ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3700A>G (p.Ile1234Val)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3700A>G (p.Ile1234Val)
Variation ID: 7215 Accession: VCV000007215.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117627753 (GRCh38) [ NCBI UCSC ] 7: 117267807 (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 Dec 12, 2017 Jun 17, 2024 Mar 17, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3700A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Ile1234Val missense NC_000007.14:g.117627753A>G NC_000007.13:g.117267807A>G NG_016465.4:g.166970A>G LRG_663:g.166970A>G LRG_663t1:c.3700A>G LRG_663p1:p.Ile1234Val P13569:p.Ile1234Val - Protein change
- I1234V
- Other names
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- Canonical SPDI
- NC_000007.14:117627752:A:G
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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
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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 |
3806 | 5170 |
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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Pathogenic (10) |
reviewed by expert panel
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Mar 17, 2017 | RCV000007636.20 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2022 | RCV001269696.10 | |
CFTR-related disorder
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Pathogenic (2) |
criteria provided, single submitter
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Jan 4, 2023 | RCV001831553.2 |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2023 | RCV004566693.1 |
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. |
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Pathogenic
(Mar 17, 2017)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Study: CFTR2
Accession: SCV000245876.2 First in ClinVar: Sep 23, 2015 Last updated: Dec 12, 2017 |
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Pathogenic
(Jan 20, 2017)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449885.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 4
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Pathogenic
(Jul 03, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713432.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 27, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844257.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: CFTR c.3700A>G (p.Ile1234Val) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. … (more)
Variant summary: CFTR c.3700A>G (p.Ile1234Val) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by activating a cryptic donor splice site 18bp upstream of the original donor splice site, resulting in deletion of six amino acids (Molinski_2014). The variant allele was found at a frequency of 4e-06 in 249440 control chromosomes. c.3700A>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Example: Claustres_1992, Abdul Wahab_2014, Wei_2006, Sosnay_2013 etc.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports significantly impaired CFTR function (Molinski_2014). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 04, 2023)
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criteria provided, single submitter
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: SCV004115658.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CFTR c.3700A>G variant is predicted to result in the amino acid substitution p.Ile1234Val. This variant has been reported in numerous patients with cystic fibrosis … (more)
The CFTR c.3700A>G variant is predicted to result in the amino acid substitution p.Ile1234Val. This variant has been reported in numerous patients with cystic fibrosis or CFTR-associated phenotypes (Hirtz et al. 2004. PubMed ID: 15480987; Wei et al. 2006. PubMed ID: 16617247; Molinski et al. 2014. PubMed ID: 24556927; El Bar Aluma et al. 2020. PubMed ID: 32843167). Functional studies showed that this variant alters splicing by activating an alternative splice site leading to a deletion of six amino acids and impacts protein function (Hirtz et al. 2004. PubMed ID: 15480987; Molinski et al. 2014. PubMed ID: 24556927; Ramalho et al. 2016. PubMed ID: 25735457). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117267807-A-G). This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Sep 28, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003826269.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169356.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Apr 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470500.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype … (more)
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Pathogenic
(Jun 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001523285.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Nov 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886213.2
First in ClinVar: Apr 12, 2018 Last updated: Dec 11, 2022 |
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Pathogenic
(Sep 09, 2023)
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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: SCV001586454.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1234 of the CFTR protein (p.Ile1234Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1234 of the CFTR protein (p.Ile1234Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs75389940, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10605524, 11336127, 15698946, 15948195, 21909392, 25593612, 26096753). ClinVar contains an entry for this variant (Variation ID: 7215). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 15480987, 24556927, 25735457). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 19 (PMID: 15480987, 24556927, 25735457). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805192.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jan 12, 2017)
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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: SCV002624131.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.I1234V pathogenic mutation (also known as c.3700A>G), located in coding exon 22 of the CFTR gene, results from an A to G substitution at … (more)
The p.I1234V pathogenic mutation (also known as c.3700A>G), located in coding exon 22 of the CFTR gene, results from an A to G substitution at nucleotide position 3700. The isoleucine at codon 1234 is replaced by valine. This mutation is the second most common CF-causing mutation in the Middle East (Molinski SV et al. Genet Med. 2014;16(8):625-32). This alteration was first described in an individual who was diagnosed with cystic fibrosis (CF) at 2 years of age and also carried the p.F508del mutation (Claustres M et al. Hum Mutat. 1992;1(4):310-3). In a large cohort of individuals homozygous for this mutation, this mutation was associated with pancreatic sufficiency (Abdel Rahman H et al. Acta Paediatr. 2006;95(9):1066-9). An in vitro functional study using reverse transcriptase-PCR found this mutation activates a cryptic donor splice site and results in the deletion of six amino acids (p.I1234_R1239del); this deletion causes a primary defect in protein folding and processing, similar to p.F508del but less severe (Molinski SV et al. Genet Med. 2014;16(8):625-32). A later study confirmed the alternative splicing described, through both an ex vivo study of RNA levels in nasal and colon epithelial cells from a CF patient, and a minigene assay using BHK cells. Furthermore, functional analysis showed reduced chloride channel function by the mutant protein (Ramalho AS, J. Cyst. Fibros. 2016 Jan; 15(1):21-33). Based on the supporting evidence, p.I1234V is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005057468.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 1993)
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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: SCV000027837.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018 |
Comment on evidence:
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an ile1234-to-val mutation in the … (more)
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an ile1234-to-val mutation in the CFTR gene. (less)
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Pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133028.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075868.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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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Serum zinc concentration in cystic fibrosis patients with CFTR I1234V mutation associated with pancreatic sufficiency. | AbdulWahab A | The clinical respiratory journal | 2017 | PMID: 26096753 |
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 |
Two Qatari siblings with cystic fibrosis and apparent mineralocorticoid excess. | Zahraldin K | Annals of thoracic medicine | 2015 | PMID: 25593612 |
Bone Mineral Density in Cystic Fibrosis Patients with the CFTR I1234V Mutation in a Large Kindred Family Is Associated with Pancreatic Sufficiency. | Abdul Wahab A | International journal of rheumatology | 2014 | PMID: 25093022 |
Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention. | Molinski SV | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24556927 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. | Roth EK | PloS one | 2011 | PMID: 21909392 |
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. | Steiner B | Human mutation | 2011 | PMID: 21520337 |
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. | Castellani C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2008 | PMID: 18456578 |
Cystic Fibrosis testing among Arab-Americans. | Wei S | Genetics in medicine : official journal of the American College of Medical Genetics | 2006 | PMID: 16617247 |
Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. | Quint A | American journal of medical genetics. Part A | 2005 | PMID: 15948195 |
High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. | des Georges M | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2004 | PMID: 15698946 |
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. | Hirtz S | Gastroenterology | 2004 | PMID: 15480987 |
Cystic fibrosis mutation I1234V in a Qatari lady. | Wahab AA | Journal of tropical pediatrics | 2003 | PMID: 12630722 |
Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). | Abdul Wahab A | Journal of tropical pediatrics | 2001 | PMID: 11336127 |
Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia. | Banjar H | Annals of tropical paediatrics | 1999 | PMID: 10605524 |
Novel and characteristic CFTR mutations in Saudi Arab children with severe cystic fibrosis. | el-Harith EA | Journal of medical genetics | 1997 | PMID: 9429141 |
Screening of 62 mutations in a cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes. | Gasparini P | Human mutation | 1993 | PMID: 7504969 |
Screening for cystic fibrosis mutations in southern France: identification of a frameshift mutation and two missense variations. | Claustres M | Human mutation | 1992 | PMID: 1284537 |
https://cftr2.org | - | - | - | - |
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Text-mined citations for rs75389940 ...
HelpRecord last updated Aug 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.