ClinVar Miner

Submissions for variant NM_002769.5(PRSS1):c.346C>T (p.Arg116Cys) (rs387906698)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000936 SCV001158034 pathogenic not specified 2018-11-29 criteria provided, single submitter clinical testing The PRSS1 c.346C>T; p.Arg116Cys variant (rs387906698), is reported in the literature in multiple individuals and families affected with pancreatitis (Kereszturi 2009, Kurian 2014, see link to Chronic Pancreatitis database and references therein). This variant is reported in ClinVar (Variation ID: 29923), and is found in the East Asian population with an allele frequency of 0.070% (14/19,950 alleles) in the Genome Aggregation Database. The arginine at codon 116 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show misfolding and intracellular retention, leading to endoplasmic reticular stress (Kereszturi 2009). Based on available information, the p.Arg116Cys variant is considered to be pathogenic. References: Link to Genetic Risk Factors in Chronic Pancreatitis database: http://pancreasgenetics.org/e107_plugins/aacgc_itemlist/Item_List.php?det.1 Kereszturi E et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009 Apr;30(4):575-82. Kurian AW et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014 Jul 1;32(19):2001-9.
Invitae RCV000022814 SCV001218550 likely pathogenic Hereditary pancreatitis 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 116 of the PRSS1 protein (p.Arg116Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs387906698, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with hereditary pancreatitis in several families (PMID: 15786540, 20502448, 19191323). It has also been observed in many individuals affected with pancreatitis (PMID: 11708864, 24909264, 19433603, 30420730, 11842279). ClinVar contains an entry for this variant (Variation ID: 29923). This variant has been reported to affect PRSS1 protein function (PMID: 19191323). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000022814 SCV000044103 pathogenic Hereditary pancreatitis 2009-04-01 no assertion criteria provided literature only
GeneReviews RCV000022814 SCV000054557 pathologic Hereditary pancreatitis 2012-03-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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