Pancreatitis
Gene: SPINK1
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.Created: 24 Jan 2019, 4:18 p.m.
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: SPINK1; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none givenCreated: 7 Jan 2019, 4:15 p.m.
This gene is within the Pancreatitis, Hereditary panel on UKGTN.Created: 6 Dec 2018, 2:09 p.m.
Comment on mode of inheritance: OMIM has Pancreatitis, hereditary as AD inheritance and this appears to be correct for several variants reported.Created: 12 Sep 2018, 2:42 p.m.
Comment on list classification: Three cases/families found with different plausible disease causing variants.Created: 12 Sep 2018, 2:40 p.m.
SPINK1 (aka PSTI) is associated with Pancreatitis, hereditary in OMIM.
Witt et al (2000)(PMID: 10835640) analysed 96 unrelated individuals for mutations in SPINK1 and found mutations in 22 patients. 18 of these had a N34S which was homozygous in 6 of the patients. 4 other variants were found including heterozygous M1T - destroys the initiation codon, heterozygous L14P - results in decreased activity).
Kaneko et al. (2001) (PMID: 11355022) found the N34S mutation in 5 unrelated Japanese patients with chronic pancreatitis with juvenile onset or family history of the disorder. They also found a novel homozygous G-to-A transition in the promoter region of PSTI 215 bp upstream from the translation initiation site in 2 patients (homozygous -215G-A)
Audrezet et al. (2002)(PMID: 11938439) analyzed the entire coding sequence and exon/intron junctions of the SPINK1 gene by denaturing gradient gel electrophoresis (DGGE) and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. The N34S missense mutation was detected in 4 patients (3 heterozygotes and 1 homozygote), as compared with 3 out of 200 blood donors. In addition, 2 variants were identified in the 5-prime-untranslated region, each identified once in different patients.
Masson et al. (2006) (PMID: 16823394) identified a 1,336-bp deletion encompassing exon 1 in the SPINK1 gene in affected members of a family with chronic pancreatitis.
Kiraly et al. (2007)(PMID: 17274009) reported 2 unrelated families with autosomal dominant chronic pancreatitis and a variant leading to L14R. First family had 2 affected members, second had 3. Functional studies showed decreased SPINK1 activity.
Lek et al. (2016)(PMID: 27535533) noted that the N34S variant has a high allele frequency (0.0219) in the South Asian population in the ExAC database, suggesting that it is not pathogenic.
However, even excluding the N34S which is now classified as a VUS, there are still 3 variants in unrelated families that are plausibily disease causing.
Not in Gene2Phenotype.Created: 12 Sep 2018, 2:40 p.m.
Gene: spink1 has been classified as Green List (High Evidence).
Source NHS GMS was added to SPINK1. Rating Changed from Green List (high evidence) to Green List (high evidence)
Eleanor Williams: SPINK1 (aka PSTI) is associate
Phenotypes for gene: SPINK1 were changed from to Pancreatitis, hereditary 167800
Publications for gene: SPINK1 were set to
Mode of inheritance for gene: SPINK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: spink1 has been classified as Green List (High Evidence).
SPINK1 was added to Pancreatitis panel. Sources: EUROPAC
SPINK1 was created by Ellen McDonagh