NM_007272.3(CTRC):c.640-12G>A AND Hereditary pancreatitis

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 17, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000507043.20

Allele description [Variation Report for NM_007272.3(CTRC):c.640-12G>A]

NM_007272.3(CTRC):c.640-12G>A

Gene:

CTRC:chymotrypsin C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.21

Genomic location:

Preferred name:

NM_007272.3(CTRC):c.640-12G>A

HGVS:

NC_000001.11:g.15445585G>A
NG_009253.1:g.12143G>A
NM_007272.3:c.640-12G>AMANE SELECT
NC_000001.10:g.15772080G>A
NM_007272.2:c.640-12G>A

Links:

dbSNP: rs183053579

NCBI 1000 Genomes Browser:

rs183053579

Molecular consequence:

NM_007272.3:c.640-12G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary pancreatitis (PCTT)
Synonyms:: Hereditary chronic pancreatitis
Identifiers:: MONDO: MONDO:0008185; MedGen: C0238339; Orphanet: 676; OMIM: 167800

Recent activity

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translation elongation factor 1-alpha, partial [Tetraploa yunnanensis]
translation elongation factor 1-alpha, partial [Tetraploa yunnanensis]
gi|1957425432|gb|QQQ16485.1|

Protein
Homo sapiens centrosomal protein 85 like (CEP85L), transcript variant 1, mRNA
Homo sapiens centrosomal protein 85 like (CEP85L), transcript variant 1, mRNA
gi|1519241722|ref|NM_001042475.3|

Nucleotide
Early B Cell Factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic fu...
Early B Cell Factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells.
Early B Cell Factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells.

BioProject
Homo sapiens C-type lectin domain containing 10A (CLEC10A), transcript variant 3...
Homo sapiens C-type lectin domain containing 10A (CLEC10A), transcript variant 3, mRNA
gi|1677501281|ref|NM_001330070.2|

Nucleotide
C-type lectin domain family 10 member A isoform X1 [Homo sapiens]
C-type lectin domain family 10 member A isoform X1 [Homo sapiens]
gi|2462552371|ref|XP_054170675.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000603264	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Oct 21, 2022)	germline	clinical testing	Citation Link,
SCV002486560	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 17, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002537668	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Apr 23, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26166474, 28502372 Citation Link,
SCV002658536	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 16, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25569187, 26166474 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations.

Giefer MJ, Lowe ME, Werlin SL, Zimmerman B, Wilschanski M, Troendle D, Schwarzenberg SJ, Pohl JF, Palermo J, Ooi CY, Morinville VD, Lin TK, Husain SZ, Himes R, Heyman MB, Gonska T, Gariepy CE, Freedman SD, Fishman DS, Bellin MD, Barth B, Abu-El-Haija M, et al.

J Pediatr. 2017 Jul;186:95-100. doi: 10.1016/j.jpeds.2017.03.063. Epub 2017 May 10. Erratum in: J Pediatr. 2018 Dec;203:468-469. doi: 10.1016/j.jpeds.2018.08.026.

PubMed [citation]

PMID:: 28502372
PMCID:: PMC5506853

See all PubMed Citations (4)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603264.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CTRC c.640-12G>A variant (rs183053579) is reported in the literature in multiple individuals affected with pancreatitis (Giefer 2017, LaRusch 2015, Masson 2015). Functional characterization of patient mRNA indicates that the variant leads to the inclusion of 10 nucleotides from intron 6, potentially introducing a frameshift in the translated protein (Masson 2015). This variant is reported in ClinVar (Variation ID: 439575), and is found in the African population with an allele frequency of 0.65% (162/24,920 alleles, including a single homozygote) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site, consistent with the functional studies. Based on available information, the c.640-12G>A variant is considered to be likely pathogenic. References: Giefer MJ et al. Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations. J Pediatr. 2017 Jul;186:95-100. PMID: 28502372. 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. Report of 2 CTRC Intronic Mutations Associated With Acute or Chronic Pancreatitis and Delineation of Their Pathogenic Molecular Mechanisms. Pancreas. 2015; 44(6):999-1001. PMID: 26166474.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002486560.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002537668.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002658536.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.640-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 7 in the CTRC gene. This variant was identified in several individuals with pancreatitis, including three from different African countries (LaRusch J et al. Clin Transl Gastroenterol, 2015 Jan;6:e68; Masson E et al. Pancreas, 2015 Aug;44:999-1001). In one individual, RT-PCR and sequencing of cultured fibroblasts demonstrated aberrant splicing leading to the creation of a novel splice acceptor, resulting in inclusion of the last 10 bp of the intron, and leading to a protein elongation (Masson E et al. Pancreas, 2015 Aug;44:999-1001). Based on data from gnomAD, the A allele has an overall frequency of 0.0698% (197/282392) total alleles studied, including 1 homozygote. The highest observed frequency was 0.6501% (162/24920) of African alleles. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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