ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3659C>T (p.Thr1220Ile)
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
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NM_000492.4(CFTR):c.3659C>T (p.Thr1220Ile)
Variation ID: 7214 Accession: VCV000007214.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117627712 (GRCh38) [ NCBI UCSC ] 7: 117267766 (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 Sep 30, 2017 Oct 8, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3659C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Thr1220Ile missense NC_000007.14:g.117627712C>T NC_000007.13:g.117267766C>T NG_016465.4:g.166929C>T LRG_663:g.166929C>T LRG_663t1:c.3659C>T LRG_663p1:p.Thr1220Ile P13569:p.Thr1220Ile - Protein change
- T1220I
- Other names
- 3791C/T
- Canonical SPDI
- NC_000007.14:117627711:C:T
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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 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00013
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
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
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. |
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CFTR | - | - |
GRCh38 GRCh37 |
3821 | 5195 |
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. |
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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Sep 5, 2022 | RCV000007635.21 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV000589624.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 2, 2024 | RCV003230350.9 | |
CFTR-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jul 8, 2024 | RCV004528090.3 |
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. |
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Uncertain significance
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001781369.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Sex: mixed
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Uncertain significance
(Apr 19, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000860875.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Aug 22, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001417932.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1220 of the CFTR protein (p.Thr1220Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1220 of the CFTR protein (p.Thr1220Ile). This variant is present in population databases (rs1800123, gnomAD 0.09%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 7522211, 9272738, 9521595, 29173301, 32777524). ClinVar contains an entry for this variant (Variation ID: 7214). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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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Uncertain significance
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005195617.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
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Uncertain significance
(Aug 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005331399.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
CFTR: PM2, BP4
Number of individuals with the variant: 1
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Uncertain significance
(Feb 02, 2024)
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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: SCV000696979.3
First in ClinVar: Mar 17, 2018 Last updated: Apr 15, 2024 |
Comment:
Variant summary: CFTR c.3659C>T (p.Thr1220Ile) 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.3659C>T (p.Thr1220Ile) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250238 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.3659C>T has been reported in the literature in individuals affected with CFTR-related conditions without strong evidence of causality (Ghanem_1994, Lazaro_1999, Onay_1998, Bozdogan_2021, Li_2022, Luo_2021, Xiao_2017, Fujita_2022, Qiao_2018, Ni_2022). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 7522211, 18716917, 9521595, 12651880, 9272738, 10571949, 26471113, 29173301, 33572515, 32777524, 35313924, 34931337, 35387941, 30060175). ClinVar contains an entry for this variant (Variation ID: 7214). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 11, 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: SCV001182346.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.T1220I variant (also known as c.3659C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide … (more)
The p.T1220I variant (also known as c.3659C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3659. The threonine at codon 1220 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a 60 year old woman with a 10 year history of chronic lung disease (Ghanem N et al. Genomics. 1994;21(2):434-6) and in a 13 year old with gastrointestinal problems, elevated sweat chloride, and pancreatic sufficiency (Onay T et al. Hum Genet. 1998;102(2):224-30); however, a second disease-causing variant in trans was not described in either case. In addition, this alteration was reported in a child with pancreatitis who was also heterozygous for disease-causing variants in PRSS1 and SPINK1 (Xiao Y et al. J. Pediatr., 2017 12;191:158-163.e3). This amino acid position is poorly conserved in available vertebrate species, and I is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated 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
(Dec 11, 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: SCV000603027.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
The CFTR c.3659C>T; p.Thr1220Ile variant (rs1800123) is reported in the literature in individuals with a clinical diagnosis of cystic fibrosis or asthma (Ghanem 1994, Lazaro … (more)
The CFTR c.3659C>T; p.Thr1220Ile variant (rs1800123) is reported in the literature in individuals with a clinical diagnosis of cystic fibrosis or asthma (Ghanem 1994, Lazaro 1999, Onay 1998, Xiao 2017). This variant is also reported in ClinVar (Variation ID: 7214). This variant is found in the East Asian population with an allele frequency of 0.085% (17/19,904 alleles) in the Genome Aggregation Database. The threonine at codon 1220 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.40). Given the lack of clinical and functional data, the significance of the p.Thr1220Ile variant is uncertain at this time. References: Ghanem N et al. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994. 21(2):434-6. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999. 14(6):510-9. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998. 102(2):224-30. Xiao Y et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. (less)
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Uncertain significance
(Sep 05, 2022)
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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: SCV002573858.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
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, PM3, PP4, BP4 (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jul 08, 2024)
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no assertion criteria provided
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104583.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The CFTR c.3659C>T variant is predicted to result in the amino acid substitution p.Thr1220Ile. This variant was detected in the compound heterozygous state in an … (more)
The CFTR c.3659C>T variant is predicted to result in the amino acid substitution p.Thr1220Ile. This variant was detected in the compound heterozygous state in an individual with uncharacterized bronchopathy (Ghanem et al. 1994. PubMed ID: 7522211), and in the heterozygous state in a patient with gastrointestinal problems and a sweat test score of 75 mEq/l, a patient with asthma, and in a patient with pancreatitis alongside variants in the SPINK1 and PRSS1 genes (Onay et al. 1998. PubMed ID: 9521595; Lázaro et al. 1999. PubMed ID: 10571949; and Xiao et al. 2017. PubMed ID: 29173301, respectively). This variant is reported in 0.085% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Pathogenic
(May 15, 1994)
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no assertion criteria provided
Method: literature only
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CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027836.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 13, 2018 |
Comment on evidence:
In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 3791 in exon 19 of the CFTR … (more)
In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 3791 in exon 19 of the CFTR gene, changing threonine to isoleucine at position 1220. No other variation in CFTR was found, but the authors could not determine if the variants were found on the same or different alleles. No other family members were available for testing. (less)
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Uncertain significance
(Apr 28, 2018)
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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: SCV001460114.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 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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Genetic assessment using whole-exome sequencing for a young hypertriglyceridemic patient with repeated acute pancreatitis. | Fujita S | Endocrine journal | 2022 | PMID: 35387941 |
Systematic estimation of cystic fibrosis prevalence in Chinese and genetic spectrum comparison to Caucasians. | Ni Q | Orphanet journal of rare diseases | 2022 | PMID: 35313924 |
Mutations in CFTR genes are associated with oligoasthenospermia in infertile men undergoing IVF. | Li Q | Andrologia | 2022 | PMID: 34931337 |
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 |
Whole exome sequencing analysis in severe chronic obstructive pulmonary disease. | Qiao D | Human molecular genetics | 2018 | PMID: 30060175 |
Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. | Xiao Y | The Journal of pediatrics | 2017 | PMID: 29173301 |
A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis. | Xie Y | The clinical respiratory journal | 2017 | PMID: 26471113 |
A novel computational and structural analysis of nsSNPs in CFTR gene. | George Priya Doss C | Genomic medicine | 2008 | PMID: 18716917 |
Chronic pancreatitis and cystic fibrosis. | Witt H | Gut | 2003 | PMID: 12651880 |
Missense mutations in the cystic fibrosis gene in adult patients with asthma. | Lázaro C | Human mutation | 1999 | PMID: 10571949 |
Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). | Onay T | Human genetics | 1998 | PMID: 9521595 |
CFTR gene mutations in adults with disseminated bronchiectasis. | Girodon E | European journal of human genetics : EJHG | 1997 | PMID: 9272738 |
Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. | Ghanem N | Genomics | 1994 | PMID: 7522211 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs1800123 ...
HelpRecord last updated Oct 08, 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.