ClinVar Miner

Submissions for variant NM_003122.4(SPINK1):c.101A>G (p.Asn34Ser) (rs17107315)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000656981 SCV000605239 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000119030 SCV000782314 pathogenic Hereditary pancreatitis 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000656981 SCV000577224 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing This variant is denoted SPINK1 c.101A>G at the cDNA level, p.Asn34Ser (N34S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant is associated with an increased risk of pancreatitis when present with other genetic or environmental risk factors (Witt 2000, Diaconu 2009, Masamune 2011, LaSaito 2016). In a meta-analysis, this variant was identified in the heterozygous state in 274/2927 Caucasian pancreatitis cases and 79/5298 controls (OR=6.82), and in the homozygous state in 54/2981 cases and 1/5299 controls (OR=97.74) (Di Leo 2017). Functional studies of SPINK1 N34S demonstrated no change in trypsin inhibition or binding activity, suggesting that SPINK1 N34S on its own is insufficient to cause pancreatitis (Kuwata 2002, Boulling 2007). SPINK1 Asn34Ser is the most common SPINK1 pancreatitis risk allele, with an allele frequency of 0.97% (590/60648) and 2.2% (332/15160) in individuals of European (non-Finnish) and South Asian ancestry, respectively, in large population cohorts (Lek 2016). This variant is located in the Kazal-like domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, we consider SPINK1 Asn34Ser to be a risk allele.
GeneReviews RCV000119030 SCV000153734 pathogenic Hereditary pancreatitis 2014-03-13 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000119030 SCV000607175 not provided Hereditary pancreatitis no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000014768 SCV000053127 pathogenic Pancreatitis, chronic, susceptibility to 2015-04-13 no assertion criteria provided clinical testing
Invitae RCV000119030 SCV000252902 risk factor Hereditary pancreatitis 2018-06-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 34 of the SPINK1 protein (p.Asn34Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs17107315, ExAC 1%). This variant is reported as heterozygous in ~12% of individuals affected with chronic pancreatitis and in ~1.9% of unaffected controls (PMID: 17466744). Based on this data, this variant is expected to confer ~6-12 fold increased risk for chronic pancreatitis in heterozygous carriers. Homozygous individuals have been reported in approximately 3-5% of individuals with chronic pancreatitis (PMID: 23951356, 10835640), ~0.015% of the general population (ExAC), and in no unaffected controls to date (reviewed in PMID: 17466744). Although homozygous individuals are presumed to have at least twice the risk of heterozygous carriers, an accurate odds ratio can not be calculated due to the small number of homozygous individuals in the general population. ClinVar contains an entry for this variant (Variation ID: 13760). Multiple studies have failed to demonstrate that this Asn34Ser missense change disrupts any known function of the SPINK1 protein (PMID: 12483248, 17568390, 17525091). In summary, this variant is a missense change that does not affect any known function of the SPINK1 protein function. While this variant is associated with a significant risk for developing chronic pancreatitis, in the absence of a deleterious protein effect it remains uncertain whether this variant directly contributes to disease or if it may be linked to an undiscovered mutation (PMID: 19299380). Therefore, it has been classified as an Increased Risk Allele.
OMIM RCV000014768 SCV000035023 uncertain significance Pancreatitis, chronic, susceptibility to 2002-10-01 no assertion criteria provided literature only

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