ClinVar Miner

Submissions for variant NM_007272.3(CTRC):c.649G>A (p.Gly217Ser) (rs202058123)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493312 SCV000583028 likely pathogenic not provided 2016-04-07 criteria provided, single submitter clinical testing The G217S variant in the CTRC gene has previously been reported in association with chronic pancreatitis (Masson et al., 2008; Beer et al., 2013; Rosendahl et al., 2013). However, G217S has also been observed in unaffected control individuals, suggesting incomplete penetrance (Beer et al., 2013; Rosendahl et al., 2013). Functional studies show G217S leads to catalytic deficiency, as well as trypsin degradation (Rosendahl et al., 2008; Beer et al., 2013). The G217S variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. A missense variant at the same residue (G217R), as well as nearby residues (G214R, L220R) have been reported in the Human Gene Mutation Database in association with CTRC-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, G217S is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000493312 SCV000883700 pathogenic not provided 2017-11-12 criteria provided, single submitter clinical testing
Invitae RCV000801338 SCV000941112 uncertain significance Hereditary pancreatitis 2019-07-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 217 of the CTRC protein (p.Gly217Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs202058123, ExAC 0.03%). This variant has been observed in several individuals affected with chronic pancreatitis (PMID: 18172691, 22427236, 22942235, 18059268, 23951356) as well as in several control individuals (PMID: 22427236, 22942235, 18059268). ClinVar contains an entry for this variant (Variation ID: 430258). Experimental studies have shown that this missense change impairs the catalytic activity and modestly decreases the secretion of the CTRC protein (PMID: 18059268, 22942235). 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.
Ambry Genetics RCV001025335 SCV001187507 pathogenic Inborn genetic diseases 2018-08-03 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence

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