1-15440577-G-A

Position:

• chr1-15440577-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3 PP5 BP4 BS2

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:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (6 hom.)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.60

Genes affected

CTRC (HGNC:2523): (chymotrypsin C) This gene encodes a member of the peptidase S1 family. The encoded protein is a serum calcium-decreasing factor that has chymotrypsin-like protease activity. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

CTRC (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-15440577-G-A is Pathogenic according to our data. Variant chr1-15440577-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132149.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33665124). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRC	NM_007272.3	c.217G>A	p.Ala73Thr	missense_variant	3/8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2	c.217G>A	p.Ala73Thr	missense_variant	3/7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTRC	ENST00000375949.5	c.217G>A	p.Ala73Thr	missense_variant	3/8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000375943.6	c.41-1870G>A		intron_variant		1		ENSP00000365110.2
CTRC	ENST00000483406.1	n.127G>A		non_coding_transcript_exon_variant	2/6	5
CTRC	ENST00000476813.5	n.53-1870G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000665 AC: 167 AN: 251050 Hom.: 1 AF XY: 0.000899 AC XY: 122 AN XY: 135702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00533

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461662 Hom.: 6 Cov.: 34 AF XY: 0.000443 AC XY: 322 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00485

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000332 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:5 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense c.217G>A(p.Ala73Thr) variant in CTRC gene has been reported previously in multiple individuals affected with pancreatitis (Beer S, et al., 2013; Paliwal S, et al., 2013; Rosendahl J, et al., 2008). Functional studies demonstrate that this variant poorly secretes from cells, resulting in retention, degradation, and increased activation of endoplasmic reticulum stress and apoptotic cascades, suggesting a deleterious effect (Binker MG, et al., 2015; Szmola R & Sahin-Tóth M., 2010). The p.Ala73Thr variant has been reported with allele frequency of 0.05% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 73 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
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, no assertion criteria provided	literature only	GeneReviews	Mar 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 08, 2024	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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.97		Loss of stability (P = 0.0776);
MVP		0.90
MPC		0.73
ClinPred		0.34	T
GERP RS		5.0
Varity_R		0.94
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs515726209; hg19: chr1-15767073;