ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000492.4(CFTR):c.1853T>C (p.Ile618Thr)
Variation ID: 53404 Accession: VCV000053404.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q31.2 7: 117592020 (GRCh38) [ NCBI UCSC ] 7: 117232074 (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 Dec 6, 2016 Feb 20, 2024 Dec 11, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000492.4:c.1853T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile618Thr missense NC_000007.14:g.117592020T>C NC_000007.13:g.117232074T>C NG_016465.4:g.131237T>C LRG_663:g.131237T>C LRG_663t1:c.1853T>C LRG_663p1:p.Ile618Thr P13569:p.Ile618Thr - Protein change
- I618T
- Other names
- -
- Canonical SPDI
- NC_000007.14:117592019: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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00015
Exome Aggregation Consortium (ExAC) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
3598 | 4891 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000046494.22 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 22, 2021 | RCV002490611.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 29, 2021 | RCV000790746.21 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001004276.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 3, 2023 | RCV003473470.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Mar 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV000886895.1
First in ClinVar: Dec 12, 2017 Last updated: Dec 12, 2017 |
Comment:
This CFTR variant (rs139468767) has been previously reported and is rare in large population datasets (gnomAD: 10/261916 total alleles; 0.003818%; no homozygotes). There are conflicting … (more)
This CFTR variant (rs139468767) has been previously reported and is rare in large population datasets (gnomAD: 10/261916 total alleles; 0.003818%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as pathogenic and a third as a variant of uncertain clinical significance. Independent functional studies determined that this protein does not mature into its fully glycosylated state. Additionally, if any protein is properly trafficked, it is predicted to have reduced chloride conductance. This variant is considered likely pathogenic. (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163152.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
Likely pathogenic
(Jan 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473402.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The CFTR c.1853T>C; p.Ile618Thr variant (rs139468767) is reported in the literature in multiple individuals affected with cystic fibrosis who also carry a pathogenic variant presumed … (more)
The CFTR c.1853T>C; p.Ile618Thr variant (rs139468767) is reported in the literature in multiple individuals affected with cystic fibrosis who also carry a pathogenic variant presumed to be on the opposite chromosome (Macek 1997, Marson 2012). This variant is reported in ClinVar (Variation ID: 53404), and is only observed on ten alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 618 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show reduced cell surface expression and channel function (Pasyk 1998, Vankeerberghen 1998). Based on available information, this variant is considered to be likely pathogenic. References: Macek M et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75 percent. Am J Hum Genet. 1997 60(5):1122-7. Marson FA et al. The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis. BMC Pulm Med. 2012 Aug 8;12:41. Pasyk EA et al. A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function. J Biol Chem. 1998 Nov 27;273(48):31759-64. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 7(11):1761-9. (less)
|
|
Pathogenic
(Mar 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696878.5
First in ClinVar: Mar 17, 2018 Last updated: Apr 23, 2022 |
Comment:
Variant summary: Variant summary: CFTR c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain … (more)
Variant summary: Variant summary: CFTR c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 3.8e-05 in 262104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (3.8e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.1853T>C, has been reported in the literature in compound heterozygosity with p.F508del or p.G542X in at-least three individuals affected with Non-classic (Pancreatically sufficient/mild phenotypes) Cystic Fibrosis (Macek 1997, Sousa 2012, Faria_2017). These data indicate that the variant may be associated with disease although multiple publications reporting the same patients confound distinct ascertainment (example, Vankeerberghen_1998, Marson_2012A, Marson_2013, Guimbellot_2017, Goncalves_2018, Pereira_2019, Faria_2017). Additionally, this variant has been observed in compound heterozygosity with other classic CFTR mutations such as p.A559T (c.1675G>A), p.F508del (c.1521_1523delCTT) and p.Ser1255X (c.3764C>A) in at-least three patients (a pair of sibs and two other distinct patients) sequenced for the CFTR gene at our laboratory. Detailed clinical information was available on one of these patients who was confirmed to have a known diagnosis of pancreatically insufficient CF with elevated sweat chloride levels, positivity for CF pathogens, severe baseline lung disease, and sinusitis. As the compound heterozygous genotypes observed in our laboratory are distinct (p.A559T and p.Ser1255X) from those reported in the literature, these data indicate that the variant is likely to be associated with disease (ACMG PP4). One publication, Pasyk_1998, reported this variant exhibits <50% of normal activity as chloride channel (ACMG PS3) while another publication, Vankeerberghen_1998, not providing primary data, reported this variant as resulting in abnormal processing leading to no or minimal functional CFTR proteins appearing at the cell membranes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a complete consensus (Likely Pathogenic, n=5, Pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Oct 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001173928.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The p.I618T variant (also known as c.1853T>C), located in coding exon 14 of the CFTR gene, results from a T to C substitution at nucleotide … (more)
The p.I618T variant (also known as c.1853T>C), located in coding exon 14 of the CFTR gene, results from a T to C substitution at nucleotide position 1853. The isoleucine at codon 618 is replaced by threonine, an amino acid with similar properties. In a cohort of individuals with cystic fibrosis, this variant was identified in one individual in conjunction with p.G542*; however, specific clinical details and the phase of the variants were not provided (Gonçalves AC et al. J Pediatr (Rio J), 2018 May;pii: S0021-7557(17)31053-7). Studies have demonstrated that this variant results in decreased chloride channel activity and abnormal protein processing (Pasyk EA et al. J. Biol. Chem., 1998 Nov;273:31759-64; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 29, 2020). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (10/26916). 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. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Nov 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
unknown
|
Mendelics
Accession: SCV000886317.2
First in ClinVar: Dec 12, 2017 Last updated: Dec 11, 2022 |
|
|
Likely pathogenic
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213339.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely pathogenic
(Oct 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244653.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PM2, PM3, PP3
|
|
Likely pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001576371.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the CFTR protein (p.Ile618Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the CFTR protein (p.Ile618Thr). This variant is present in population databases (rs139468767, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9150159, 23857699; external communication, http//www.genet.sickkids.on.ca/). This variant is also known as c.1985T>C. ClinVar contains an entry for this variant (Variation ID: 53404). 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 CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 9736778, 9822639). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
Pathogenic
(Jan 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226031.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 4
Sex: mixed
|
|
Likely pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pancreatitis
Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810431.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Likely pathogenic
(Jul 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714837.2
First in ClinVar: Jun 15, 2021 Last updated: Apr 09, 2023 |
Comment:
PP3, PM2, PM3_strong, PS3
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools. | Pereira SV | Scientific reports | 2019 | PMID: 30996306 |
Chloride and sodium ion concentrations in saliva and sweat as a method to diagnose cystic fibrosis. | Gonçalves AC | Jornal de pediatria | 2019 | PMID: 29782810 |
Nasospheroids permit measurements of CFTR-dependent fluid transport. | Guimbellot JS | JCI insight | 2017 | PMID: 29202459 |
Thirty Years of Sweat Chloride Testing at One Referral Center. | Faria AG | Frontiers in pediatrics | 2017 | PMID: 29124052 |
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 |
Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis. | Marson FA | Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia | 2013 | PMID: 23857699 |
Genetic interaction of GSH metabolic pathway genes in cystic fibrosis. | de Lima Marson FA | BMC medical genetics | 2013 | PMID: 23758905 |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. | Sousa M | PloS one | 2012 | PMID: 23082198 |
Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis. | Marson FA | BMC pulmonary medicine | 2012 | PMID: 22950544 |
The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis. | Marson FA | BMC pulmonary medicine | 2012 | PMID: 22874010 |
Phenotype prediction of non-synonymous single-nucleotide polymorphisms in human ATP-binding cassette transporter genes. | Wang LL | Basic & clinical pharmacology & toxicology | 2011 | PMID: 20849526 |
A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function. | Pasyk EA | The Journal of biological chemistry | 1998 | PMID: 9822639 |
Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. | Vankeerberghen A | Human molecular genetics | 1998 | PMID: 9736778 |
Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. | Macek M Jr | American journal of human genetics | 1997 | PMID: 9150159 |
http//www.genet.sikkids.on.a/ | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs139468767 ...
HelpRecord last updated Apr 20, 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.