VCV000013760.80 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(28)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity; association; risk factor
Pathogenic(10); Likely pathogenic(2); Established risk allele(1); Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 13760 Accession: VCV000013760.80

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q32 5: 147828115 (GRCh38) [ NCBI UCSC ] 5: 147207678 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	Nov 24, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001379610.1:c.101A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001366539.1:p.Asn34Ser	missense
NM_001354966.1:c.101A>G
NM_001354966.2:c.101A>G	NP_001341895.1:p.Asn34Ser	missense
NM_003122.5:c.101A>G	NP_003113.2:p.Asn34Ser	missense
NC_000005.10:g.147828115T>C
NC_000005.9:g.147207678T>C
NG_008356.2:g.16117A>G
	P00995:p.Asn34Ser

... more HGVS ... less HGVS

Protein change

N34S

Other names

Canonical SPDI

NC_000005.10:147828114:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00639 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00639

Trans-Omics for Precision Medicine (TOPMed) 0.00661

The Genome Aggregation Database (gnomAD) 0.00797

The Genome Aggregation Database (gnomAD), exomes 0.00906

Exome Aggregation Consortium (ExAC) 0.00987

1000 Genomes Project 30x 0.00625

Links

ClinGen: CA123440 Genetic Testing Registry (GTR): GTR000556585 UniProtKB: P00995#VAR_011689 OMIM: 167790.0001 dbSNP: rs17107315 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SPINK1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	203	224

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Pancreatitis, chronic, susceptibility to	Uncertain significance (1)	no assertion criteria provided	Oct 1, 2002	RCV000014768.16
Hereditary pancreatitis	Conflicting interpretations of pathogenicity; association; risk factor (20)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000119030.55
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000656981.44
Finnish congenital nephrotic syndrome	Likely benign (1)	criteria provided, single submitter	-	RCV001258230.11
Pancreatitis	Likely risk allele (1)	no assertion criteria provided	-	RCV002468556.9
Tropical pancreatitis	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV002283443.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 31, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577224.4 First in ClinVar: May 22, 2017 Last updated: Jul 09, 2018	Comment: 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 … (more) 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. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Finnish congenital nephrotic syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435136.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (13) PubMed: 10835640‚ 19888199‚ 22995991‚ 17568390‚ 19565042‚ 17525091‚ 12483248‚ 21303407‚ 23951356‚ 24844923‚ 23741238‚ 21375584‚ 25010710 Comment: 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 … (more) 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. (less)
Pathogenic (Aug 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366803.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: 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.
Pathogenic (Nov 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522929.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Nov 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001736855.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Number of individuals with the variant: 1 Clinical Features: Delayed speech and language development (present) , Pancreatitis (present) , Recurrent fever (present) , Abdominal pain (present) , Lymphadenopathy (present) , Episodic fatigue (present) , … (more) Delayed speech and language development (present) , Pancreatitis (present) , Recurrent fever (present) , Abdominal pain (present) , Lymphadenopathy (present) , Episodic fatigue (present) , Chronic constipation (present) , Lower limb pain (present) , Abnormal inflammatory response (present) , Halitosis (present) , Recurrent ear infections (present) , Premature birth (present) , Tachypnea (present) , Prolonged neonatal jaundice (present) , Maternal hypertension (present) , Gestational diabetes (present) , Whooping cough (present) (less) Family history: yes Age: 0-9 years Sex: male Ethnicity/Population group: Caucasians Tissue: blood
Likely pathogenic (Mar 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tropical pancreatitis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836313.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Likely pathogenic (Dec 01, 2022)	criteria provided, single submitter (Accession Criteria ClinVar Biomnis) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	Eurofins-Biomnis Accession: SCV003935033.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023
Pathogenic (Nov 28, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605239.8 First in ClinVar: May 22, 2017 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. (less)
Uncertain significance (May 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048160.4 First in ClinVar: Oct 28, 2023 Last updated: Nov 24, 2024	Comment: The missense c.101A>G(p.Asn34Ser) variant in SPINK1 gene has been reported previously in heterozygous as well as homozygous state in multiple individuals affected with chronic pancreatitis … (more) The missense c.101A>G(p.Asn34Ser) variant in SPINK1 gene has been reported previously in heterozygous as well as homozygous state in multiple individuals affected with chronic pancreatitis (Witt H et al., 2007). This variant has been reported with the allele frequency of 0.9% in the gnomAD Exomes database. This variant has been submitted to the ClinVar database with Likely Benign / Uncertain Significance / Established risk allele / Likely pathogenic / Pathogenic. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid Asn at position 34 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Though functional studies have not proven a damaging effect, the variant is enriched in patients with pancreatitis as compared to the general population (Király O et al., 2007,Rosendahl J et al. ,2013 ). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of pancreatitis. (less) Clinical Features: Abnormality of the endocrine system (present)
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782314.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136991.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001316926.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (5) PubMed: 12011155‚ 12187509‚ 12629264‚ 12853682‚ 10835640 Comment: 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, … (more) 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. (less)
Pathogenic (Jun 08, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000053127.4 First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2020	Publications: PubMed (17) PubMed: 18286680‚ 28609377‚ 28556356‚ 25206283‚ 24522117‚ 12187509‚ 23951356‚ 22749696‚ 22427236‚ 12011155‚ 19453252‚ 17525091‚ 10835640‚ 10691414‚ 17204147‚ 16885867‚ 12743777 Comment: 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 … (more) 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. (less)
risk factor (Mar 12, 2021)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967008.2 First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021	Publications: PubMed (8) PubMed: 12483248‚ 10835640‚ 28556356‚ 18414673‚ 17568390‚ 28546062‚ 28984793‚ 17525091 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 1
Established risk allele (Mar 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002505611.1 First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022	Publications: PubMed (1) PubMed: 34828289 Comment: 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, … (more) 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 (less)
Pathogenic (May 24, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002535378.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The SPINK1 c.101A>G (p.N34S) variant has been reported in the compound heterozygous and homozygous state in numerous patients with chronic pancreatitis (PMID: 10835640, 12011155, 25206283). … (more) The SPINK1 c.101A>G (p.N34S) variant has been reported in the compound heterozygous and homozygous state in numerous patients with chronic pancreatitis (PMID: 10835640, 12011155, 25206283). A meta-analysis in European individuals (2981 cases and 5819 controls from 25 studies) showed that p.N34S variant carriers are at increased risk for chronic pancreatitis [OR 9.695 (CI 95% 7.931-11.851)]. However, multiple functional studies failed to show that this p.N34S missense change disrupted any known function of the SPINK1 protein (PMID: 12483248, 17525091, 17568390). This variant was observed in 602/30476 chromosomes in the South Asian population, with 6 homozygotes and 23 homozygotes among all ethnicities, according to the Genome Aggregation Database (PMID: 27535533) and has been reported in ClinVar (Variation ID: 13760). In summary, the SPINK1 c.101A>G (p.N34S) variant is a relatively common variant associated with a significant risk for developing chronic pancreatitis. Based on the current evidence available, this variant is interpreted as an established risk allele. (less)	Publications: PubMed (6) PubMed: 10835640‚ 12011155‚ 25206283‚ 12483248‚ 17525091‚ 17568390
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tropical pancreatitis Affected status: yes Allele origin: germline	3billion Accession: SCV002572766.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (4) PubMed: 11950815‚ 12187509‚ 22427236‚ 10835640 Comment: 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. … (more) 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. (less) Clinical Features: Recurrent pancreatitis (present) , Chronic pancreatitis (present) , Acute pancreatitis (present) , Pancreatitis (present)
association (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000252902.12 First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 28492532‚ 17466744‚ 23951356‚ 10835640‚ 12483248‚ 17568390‚ 17525091‚ 19299380 Comment: 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). … (more) 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. (less)
Pathogenic (Aug 21, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001169814.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 10835640‚ 18617776‚ 22427236‚ 23951356 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248360.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: SPINK1: PP1:Strong, PS1, PS4, PP4:Moderate, BP4 Number of individuals with the variant: 8
Uncertain significance (Oct 01, 2002)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035023.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017	Publications: PubMed (5) PubMed: 27535533‚ 10835640‚ 12187509‚ 12011155‚ 12483248 Comment on evidence: This variant, formerly titled PANCREATITIS, CHRONIC, SUSCEPTIBILITY TO, has been reclassified based on the report of Lek et al. (2016). Witt et al. (2000) studied … (more) This variant, formerly titled PANCREATITIS, CHRONIC, SUSCEPTIBILITY TO, has been reclassified based on the report of Lek et al. (2016). Witt et al. (2000) studied 96 children and adolescents with chronic pancreatitis (167800) and in 18 found an asn34-to-ser (N34S) missense mutation in the SPINK1 gene. In 6 of the patients, the mutation was homozygous. In 279 healthy controls, only 1 individual was heterozygous for the N34S mutation, and no homozygous individuals were found. To exclude compound heterozygosity in the 12 individuals heterozygous for the N34S mutation, Witt et al. (2000) analyzed the complete intronic sequence of the SPINK1 gene after long-range PCR. Using family-based and case-control methods, Hassan et al. (2002) found a striking association between N34S and fibrocalculous pancreatic diabetes on the Indian subcontinent, with the variant being present in 33% of 180 subjects with FCPD, compared with 4.4% of 861 subjects without diabetes (odds ratio, 10.8; CI 6.9-17.0). Hassan et al. (2002) concluded that the N34S variant of SPINK1 confers susceptibility to FCPD, but does not appear to be sufficient by itself to cause the disease. Chandak et al. (2002) confirmed the causal role of the N34S mutation in pancreatitis and simultaneously established the role of mutated inhibitor in the pathogenesis of tropical calcific pancreatitis (608189). Of 31 patients with the N34S mutation, 8 were homozygous, 22 heterozygous, and 1 compound heterozygous for N34S and another mutation in the SPINK1 gene. Three patients were compound heterozygous for N34S and a -215G-T promoter mutation (167790.0004). Analysis of the phenotype in terms of the age at onset, frequency of attacks, and presence and age at onset of diabetes mellitus did not show any significant difference between patients heterozygous or homozygous for the N34S mutation. Kuwata et al. (2002) performed biochemical analysis of recombinant wildtype and N34S SPINK1. The function of mutant SPINK1 protein remained unchanged from that of wildtype under both the usual alkaline and acidic conditions. Calcium concentration did not affect the activity of N34S, and N34S protein showed no increased susceptibility to trypsin. Kuwata et al. (2002) concluded that a mechanism other than a conformational change of N34S SPINK1, such as abnormal splicing, may underlie the predisposition to pancreatitis associated with this mutation. Lek et al. (2016) noted that the N34S variant has a high allele frequency (0.0219) in the South Asian population in the ExAC database, suggesting that it is not pathogenic. (less)
Likely risk allele (-)	no assertion criteria provided Method: research	Pancreatitis Affected status: unknown Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV002764629.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: 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 … (more) 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. (less)
Likely risk allele (Jun 15, 2023)	no assertion criteria provided Method: clinical testing	Hereditary pancreatitis (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV003932346.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: 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). … (more) 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. (less) Age: 30-39 years Sex: female
Established risk allele (Jul 20, 2023)	no assertion criteria provided Method: case-control	Hereditary pancreatitis (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center Accession: SCV004014855.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023
Pathogenic (Nov 02, 2023)	no assertion criteria provided Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004101105.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023
not provided (-)	no classification provided Method: phenotyping only	Hereditary pancreatitis Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607175.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017	Comment: 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 … (more) 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. (less) Clinical Features: Myopia (present) , Depression (present) , Anxiety (present) , Abnormality of the pancreas (present) Age: 30-39 years Sex: female Testing laboratory: Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center,Mayo Clinic Date variant was reported to submitter: 2017-04-13 Testing laboratory interpretation: risk factor
not provided (-)	no classification provided Method: literature only	Hereditary pancreatitis Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000153734.3 First in ClinVar: May 31, 2014 Last updated: Oct 01, 2022	Publications: BookShelf: NBK190101 BookShelf: NBK190101
not provided (-)	no classification provided Method: phenotyping only	Hereditary pancreatitis Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228974.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: 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 … (more) 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. (less) Clinical Features: Neoplasm of the pancreas (present) Indication for testing: Diagnostic Age: 70-79 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2020-01-31 Testing laboratory interpretation: Established risk allele
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The missense c.101A>G(p.Asn34Ser) variant in SPINK1 gene has been reported previously in heterozygous as well as homozygous state in multiple individuals affected with chronic pancreatitis (Witt H et al., 2007). This variant has been reported with the allele frequency of 0.9% in the gnomAD Exomes database. This variant has been submitted to the ClinVar database with Likely Benign / Uncertain Significance / Established risk allele / Likely pathogenic / Pathogenic. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid Asn at position 34 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Though functional studies have not proven a damaging effect, the variant is enriched in patients with pancreatitis as compared to the general population (Király O et al., 2007,Rosendahl J et al. ,2013 ). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of pancreatitis.

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large.	Pu N	Genes	2021	PMID: 34828289
Pancreatitis Overview.	Adam MP	-	2020	PMID: 24624459
SPINK1 Gene is Significantly Associated With Pancreatitis: A Comprehensive Meta-Analysis.	Liu J	Pancreas	2017	PMID: 28984793
Pancreatic Cancer Cell Lines Heterozygous for the SPINK1 p.N34S Haplotype Exhibit Diminished Expression of the Variant Allele.	Kereszturi É	Pancreas	2017	PMID: 28609377
Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype.	Boulling A	Human mutation	2017	PMID: 28556356
Meta-analysis of the impact of SPINK1 p.N34S gene variation in Caucasic patients with chronic pancreatitis. An update.	Di Leo M	Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver	2017	PMID: 28546062
Analysis of protein-coding genetic variation in 60,706 humans.	Lek M	Nature	2016	PMID: 27535533
PRSS1 and SPINK1 mutations in idiopathic chronic and recurrent acute pancreatitis.	Pelaez-Luna M	World journal of gastroenterology	2014	PMID: 25206283
Pedigree of a kindred with Transheterozygous PRSS1 R122C and SPINK1 N34S mutations.	Sinha A	Pancreas	2014	PMID: 25010710
Frequency of SPINK1 N34S mutation in acute and recurrent acute pancreatitis.	Rai P	Journal of hepato-biliary-pancreatic sciences	2014	PMID: 24844923
Genetics of pancreatitis: the 2014 update.	Masamune A	The Tohoku journal of experimental medicine	2014	PMID: 24522117
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.	Masson E	PloS one	2013	PMID: 23951356
Two cases of chronic pancreatitis associated with anomalous pancreaticobiliary ductal union and SPINK1 mutation.	Rho ES	Korean journal of pediatrics	2013	PMID: 23741238
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?	Rosendahl J	Gut	2013	PMID: 22427236
Genetics and pathogenesis of chronic pancreatitis: the 2012 update.	Chen JM	Clinics and research in hepatology and gastroenterology	2012	PMID: 22749696
Presence of SPINK-1 variant alters the course of chronic pancreatitis.	Sandhu B	Journal of gastroenterology and hepatology	2011	PMID: 21375584
Genetic background is different between sentinel and recurrent acute pancreatitis.	Masamune A	Journal of gastroenterology and hepatology	2011	PMID: 21303407
SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event.	Aoun E	The American journal of gastroenterology	2010	PMID: 19888199
Investigation of the SPINK1 N34S mutation in Romanian patients with alcoholic chronic pancreatitis. A clinical analysis based on the criteria of the M-ANNHEIM classification.	Diaconu BL	Journal of gastrointestinal and liver diseases : JGLD	2009	PMID: 19565042
Chronic pancreatitis: genetics and pathogenesis.	Chen JM	Annual review of genomics and human genetics	2009	PMID: 19453252
The true culprit within the SPINK1 p.N34S-containing haplotype is still at large.	Chen JM	Gut	2009	PMID: 19299380
The SPINK1 N34S variant is associated with acute pancreatitis.	O'Reilly DA	European journal of gastroenterology & hepatology	2008	PMID: 18617776
Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.	Aoun E	PloS one	2008	PMID: 18414673
Role of genetic disorders in acute recurrent pancreatitis.	Keim V	World journal of gastroenterology	2008	PMID: 18286680
Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene.	Boulling A	European journal of human genetics : EJHG	2007	PMID: 17568390
Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation.	Király O	Gut	2007	PMID: 17525091
Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy.	Witt H	Gastroenterology	2007	PMID: 17466744
Hereditary chronic pancreatitis.	Rosendahl J	Orphanet journal of rare diseases	2007	PMID: 17204147
Estimation of the prevalence and incidence of chronic pancreatitis and its complications.	Lévy P	Gastroenterologie clinique et biologique	2006	PMID: 16885867
The course of genetically determined chronic pancreatitis.	Keim V	JOP : Journal of the pancreas	2003	PMID: 12853682
Mutational analysis of the pancreatic secretory trypsin inhibitor gene in familial and juvenile pancreatitis in Japan.	Kuwata K	Journal of gastroenterology	2003	PMID: 12743777
From acute to chronic pancreatitis: the role of mutations in the pancreatic secretory trypsin inhibitor gene.	Hirota M	JOP : Journal of the pancreas	2003	PMID: 12629264
Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution.	Kuwata K	Journal of gastroenterology	2002	PMID: 12483248
SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent.	Hassan Z	American journal of human genetics	2002	PMID: 12187509
Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis.	Chandak GR	Journal of medical genetics	2002	PMID: 12011155
The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease.	Threadgold J	Gut	2002	PMID: 11950815
Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.	Witt H	Nature genetics	2000	PMID: 10835640
Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis.	Chen JM	Journal of medical genetics	2000	PMID: 10691414
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Text-mined citations for rs17107315 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

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Conditions - Germline

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Citations for germline classification of this variant

Text-mined citations for rs17107315 ...