This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.374T>C (p.Ile125Thr)
Germline
Classification
Help
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.
(12)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(4)
Uncertain significance(6); Likely benign(4)
12
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.374T>C (p.Ile125Thr)
Variation ID: 53802 Accession: VCV000053802.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117530999 (GRCh38) [ NCBI UCSC ] 7: 117171053 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 17, 2018 Oct 8, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000492.4:c.374T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile125Thr missense NC_000007.14:g.117530999T>C NC_000007.13:g.117171053T>C NG_016465.4:g.70216T>C LRG_663:g.70216T>C LRG_663t1:c.374T>C LRG_663p1:p.Ile125Thr - Protein change
- I125T
- Other names
- -
- Canonical SPDI
- NC_000007.14:117530998:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00160 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00026
Trans-Omics for Precision Medicine (TOPMed) 0.00047
Exome Aggregation Consortium (ExAC) 0.00061
The Genome Aggregation Database (gnomAD), exomes 0.00071
1000 Genomes Project 0.00160
1000 Genomes Project 30x 0.00172
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| CFTR | - | - |
GRCh38 GRCh37 |
3832 | 5210 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 15, 2022 | RCV000595646.14 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV001081823.21 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001163272.14 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 25, 2023 | RCV001509309.24 |
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
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
CFTR-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001325295.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001821996.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Uncertain significance
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046709.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
The CFTR c.374T>C (p.Ile125Thr) variant has been reported in the published literature in individuals with cystic fibrosis ((PMID: 12439892 (2002), 26437683 (2015)), pancreatitis (PMID: 12952861 … (more)
The CFTR c.374T>C (p.Ile125Thr) variant has been reported in the published literature in individuals with cystic fibrosis ((PMID: 12439892 (2002), 26437683 (2015)), pancreatitis (PMID: 12952861 (2003), 25492507 (2015), 25869325 (2015), 29173301 (2017)), bronchiectasis (PMID: 12952861 (2003), 16678503 (2006), 29997923 (2018)) as well as in healthy individuals (PMID: 12952861 (2003), 16678503 (2006), 16778407 (2006), 29997923 (2018)). The frequency of this variant in the general population, 0.011 (155/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Jan 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003831640.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(Apr 18, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001182605.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Likely benign
(Mar 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000706922.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely benign
(Jan 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696986.4
First in ClinVar: Mar 17, 2018 Last updated: Feb 13, 2022 |
Comment:
Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more)
Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 252614 control chromosomes, predominantly at a frequency of 0.0094 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis allowing no conclusion about variant significance. c.374T>C has been reported in the literature in sequencing studies of healthy controls and individuals affected with Cystic Fibrosis, pancreatitis of idiopathic, chronic, acute and autoimmume etiologies, and as a VUS reported in settings of carrier screening (example, Kilinc_2002, Chang_2007, Kim_2010, Ngiam_2006, Jang_2013, Nakano_2015, Chang_2015, Lee_2003, DeWachter_2017, Archibald_2017, Xiao_2017, Guan_2018, Schrijver_2016). Specifically, this variant was reported in trans with p.F508del in a female patient of Chinese ethnicity who was reportedly pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L) (DeWachter_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Uncertain significance
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715935.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
BS2
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Mar 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885191.3
First in ClinVar: Mar 17, 2018 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.374T>C; p.Ile125Thr variant (rs141723617) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or CFTR-related disorders such … (more)
The CFTR c.374T>C; p.Ile125Thr variant (rs141723617) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or CFTR-related disorders such as bronchiectasis and pancreatitis, but its clinical significance was not determined (Chang 2007, Kilinc 2002, Lee 2003, Nakano 2015, Ngiam 2006, Zhang 2022). This variant is listed in ClinVar (Variation ID: 53802), and is found in the East Asian population with an allele frequency of 0.96% (192/19944 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.668). However, given the limited clinical and lack of functional data, the significance of the p.Ile125Thr variant is uncertain at this time. References: Chang M et al. Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. Clin Genet. 2007; 71(6):530-9. PMID: 17539902. Kilinc MO et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002 Dec 1;113(3):250-7. PMID: 12439892. Lee K et al. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci. 2005; 50(10):1852-6. PMID: 16187186. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015; 60(5):1297-307. PMID: 25492507. Ngiam N et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. J Cyst Fibros. 2006; 5(3):159-64. PMID: 16678503. Zhang N et al. Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. Zhongguo Dang Dai Er Ke Za Zhi. 2022 Jul 15;24(7):771-777. Chinese. PMID: 35894192. (less)
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000074982.11
First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024 |
|
|
|
Benign
(Apr 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453947.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Likely benign
(Jun 17, 2019)
|
no assertion criteria provided
Method: clinical testing
|
CFTR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004724100.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
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Comment:
Comment:
The CFTR c.374T>C (p.Ile125Thr) variant has been reported in the published literature in individuals with cystic fibrosis ((PMID: 12439892 (2002), 26437683 (2015)), pancreatitis (PMID: 12952861 (2003), 25492507 (2015), 25869325 (2015), 29173301 (2017)), bronchiectasis (PMID: 12952861 (2003), 16678503 (2006), 29997923 (2018)) as well as in healthy individuals (PMID: 12952861 (2003), 16678503 (2006), 16778407 (2006), 29997923 (2018)). The frequency of this variant in the general population, 0.011 (155/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 252614 control chromosomes, predominantly at a frequency of 0.0094 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis allowing no conclusion about variant significance. c.374T>C has been reported in the literature in sequencing studies of healthy controls and individuals affected with Cystic Fibrosis, pancreatitis of idiopathic, chronic, acute and autoimmume etiologies, and as a VUS reported in settings of carrier screening (example, Kilinc_2002, Chang_2007, Kim_2010, Ngiam_2006, Jang_2013, Nakano_2015, Chang_2015, Lee_2003, DeWachter_2017, Archibald_2017, Xiao_2017, Guan_2018, Schrijver_2016). Specifically, this variant was reported in trans with p.F508del in a female patient of Chinese ethnicity who was reportedly pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L) (DeWachter_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
BS2
Comment:
The CFTR c.374T>C; p.Ile125Thr variant (rs141723617) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or CFTR-related disorders such as bronchiectasis and pancreatitis, but its clinical significance was not determined (Chang 2007, Kilinc 2002, Lee 2003, Nakano 2015, Ngiam 2006, Zhang 2022). This variant is listed in ClinVar (Variation ID: 53802), and is found in the East Asian population with an allele frequency of 0.96% (192/19944 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.668). However, given the limited clinical and lack of functional data, the significance of the p.Ile125Thr variant is uncertain at this time. References: Chang M et al. Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. Clin Genet. 2007; 71(6):530-9. PMID: 17539902. Kilinc MO et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002 Dec 1;113(3):250-7. PMID: 12439892. Lee K et al. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci. 2005; 50(10):1852-6. PMID: 16187186. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015; 60(5):1297-307. PMID: 25492507. Ngiam N et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. J Cyst Fibros. 2006; 5(3):159-64. PMID: 16678503. Zhang N et al. Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. Zhongguo Dang Dai Er Ke Za Zhi. 2022 Jul 15;24(7):771-777. Chinese. PMID: 35894192.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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. |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
The CFTR c.374T>C (p.Ile125Thr) variant has been reported in the published literature in individuals with cystic fibrosis ((PMID: 12439892 (2002), 26437683 (2015)), pancreatitis (PMID: 12952861 (2003), 25492507 (2015), 25869325 (2015), 29173301 (2017)), bronchiectasis (PMID: 12952861 (2003), 16678503 (2006), 29997923 (2018)) as well as in healthy individuals (PMID: 12952861 (2003), 16678503 (2006), 16778407 (2006), 29997923 (2018)). The frequency of this variant in the general population, 0.011 (155/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: CFTR c.374T>C (p.Ile125Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 252614 control chromosomes, predominantly at a frequency of 0.0094 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis allowing no conclusion about variant significance. c.374T>C has been reported in the literature in sequencing studies of healthy controls and individuals affected with Cystic Fibrosis, pancreatitis of idiopathic, chronic, acute and autoimmume etiologies, and as a VUS reported in settings of carrier screening (example, Kilinc_2002, Chang_2007, Kim_2010, Ngiam_2006, Jang_2013, Nakano_2015, Chang_2015, Lee_2003, DeWachter_2017, Archibald_2017, Xiao_2017, Guan_2018, Schrijver_2016). Specifically, this variant was reported in trans with p.F508del in a female patient of Chinese ethnicity who was reportedly pancreatic sufficient and had sweat chloride of < 60 mmol/L (36mmol/L) (DeWachter_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3; benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
BS2
Comment:
The CFTR c.374T>C; p.Ile125Thr variant (rs141723617) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or CFTR-related disorders such as bronchiectasis and pancreatitis, but its clinical significance was not determined (Chang 2007, Kilinc 2002, Lee 2003, Nakano 2015, Ngiam 2006, Zhang 2022). This variant is listed in ClinVar (Variation ID: 53802), and is found in the East Asian population with an allele frequency of 0.96% (192/19944 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.668). However, given the limited clinical and lack of functional data, the significance of the p.Ile125Thr variant is uncertain at this time. References: Chang M et al. Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. Clin Genet. 2007; 71(6):530-9. PMID: 17539902. Kilinc MO et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet. 2002 Dec 1;113(3):250-7. PMID: 12439892. Lee K et al. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci. 2005; 50(10):1852-6. PMID: 16187186. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015; 60(5):1297-307. PMID: 25492507. Ngiam N et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. J Cyst Fibros. 2006; 5(3):159-64. PMID: 16678503. Zhang N et al. Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. Zhongguo Dang Dai Er Ke Za Zhi. 2022 Jul 15;24(7):771-777. Chinese. PMID: 35894192.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cystic Fibrosis Screen Positive, Inconclusive Diagnosis Genotypes in People with Cystic Fibrosis from the U.S. Patient Registry. | Salinas DB | Annals of the American Thoracic Society | 2023 | PMID: 36409994 |
| Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations. | Fang J | Frontiers in genetics | 2022 | PMID: 36437957 |
| Heterogeneous spectrum of CFTR gene mutations in Chinese patients with CAVD and the dilemma of genetic blocking strategy. | Feng J | Reproduction (Cambridge, England) | 2022 | PMID: 35913788 |
| [Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. | Zhang N | Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics | 2022 | PMID: 35894192 |
| Systematic estimation of cystic fibrosis prevalence in Chinese and genetic spectrum comparison to Caucasians. | Ni Q | Orphanet journal of rare diseases | 2022 | PMID: 35313924 |
| Genetic mutation analysis of 22 patients with congenital absence of vas deferens: a single-center study†. | Tan MQ | Biology of reproduction | 2022 | PMID: 34673937 |
| Analysis of Clinical Manifestations, Imaging Features, and Gene Mutation Characteristics of 6 Children with Cystic Fibrosis in China. | Chu Y | Evidence-based complementary and alternative medicine : eCAM | 2021 | PMID: 34765005 |
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey. | Bozdogan ST | Genes | 2021 | PMID: 33572515 |
| Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. | Luo S | Gene | 2021 | PMID: 32777524 |
| Identification of potential candidate genes and pathways in atrioventricular nodal reentry tachycardia by whole-exome sequencing. | Luo R | Clinical and translational medicine | 2020 | PMID: 32508047 |
| Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. | Guan WJ | Journal of thoracic disease | 2018 | PMID: 29997923 |
| Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. | Archibald AD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29261177 |
| Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. | Xiao Y | The Journal of pediatrics | 2017 | PMID: 29173301 |
| What can the CF registry tell us about rare CFTR-mutations? A Belgian study. | De Wachter E | Orphanet journal of rare diseases | 2017 | PMID: 28830496 |
| Genetic Background and Clinical Characters of Pediatric Chronic Pancreatitis: Data and Implications from the East. | Liu M | Gastroenterology research and practice | 2017 | PMID: 28348582 |
| Risk of asthma in heterozygous carriers for cystic fibrosis: A meta-analysis. | Nielsen AO | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 27324553 |
| The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. | Schrijver I | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26708955 |
| Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
| Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next-generation treatments. | Singh M | Respirology (Carlton, Vic.) | 2015 | PMID: 26437683 |
| Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. | Chang MC | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25869325 |
| Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. | Nakano E | Digestive diseases and sciences | 2015 | PMID: 25492507 |
| Association of CFTR gene variants with nontuberculous mycobacterial lung disease in a Korean population with a low prevalence of cystic fibrosis. | Jang MA | Journal of human genetics | 2013 | PMID: 23514810 |
| The contribution of the SPINK1 c.194+2T>C mutation to the clinical course of idiopathic chronic pancreatitis in Chinese patients. | Sun C | Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2013 | PMID: 23017645 |
| Association of CFTR gene mutation with bronchial asthma. | Maurya N | The Indian journal of medical research | 2012 | PMID: 22664493 |
| Association of CFTR gene mutation with bronchial asthma and its severity in Indian children: a case-control study. | Awasthi S | Annals of human biology | 2012 | PMID: 22324837 |
| Association between cystic fibrosis transmembrane conductance regulator gene mutations and susceptibility for childhood asthma in Korea. | Kim KW | Yonsei medical journal | 2010 | PMID: 20879059 |
| Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis. | Chang MC | Clinical genetics | 2007 | PMID: 17539902 |
| Report of a Korean patient with cystic fibrosis, carrying Q98R and Q220X mutations in the CFTR gene. | Koh WJ | Journal of Korean medical science | 2006 | PMID: 16778407 |
| Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study. | Ngiam NS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2006 | PMID: 16678503 |
| A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. | Lee JH | Human molecular genetics | 2003 | PMID: 12952861 |
| Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. | Kilinç MO | American journal of medical genetics | 2002 | PMID: 12439892 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs141723617 ...
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Record last updated Nov 25, 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.