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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 ValidityPoints Total
12
Source:
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
Definitive
Source:
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Loss of function
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Severity
Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary
- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
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.