ClinVar Miner

Submissions for variant NM_003122.4(SPINK1):c.198A>C (p.Lys66Asn) (rs143014431)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476237 SCV000551551 uncertain significance Hereditary pancreatitis 2018-01-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 66 of the SPINK1 protein (p.Lys66Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs143014431, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with pancreatitis (PMID: 17003641). ClinVar contains an entry for this variant (Variation ID: 410699). An experimental study has shown that this missense change results in a complete loss of SPINK1 protein expression in cell culture (PMID: 22343981). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000780756 SCV000918270 uncertain significance not specified 2018-11-01 criteria provided, single submitter clinical testing Variant summary: SPINK1 c.198A>C (p.Lys66Asn) results in a non-conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 276004 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6-fold of the estimated maximal expected allele frequency for a pathogenic variant in SPINK1 causing Chronic Pancreatitis phenotype (0.00025), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.198A>C, has been reported in the literature in individuals affected with Chronic Pancreatitis (Keiles 2006, Giefer 2017), without strong evidence for pathogenicity. These data however do not allow any conclusion about variant significance. Co-occurrence with another pathogenic variant has been reported in one of these reports (SPINK1 c.101A>G (p.Asn34Ser); Giefer 2017). One study reported a complete loss of expression of the protein product encoding the SPINK1 gene (PTS1) in human embryonic kidney 293T cells transfected with a mutant construct bearing this variant (Bouling 2012). The authors speculate that the possibility of reduced or lack of binding activity of the mutant protein to the monoclonal anti-hPST1 antibody used in their experimental system cannot be ruled out (Boulling 2007). Contradicting this observation, another study reported no difference in splicing or mRNA expression associated with this variant when compared to the wild type (Wu 2017). Therefore the functional evidence surrounding this variant is conflicting with authorship overlap between reported studies and later reports (Wu 2017) not citing the previous report (Boulling 2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a variant of uncertain significance.
Ambry Genetics RCV001013930 SCV001174574 pathogenic Inborn genetic diseases 2018-10-12 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation

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