rs515726209
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3PP5BP4BS2
The NM_007272.3(CTRC):c.217G>A(p.Ala73Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,613,966 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A73S) has been classified as Uncertain significance.
Frequency
Consequence
NM_007272.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTRC | NM_007272.3 | c.217G>A | p.Ala73Thr | missense_variant | 3/8 | ENST00000375949.5 | |
CTRC | XM_011540550.2 | c.217G>A | p.Ala73Thr | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTRC | ENST00000375949.5 | c.217G>A | p.Ala73Thr | missense_variant | 3/8 | 1 | NM_007272.3 | P1 | |
CTRC | ENST00000375943.6 | c.41-1870G>A | intron_variant | 1 | |||||
CTRC | ENST00000483406.1 | n.127G>A | non_coding_transcript_exon_variant | 2/6 | 5 | ||||
CTRC | ENST00000476813.5 | n.53-1870G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152186Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000665 AC: 167AN: 251050Hom.: 1 AF XY: 0.000899 AC XY: 122AN XY: 135702
GnomAD4 exome AF: 0.000309 AC: 451AN: 1461662Hom.: 6 Cov.: 34 AF XY: 0.000443 AC XY: 322AN XY: 727114
GnomAD4 genome AF: 0.000177 AC: 27AN: 152304Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74468
ClinVar
Submissions by phenotype
Hereditary pancreatitis Pathogenic:4Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the CTRC protein (p.Ala73Thr). This variant is present in population databases (rs515726209, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 18059268, 18172691, 22580415, 25569187). ClinVar contains an entry for this variant (Variation ID: 132149). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTRC function (PMID: 18059268, 22942235, 26022124). 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. - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Mar 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | The CTRC c.217G>A; p.Ala73Thr variant (rs515726209) is reported in the literature in multiple individuals affected with chronic pancreatitis (Beer 2013, LaRusch 2015, Masson 2008, Paliwal 2013, Rosendahl 2008). While this variant has also been observed in healthy controls, case-control studies reproducibly demonstrate enrichment in affected individuals with odds ratios >8.0 (Beer 2013, Paliwal 2013, Rosendahl 2008). This variant is found in the South Asian population with an overall allele frequency of 0.53% (163/30556 alleles, including one homozygote) in the Genome Aggregation Database; however, most affected individuals with this variant are reported to be of South Asian descent (Beer 2013, Paliwal 2013, Rosendahl 2008). Functional studies of the p.Ala73Thr variant suggest that the variant protein has normal enzymatic activity but is poorly secreted from cells, resulting in retention, degradation, and increased activation of endoplasmic reticulum stress and apoptotic cascades (Beer 2013, Rosendahl 2008, Szmola 2010). Based on available information, this variant is considered to be pathogenic. References: Beer S et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut. 2013 Nov;62(11):1616-24. PMID: 22942235. LaRusch J et al. The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol. 2015 Jan 8;6:e68. PMID: 25569187. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. PMID: 18172691. Paliwal S et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2013 Nov;62(11):1602-6. PMID: 22580415. Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008 Jan;40(1):78-82. PMID: 18059268. Szmola R and Sahin-Toth M. Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells. Gut. 2010 Mar;59(3):365-72. PMID: 19951900. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 2023 | The p.A73T variant (also known as c.217G>A), located in coding exon 3 of the CTRC gene, results from a G to A substitution at nucleotide position 217. The alanine at codon 73 is replaced by threonine, an amino acid with similar properties. In one study, this variant was identified in 5/71 individuals with tropical pancreatitis and 0/84 healthy controls; expression of this variant in HEK293T cells showed diminished secretion relative to wild type (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82). In another study, this variant was associated with a significant odds ratio (OR 8.2, CI 2.5-27.5) for pancreatitis in the Indian population. In addition, functional studies in HEK293T cells demonstrated a defect in secretion of protein bearing this alteration, a small decrease in catalytic efficiency, and that the protein was resistant to degradation (Beer S et al. Gut, 2013 Nov;62:1616-24). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at