Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - dosage sensitivitiy, sufficient evidence for haploinsufficiency. GenCC - only US lab is Invitae (strong). No BabySeq.

Clinical Validity Scoring Notes and points

From Dosage sensitivity:

• PUBMED: 17681820 - Masson et al. (2007) identified a 30,588-bp deletion encompassing the entire SPINK1 gene in a 47 year old female with chronic pancreatitis and her affected father and paternal uncle. 2 point LOF

• PUBMED: 22427236 - Rosendahl et al. (2013) used PCR and gene sequencing on 660 unrelated individuals with hereditary chronic pancreatitis (HP) or Idiopathic chronic pancreatitis (ICP) and a control group of 1758 individuals. 12 variants were detected in SPINK1, 10 variants were missense, a variant found in one individual was frameshift (p.V60YfsX35), and a variant found in one individual was a deletion (c.27delC). Inheritance for all variants identified is unknown. 2x2 point LOF = 4 points

• PUBMED: 16823394 Previously, a heterozygous 1,336-bp deletion encompassing exon 1 of the SPINK1 gene was detected in an individual and her two brothers, both with chronic pancreatitis, by HPLC. Parental samples were unavailable. 2 point

• PUBMED: 14722925 Marechal, et al. (2003) used denaturing high performance liquid chromatography (DHPLC) and PCR on 46 families with pancreatitis. Two families were identified to have a microdeletion in SPINK1 (c.27delC). In Family 1, three individuals were identified to have this variant, two affected family members and one unaffected family member. In Family 2, 7 individuals had this variant, 2 affected and 5 unaffected. Confirmed these are different authors from PMID: 22427236. 2x2 point = 4 point.

Source:

Clinical Validity Points Total

12

Source:

Clinical Validity Classification

Definitive

Source:

Molecular Mechanism

Loss of function

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

The SPINK1 gene is associated with autosomal dominant chronic pancreatitis, which is is characterized by inflammation of the pancreas. Symptoms can include abdominal pain, steatorrhea, abdominal symptoms (bloating, gas, cramps, diarrhea), elevated serum amylase or lipase, systemic inflammation, and multiorgan failure (PMID: 24624459). Risk factors for chronic pancreatitis include smoking, alcohol use, and genetic risk.

Case ID, Curator name, Date, Jira ticket link

AO 01.24.25 56752207081045