ClinVar Miner

Submissions for variant NM_001379610.1(SPINK1):c.101A>G (p.Asn34Ser)

gnomAD frequency: 0.00797  dbSNP: rs17107315
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Total submissions: 28
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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 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the SPINK1 protein (p.Asn34Ser). This variant is present in population databases (rs17107315, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. 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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV000656981 SCV000605239 pathogenic not provided 2023-11-28 criteria provided, single submitter clinical testing The SPINK1 c.101A>G; p.Asn34Ser variant (rs17107315) has been detected at a statistically significant increased frequency in individuals with pancreatitis as compared to the general population (Aoun 2010, Masson 2013, Rosendahl 2013), co-segregating with pancreatitis patients in multiple families (Wu 2022). This variant and its associated haplotype is a risk factor for developing pancreatitis when combined with an additional pathogenic SPINK1 variant on the opposite chromosome, a severe pathogenic CFTR gene variant, or a pathogenic CTRC gene variant (Boulling 2017, Rosendahl 2013, Zou 2018). The p.Asn34Ser variant is reported in ClinVar (Variation ID: 13760). This variant is found in the general population with an overall allele frequency of 0.9% (2537/281004 alleles, 23 homozygotes) in the Genome Aggregation Database. The asparagine at codon 34 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.199). 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. PMID: 19888199. Boulling A et al. Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype. Hum Mutat. 2017 Aug;38(8):1014-1024. PMID: 28556356. 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. PLoS One. 2013 8(8):e73522. PMID: 23951356. 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. PMID: 22427236. Wu D et al. The clinical and genetic features of hereditary pancreatitis in South Australia. Med J Aust. 2022 Jun 20;216(11):578-582. PMID: 35578795. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730.
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, Mass General Brigham 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 RCV000119030 SCV001169814 pathogenic Hereditary pancreatitis 2023-08-21 criteria provided, single submitter clinical testing The c.101A>G (p.N34S) alteration is located in exon 3 (coding exon 3) of the SPINK1 gene. This alteration results from an A to G substitution at nucleotide position 101, causing the asparagine (N) at amino acid position 34 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.903% (2537/281004) total alleles studied. The highest observed frequency was 1.975% (602/30476) of South Asian alleles. This mutation has been observed in heterozygous and homozygous states in individuals with chronic pancreatitis (Witt, 2000). In case control studies, p.N34S has has been associated with a significant odds ratio for both acute pancreatitis and chronic pancreatitis (O'Reilly, 2008; Rosendahl, 2013). Heterozygous p.N34S confers an increased risk, while homozygous p.N34S is considered to be disease-causing (Masson, 2013). This amino acid position is poorly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000656981 SCV001248360 pathogenic not provided 2024-02-01 criteria provided, single submitter clinical testing SPINK1: PP1:Strong, PS1, PS4, PP4:Moderate, BP4
Illumina Laboratory Services, 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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard 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 (http://gnomad.broadinstitute.org/). 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
Institute of Human Genetics, University of Leipzig Medical Center RCV000119030 SCV002505611 established risk allele Hereditary pancreatitis 2022-03-08 criteria provided, single submitter clinical testing One of the most important CP-associated heritable risk factors (odds ratio (OR) = 10.90; 95% confidence interval 7.56–15.72). No functional data support pathogenic effect (expression, secretion or trypsin inhibitory activity of SPINK1). Linked with SNP rs142703147:C>A (c.-4141G>T) in this individual (this variant disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module (CRM). Co-transfection transactivation experiments have demonstrated that this variant leads to reduced gene expression. Two pancreatic cancer cell lines heterozygous for the SPINK1 N34S haplotype exhibited reduced expression of the variant allele and suggested that c.-4141G>T might be a candidate causal variant. See Pu et al., 2021, PMID: 34828289
Sema4, Sema4 RCV000119030 SCV002535378 pathogenic Hereditary pancreatitis 2021-05-24 criteria provided, single submitter curation
3billion RCV002283443 SCV002572766 pathogenic Tropical pancreatitis 2022-09-01 criteria provided, single submitter clinical testing The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.903%. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SPINK1 -related disorder (ClinVar ID: VCV000013760 / PMID: 10835640 / 3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22427236). It has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11950815 , 12187509). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV002283443 SCV003836313 likely pathogenic Tropical pancreatitis 2022-03-17 criteria provided, single submitter clinical testing
Eurofins-Biomnis RCV000119030 SCV003935033 likely pathogenic Hereditary pancreatitis 2022-12-01 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000119030 SCV004048160 likely pathogenic Hereditary pancreatitis 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), an amino acid with highly similar properties. The p.Asn34Ser variant in SPINK1 has been reported in 12 heterozygous and 6 homozygous individuals with chronic pancreatitis (H. Witt, 2000). In case control studies, p.N34S has has been associated with a significant odds ratio for both acute pancreatitis and chronic pancreatitis (Rosendahl J, 2012). Based on above evidence, the variant has been classified as Likely Pathogenic
OMIM RCV000014768 SCV000035023 uncertain significance Pancreatitis, chronic, susceptibility to 2002-10-01 no assertion criteria provided literature only
GeneReviews RCV000119030 SCV000153734 not provided Hereditary pancreatitis no assertion 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV002468556 SCV002764629 likely risk allele Pancreatitis no assertion criteria provided research The SPINK1 c.101A>G (p.Asn34Ser) variant is a commonly reported risk variant associated with pancreatitis and has been reported in >300 affected individuals, as well as in >100 unaffected controls (Di Leo_2017_PMID: 28546062; Diaconu_2009_PMID: 19565042; Masamune_2011_PMID: 21303407; Chandak_2002_PMID: 12011155; Rosendahl_2013_PMID: 22427236; Witt_2000_PMID: 10835640). In a large meta-analysis, this variant has a reported odds ratio of 9.695 (CI 95% 7.931–11.851) in pancreatitis cases vs controls (Di Leo_2017_PMID: 28546062). The variant was identified in dbSNP (ID: rs17107315) and ClinVar (classified as pathogenic by Ambry Genetics and 8 other submitters; as uncertain significance by GeneDx and 4 other submitters; as "risk factor" by Laboratory for Molecular Medicine; and as "association" by Invitae). The variant was identified in control databases in 2537 of 281004 chromosomes (23 homozygous) at a frequency of 0.009028, and was observed at the highest frequency in the South Asian population in 602 of 30476 chromosomes (freq: 0.01975) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Asn34 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein. Three in vitro functional studies have demonstrated that this variant does not affect protein expression or trypsin inhibitory activity (Kuwata_2002_PMID: 12483248; Boulling_2007_PMID: 17568390; Kiraly_2007_PMID: 17525091). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for pancreatitis.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000119030 SCV003932346 likely risk allele Hereditary pancreatitis 2023-06-15 no assertion criteria provided clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the SPINK1 protein (p.Asn34Ser). This variant is present in population databases (rs17107315, gnomAD 2.0%). 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center RCV000119030 SCV004014855 established risk allele Hereditary pancreatitis 2023-07-20 no assertion criteria provided case-control
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000119030 SCV004101105 pathogenic Hereditary pancreatitis 2023-11-02 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000119030 SCV004228974 not provided Hereditary pancreatitis no assertion provided phenotyping only Variant interpreted as Established risk allele and reported on 01-31-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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