publications for gene: SPINK1 were set to
Pancreatitis v0.3 SPINK1 Eleanor Williams Added comment: Comment on mode of inheritance: OMIM has Pancreatitis, hereditary as AD inheritance and this appears to be correct for several variants reported.
Pancreatitis v0.3 SPINK1 Eleanor Williams Mode of inheritance for gene: SPINK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pancreatitis v0.2 SPINK1 Eleanor Williams Classified gene: SPINK1 as Green List (high evidence)
Pancreatitis v0.2 SPINK1 Eleanor Williams Added comment: Comment on list classification: Three cases/families found with different plausible disease causing variants found.
Pancreatitis v0.2 SPINK1 Eleanor Williams Gene: spink1 has been classified as Green List (High Evidence).
Pancreatitis v0.1 SPINK1 Eleanor Williams commented on gene: SPINK1
Pancreatitis SPINK1 Ioannis Sarantitis reviewed gene: SPINK1
Pancreatitis SPINK1 Ellen McDonagh Added gene to panel