ClinVar Miner

Submissions for variant NM_003122.4(SPINK1):c.200G>A (p.Arg67His) (rs35523678)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119161 SCV000153887 benign Hereditary pancreatitis 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119161 SCV000453727 likely benign 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000855656 SCV000605250 likely benign not specified 2018-07-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855656 SCV000698174 likely benign not specified 2019-02-11 criteria provided, single submitter clinical testing Variant summary: SPINK1 c.200G>A (p.Arg67His) results in a non-conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 276046 control chromosomes, predominantly within the African subpopulation at a frequency of 0.03 in the gnomAD database, including 8 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPINK1 causing Chronic Pancreatitis phenotype by dominant inheritance (0.00025). However, this subpopulation frequency (0.03) is only slightly higher than the maximal expected allele frequency of a recessive CPANC pathogenic SPINK1 allele (0.022). Recent research studies suggest that at least one third of recurrent acute and chronic pancreatitis results from complex genetic mechanisms (Whitcomb, NAPS2 study 2014, unpublished; GeneReviews), commonly complex multi-gene variants in SPINK1/CFTR. The majority of kindreds with familial pancreatitis without risk associated with a single locus (e.g., PRSS1, CFTR, or SPINK1) are small, with two to four affected individuals. These families and simplex cases (i.e. a single occurrence in a family) are increasingly found to have complex, multi-genic, or gene-environmental disorders with a variable number of germline pathogenic variants in genes that affect trypsin regulation. Therefore, it is difficult to establish the mode of inheritance or an accurate estimate of the maximal expected allele frequency for pathogenic SPINK1 variants. Additionally, in the United States, Europe, and India, a high-risk haplotype containing SPINK1 p.Asn34Ser (NM_003122.3:c.101A>G) is common, with a minor allele frequency as high as 3% (Gene Reviews), suggesting that an allele frequency of 3% for this missense variant, as observed in the African gnomAD subpopulation, should not automatically rule out pathogenicity. c.200G>A has been reported in the literature in individuals affected with chronic or acute recurrent pancreatitis (Werlin 2014, Boulling 2012, Giefer 2017, Jalaly 2017). These reports however, do not provide unequivocal conclusions about association of the variant with the disease. At least two publications reported experimental evidence evaluating the variant impact, and demonstrated no splice change or mRNA expression level alteration (Wu 2017), but loss of PST1 protein (encoded by SPINK1) via Western blotting; however, authors used a monoclonal antibody in these expression studies which might be subject to loss of binding with certain amino acid alterations, so the reduction in PST1 levels based on this experiment alone could not be accurately assessed (Boulling 2012). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign, until additional information becomes available.
Mendelics RCV000119161 SCV001136989 benign Hereditary pancreatitis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001014025 SCV001174682 benign Inborn genetic diseases 2015-12-28 criteria provided, single submitter clinical testing

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