ClinVar Genomic variation as it relates to human health
NM_007272.3(CTRC):c.649G>C (p.Gly217Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007272.3(CTRC):c.649G>C (p.Gly217Arg)
Variation ID: 420177 Accession: VCV000420177.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.21 1: 15445606 (GRCh38) [ NCBI UCSC ] 1: 15772101 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 May 1, 2024 Oct 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007272.3:c.649G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009203.2:p.Gly217Arg missense NC_000001.11:g.15445606G>C NC_000001.10:g.15772101G>C NG_009253.1:g.12164G>C - Protein change
- G217R
- Other names
- p.Gly217Arg
- Canonical SPDI
- NC_000001.11:15445605:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CTRC | - | - |
GRCh38 GRCh37 |
603 | 632 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2023 | RCV000483666.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 30, 2023 | RCV001856839.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568860.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The G217R variant in the CTRC gene has been reported previously in at least two individuals with chronic pancreatitis (Rosendahl et al., 2008; Masson et … (more)
The G217R variant in the CTRC gene has been reported previously in at least two individuals with chronic pancreatitis (Rosendahl et al., 2008; Masson et al., 2008). Functional studies demonstrate that this variant results in decreased protein and enzyme activity, as well as trypsin degradation (Beer et al., 2013). The G217R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). 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, and occurs at a position that is conserved across species. A different missense variant at the same codon (G217S) has been previously reported in association with chronic pancreatitis (Masson et al., 2008; Beer et al., 2013; Rosendahl et al., 2013), supporting the functional importance of this position within the protein. We interpret G217R as a pathogenic variant. (less)
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Uncertain significance
(Oct 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002122776.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the CTRC protein (p.Gly217Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the CTRC protein (p.Gly217Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 18059268, 18172691, 20625975, 21631589, 22942235). ClinVar contains an entry for this variant (Variation ID: 420177). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTRC protein function. Experimental studies have shown that this missense change affects CTRC function (PMID: 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. (less)
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Likely pathogenic
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226712.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2, PM5, PS3
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002655539.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G217R pathogenic mutation (also known as c.649G>C), located in coding exon 7 of the CTRC gene, results from a G to C substitution at … (more)
The p.G217R pathogenic mutation (also known as c.649G>C), located in coding exon 7 of the CTRC gene, results from a G to C substitution at nucleotide position 649. The glycine at codon 217 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with chronic pancreatitis, but not in control subjects (Rosendahl J et al. Nat Genet, 2008 Jan;40:78-82; Masson E et al. Hum Genet, 2008 Feb;123:83-91; Beer S et al. Gut, 2013 Nov;62:1616-24). The alteration was detected in conjunction with a second alteration in CTRC (Masson E et al. Hum Genet, 2008 Feb;123:83-91; Masson E et al. PLoS One, 2013 Aug;8:e73522). In vitro studies showed that the amino acid substitution results in reduced secretion and catalytic activity and increased trypsin-mediated degradation of the CTRC protein (Beer S et al. Gut, 2013 Nov;62:1616-24). Another alteration at the same codon, p.G217S (c.649G>A), has been detected in individuals with chronic pancreatitis and shown to result in similar deficient protein function (Rosendahl J et al. Nat Genet, 2008 Jan;40:78-82; Masson E et al. Hum Genet, 2008 Feb;123:83-91; Rosendahl J et al. Gut, 2013 Apr;62:582-92; Beer S et al. Gut, 2013 Nov;62:1616-24; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204). Internal structural analysis revealed that p.G217R destabilizes the protein structure (Pignol D et al. EMBO J, 1994 Apr;13:1763-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic, but may represent a risk factor. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical interpretation of SPINK1 and CTRC variants in pancreatitis. | Girodon E | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] | 2020 | PMID: 32948427 |
A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. | Masson E | PloS one | 2013 | PMID: 23951356 |
Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. | Beer S | Gut | 2013 | PMID: 22942235 |
Chymotrypsin C mutations in chronic pancreatitis. | Zhou J | Journal of gastroenterology and hepatology | 2011 | PMID: 21631589 |
Multifactorial genesis of pancreatitis in primary hyperparathyroidism: evidence for "protective" (PRSS2) and "destructive" (CTRC) genetic factors. | Felderbauer P | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2011 | PMID: 20625975 |
Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. | Masson E | Human genetics | 2008 | PMID: 18172691 |
Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. | Rosendahl J | Nature genetics | 2008 | PMID: 18059268 |
Crystal structure of bovine procarboxypeptidase A-S6 subunit III, a highly structured truncated zymogen E. | Pignol D | The EMBO journal | 1994 | PMID: 8168476 |
Text-mined citations for rs202058123 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.