ClinVar Miner

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

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000119030 SCV000053127 pathogenic Hereditary pancreatitis 2020-06-08 criteria provided, single submitter clinical testing SPINK1 c.101A>G (p.Asn34Ser) results in a conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.009 in 254072 control chromosomes (gnomAD and publication data), including 20 homozygotes. This frequency is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SPINK1 variant. However, this variant is a well-reported pathogenic risk factor that is known to be relatively frequent in the general population. Multiple studies have identified the variant in the compound heterozygous and homozygous state in numerous patients with chronic pancreatitis (example, Witt_2000, Chandak_2002, Rosendahl_2012, Pelaez-Luna_2014). Large association studies have been performed that suggest a strong association between the variant and disease, with odds ratios ranging from 10 to over 50 (example, Chen_2009, Witt_2000). However, experimental data reported that the trypsin inhibitory activity of the variant protein was preserved (> 90% of normal) and there was no significant difference in mRNA expression or splicing compared to wild-type (Kuwata_2002, Kiraly_2007, Boulling_2012). Although it has been proposed that other cis-linked variant(s) might be responsible for the observed increased pancreatitis risk conferred by the N34S haplotype, studies reporting a causative role of this variant within its associated haplotype have also been reported (Boulling_2012, Boulling_2017, Kereszturi_2017). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (n=3), Pathogenic (n=4) or Risk factor (n=2)). Based on the evidence outlined above, the variant was classified as a pathogenic risk factor for predisposition to Chronic Pancreatitis.
Invitae RCV000119030 SCV000252902 association Hereditary pancreatitis 2020-10-29 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.
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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999823 SCV000605239 pathogenic none provided 2020-08-27 criteria provided, single submitter clinical testing The SPINK1 c.101A>G (p.Asn34Ser) variant has been detected at a statistically significant increased frequency in individuals with pancreatitis as compared to the general population (Aoun 2008, Masson 2013, Rosendahl 2013). It is associated with a higher risk for developing pancreatitis when combined with either an additional pathogenic SPINK1 variant on the opposite chromosome or with a severe pathogenic CFTR gene variant (Rosendahl 2013). Based on this variant's strong association with pancreatitis, we consider it pathogenic. REFERENCES Aoun E et al. SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event. Am J Gastroenterol. 2010; 105(2):446-51. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. 2013; PLoS One. 8(8):e73522. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013; 62(4):582-92.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000119030 SCV000782314 pathogenic Hereditary pancreatitis 2016-11-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000119030 SCV000967008 risk factor Hereditary pancreatitis 2021-03-12 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Mendelics RCV000119030 SCV001136991 uncertain significance Hereditary pancreatitis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001009715 SCV001169814 pathogenic Inborn genetic diseases 2019-02-07 criteria provided, single submitter clinical testing The p.N34S pathogenic mutation (also known as c.101A>G), located in coding exon 3 of the SPINK1 gene, results from an A to G substitution at nucleotide position 101. The asparagine at codon 34 is replaced by serine, an amino acid with highly similar properties. This mutation has been observed in heterozygous and homozygous states in individuals with chronic pancreatitis (Witt H et al. Nat Genet. 2000;25(2):213-216). In case control studies, p.N34S has has been associated with a significant odds ratio for both acute pancreatitis and chronic pancreatitis (O'Reilly DA et al. Eur J Gastroenterol Hepatol, 2008 Aug;20:726-31; Rosendahl J et al. Gut, 2013 Apr;62:582-92). Heterozygous p.N34S confers an increased risk, while homozygous p.N34S is considered to be disease-causing (Masson E et al. PLoS One. 2013;8(8):e73522). Based on the supporting evidence, this alteration is interpreted as a pathogenic mutation.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656981 SCV001248360 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119030 SCV001316926 uncertain significance Hereditary pancreatitis 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000119030 SCV001366803 pathogenic Hereditary pancreatitis 2019-08-23 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: BS1,PS4,PS1. This variant was detected in homozygous state.
Broad Institute Rare Disease Group, Broad Institute RCV001258230 SCV001435136 likely benign Finnish congenital nephrotic syndrome criteria provided, single submitter research The p.Asn34Ser variant in SPINK1 has been reported in 12 heterozygous and 6 homozygous individuals with chronic pancreatitis (PMID: 10835640). It has also been identified in >0.1% of chromosomes, including 9 homozygotes, by ExAC ( In vitro functional studies provide some evidence that this variant does not impact protein function (PMID: 12483248, 17568390, 17525091). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant chronic pancreatitis.
Baylor Genetics RCV000119030 SCV001522929 pathogenic Hereditary pancreatitis 2020-11-17 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Undiagnosed Diseases Network,NIH RCV000119030 SCV001736855 pathogenic Hereditary pancreatitis 2020-11-17 criteria provided, single submitter clinical testing
OMIM RCV000014768 SCV000035023 uncertain significance Pancreatitis, chronic, susceptibility to 2002-10-01 no assertion criteria provided literature only
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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000656981 SCV001739790 uncertain significance not provided no assertion criteria provided clinical testing

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