ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.4097T>C (p.Ile1366Thr)
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(1); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.4097T>C (p.Ile1366Thr)
Variation ID: 526019 Accession: VCV000526019.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117664821 (GRCh38) [ NCBI UCSC ] 7: 117304875 (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 Aug 4, 2018 May 1, 2024 Apr 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.4097T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile1366Thr missense NC_000007.14:g.117664821T>C NC_000007.13:g.117304875T>C NG_016465.4:g.204038T>C LRG_663:g.204038T>C LRG_663t1:c.4097T>C LRG_663p1:p.Ile1366Thr - Protein change
- I1366T
- Other names
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- Canonical SPDI
- NC_000007.14:117664820:T: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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0.00020 (C)
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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) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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 | ||
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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
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. |
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CFTR | - | - |
GRCh38 GRCh37 |
3736 | 5066 |
Conditions - Germline
Condition
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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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 19, 2023 | RCV000630457.18 | |
CFTR-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2018 | RCV001009486.9 |
Uncertain significance (3) |
criteria provided, single submitter
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Aug 13, 2020 | RCV001726278.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 10, 2023 | RCV003230560.8 |
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
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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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Uncertain significance
(Jun 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791936.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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CFTR-related disorders
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169581.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Uncertain significance
(Aug 13, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472102.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The CFTR c.4097T>C; p.Ile1366Thr variant (rs200955612) is reported in the literature in the heterozygous state in individuals affected with congenital bilateral absence of the vas … (more)
The CFTR c.4097T>C; p.Ile1366Thr variant (rs200955612) is reported in the literature in the heterozygous state in individuals affected with congenital bilateral absence of the vas deferens and also in healthy carriers (Le Marechal 2001, Steiner 2011). This variant is reported in ClinVar (Variation ID: 526019), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 1366 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.4097T>A; p.Ile1366Asn; c.4096A>T; p.Ile1366Phe) have been reported in individuals with cystic fibrosis (see link to CFTR2 database, Arslan 2020). However, given the lack of clinical and functional data, the significance of the p.Ile1366Thr variant is uncertain at this time. References: Link to CFTR2 database: https://cftr2.org/ Arslan AB et al. A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype-c.4096A?>?T. J Pediatr Genet. 2020;9(1):40-43. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001;108(4):290-298. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2012 Feb;33(2):456. Hum Mutat. 2011;32(8):912-920. (less)
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Uncertain significance
(Aug 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000751413.3
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces isoleucine with threonine at codon 1366 of the CFTR protein (p.Ile1366Thr). The isoleucine residue is highly conserved and there is a … (more)
This sequence change replaces isoleucine with threonine at codon 1366 of the CFTR protein (p.Ile1366Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs200955612, ExAC 0.009%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas defense (PMID: 21520337). ClinVar contains an entry for this variant (Variation ID: 526019). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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
(Jan 19, 2023)
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criteria provided, single submitter
Method: curation
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002573951.2
First in ClinVar: Sep 24, 2022 Last updated: Mar 04, 2023 |
Comment:
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more)
This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM5_STR, PP3 (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929007.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: CFTR c.4097T>C (p.Ile1366Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. … (more)
Variant summary: CFTR c.4097T>C (p.Ile1366Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 252084 control chromosomes (gnomAD, Steiner_2011, Berg_2013). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4097T>C has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (Steiner_2011) and Cystic Fibrosis (Feuillet_Fieux_2002, Raraigh_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants impacting codon 1366 have been described as pathogenic (c.4097T>A [p.Ile1366Asn] ClinVar:551822) or of uncertain significance (c.4096A>T [p.Ile1366Phe] ClinVar:632751). Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002629331.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.I1366T variant (also known as c.4097T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide … (more)
The p.I1366T variant (also known as c.4097T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide position 4097. The isoleucine at codon 1366 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a subject with congenital bilateral absence of the vas deferens (CBAVD) and in one ostensibly healthy individual (Le Maréchal C et al. Hum. Genet., 2001 Apr;108:290-8; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). Another alteration affecting the same amino acid, p.I1366N (c.4097T>A), has been reported in a cystic fibrosis (CF) cohort (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454294.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963615.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969441.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. | Raraigh KS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2022 | PMID: 34782259 |
Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. | Křenková P | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2013 | PMID: 23276700 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. | Le Maréchal C | Human genetics | 2001 | PMID: 11379874 |
Text-mined citations for rs200955612 ...
HelpRecord last updated Jul 23, 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.