ClinVar Miner

Submissions for variant NM_003122.4(SPINK1):c.194G>A (p.Arg65Gln) (rs141634296)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030459 SCV000053129 uncertain Hereditary pancreatitis 2011-08-18 criteria provided, single submitter curation Converted during submission to Uncertain significance.
Invitae RCV000030459 SCV000551548 uncertain significance Hereditary pancreatitis 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 65 of the SPINK1 protein (p.Arg65Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. It also falls at the last nucleotide of exon 4 of the SPINK1 coding sequence. This variant is present in population databases (rs141634296, ExAC 0.08%). This variant has been reported in individuals affected with idiopathic chronic pancreatitis (PMID: 11368029, 23951356, 17003641,22427236), as well as unaffected family members (PMID: 11368029). ClinVar contains an entry for this variant (Variation ID: 36779). Experimental studies have shown that when cDNA containing this variant is expressed in cell culture, the resulting variant protein is present at lower levels (~40-50%) than the wildtype protein (PMID: 17525091, 17568390). This data suggests that this variant may result in a partial reduction of SPINK1 expression in the pancreas. Two experimental studies evaluating the impact of this variant on mRNA splicing have reported conflicting results (PMID: 24052272, 28320769). In summary, this variant is a rare missense change that results in decreased expression of the SPINK1 protein in cell culture. However, it is unclear from the genetic and functional data found in the literature if this decrease results in an increased risk for pancreatitis. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506401 SCV000605247 uncertain significance not specified 2018-12-11 criteria provided, single submitter clinical testing The SPINK1 c.194G>A; p.Arg65Gln variant (rs141634296) is reported in the literature in individuals diagnosed with chronic pancreatitis (Keiles 2006, Ockenga 2001, Rosendahl 2013). This variant is reported as uncertain in ClinVar (Variation ID: 36779), and is found in the general population with an overall allele frequency of 0.055% (154/280,326 alleles) in the Genome Aggregation Database. The arginine at residue 65 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant is tolerated. Functional characterization of the variant indicates a reduced production and secretion of the SPINK1 mRNA and protein, resulting in reduced overall enzymatic activity (Boulling 2007, Beer 2014, Kiraly 2007). However, the variant has also been described as a reduced penetrance allele based on familial segregation (Ockenga 2001). Due to the conflicting information, the clinical significance of the p.Arg65Gln variant is uncertain at this time. References: Beer S et al. Exonic variants affecting pre-mRNA splicing add to genetic burden in chronic pancreatitis. Gut. 2014 May;63(5):860-1. Boulling A et al. Functional analysis of eight missense mutations in the SPINK1 gene. Pancreas. 2012 Mar;41(2):329-30. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Kiraly O et al. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut. 2007 Oct;56(10):1433-8. Ockenga J et al. Low prevalence of SPINK1 gene mutations in adult patients with chronic idiopathic pancreatitis. J Med Genet. 2001 Apr;38(4):243-4. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92.
Integrated Genetics/Laboratory Corporation of America RCV000589789 SCV000698170 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The SPINK1 c.194G>A (p.Arg65Gln) variant involves the alteration of a non-conserved nucleotide, which is the last nucleotide of exon 3. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict that this variant may slightly weaken the 5' splicing donor site. ESE finder predicts that this variant does not affect any ESE site. In vitro study has shown that this variant does not affect normal splicing (Ockenga_2001). This variant was found in 49/104188 control chromosomes at a frequency of 0.0004703, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SPINK1 variant (0.00025), suggesting this variant is likely a benign polymorphism. This variant has been reported in chronic pancreatitis patients who also carry other pathogenic variants, suggesting this variant is not associated with the disease. Although some functional studies showed this variant causes decrease of SPINK1 protein expression (Boulling_2007, Beer_2014), other studies showed conflicting effect of this variant on the trypsin inhibitory activity of SPINK1 or splicing assays (Ockenga_2001, Kiraly_2007, Beer_2014). One internal sample carrying this variant also carries another known risk variant p.N34S, supporting for a possible benign outcome. Reliable case-control studies are required as to know whether this variant is a risk factor. Taken together, this variant is classified as VUS-possibly benign.
Ambry Genetics RCV001013719 SCV001174342 uncertain significance Inborn genetic diseases 2019-10-18 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Insufficient or conflicting evidence;Last nucleotide of exon;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Illumina Clinical Services Laboratory,Illumina RCV000030459 SCV001316924 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.

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