ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1766+1G>A
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1766+1G>A
Variation ID: 7168 Accession: VCV000007168.89
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117590440 (GRCh38) [ NCBI UCSC ] 7: 117230494 (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 Mar 24, 2015 Jun 9, 2024 Mar 3, 2004 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1766+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000007.14:g.117590440G>A NC_000007.13:g.117230494G>A NG_016465.4:g.129657G>A LRG_663:g.129657G>A LRG_663t1:c.1766+1G>A - Protein change
- Other names
- 1898+1G>A
- 1898+1G->A
- IVS12, G-A, +1
- Canonical SPDI
- NC_000007.14:117590439:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 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
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. |
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CFTR | - | - |
GRCh38 GRCh37 |
3704 | 5025 |
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 (11) |
practice guideline
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Mar 3, 2004 | RCV000007588.32 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 21, 2023 | RCV000985681.16 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004273.8 | |
CFTR-related disorder
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Pathogenic (1) |
no assertion criteria provided
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May 20, 2019 | RCV001027908.8 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2019 | RCV001002343.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2022 | RCV002496300.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2023 | RCV003473031.1 |
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 03, 2004)
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practice guideline
Method: curation
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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American College of Medical Genetics and Genomics (ACMG)
Study: The ACMG recommended carrier screening panel
Accession: SCV000071398.2 First in ClinVar: Jun 04, 2013 Last updated: Mar 24, 2015 |
Comment:
Converted during submission to Pathogenic.
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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: SCV000071454.4 First in ClinVar: Oct 18, 2013 Last updated: Oct 11, 2015 |
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Pathogenic
(Apr 01, 2019)
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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: SCV001363800.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: CFTR c.1766+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: CFTR c.1766+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 3.6e-05 in 275450 control chromosomes (gnomAD). The variant, c.1766+1G>A (also known as 1898+1G>A) is a common disease variant and has been reported in the literature and databases in numerous individuals affected with Cystic Fibrosis (see e.g. Sosnay 2013). There are 415 patients listed with this variant in the CFTR2 database, and 94% of these patients are pancreatic insufficient. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. The variant has been also classified as pathogenic by the CFTR2 database expert panel. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 29, 2020)
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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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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001371812.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information.
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Pathogenic
(Dec 15, 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: SCV001173564.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.1766+1G>A intronic pathogenic mutation (also known as c.1898+1G>A) results from a G to A substitution one nucleotide after coding exon 13 of the CFTR … (more)
The c.1766+1G>A intronic pathogenic mutation (also known as c.1898+1G>A) results from a G to A substitution one nucleotide after coding exon 13 of the CFTR gene. This mutation was reported in two unrelated individuals with cystic fibrosis who had pancreatic insufficiency, pulmonary disease, and abnormal sweat chloride levels; both individuals were also heterozygous for p.F508del (Strong TV et al. Hum. Mutat., 1992;1:380-7). Two other mutations at the same nucleotide position, c.1766+1G>C and c.1766+1G>T, have been reported in individuals with cystic fibrosis (Cuppens H et al. Genomics, 1993 Dec;18:693-7; Crawford J et al. Hum. Mutat., 1995;5:101-2; Petrova NV et al. Genes (Basel), 2020 May;11(5):554). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Oct 21, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005046898.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Jan 28, 2019)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160247.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The CFTR c.1766+1G>A variant (rs121908748), also known as 1898+1G>A, is reported in the literature in multiple individuals affected with pancreatic insufficient cystic fibrosis (Sosnay 2013, … (more)
The CFTR c.1766+1G>A variant (rs121908748), also known as 1898+1G>A, is reported in the literature in multiple individuals affected with pancreatic insufficient cystic fibrosis (Sosnay 2013, Strong 1992). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7168), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. Strong TV et al. Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1992;1(5):380-7. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163149.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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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: SCV001169430.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Nov 20, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001193951.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000492.3(CFTR):c.1766+1G>A(aka 1898+1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification … (more)
NM_000492.3(CFTR):c.1766+1G>A(aka 1898+1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1766+1G>A(aka 1898+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã (less)
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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: SCV000886222.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022 |
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Pathogenic
(Feb 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809356.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 10, 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: SCV004213321.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 21, 2023)
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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: SCV001134123.4
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2024 |
Comment:
The CFTR c.1766+1G>A variant disrupts a canonical splice-donor site and interferes with normal CFTR mRNA splicing. This variant has been shown to maintain the translation … (more)
The CFTR c.1766+1G>A variant disrupts a canonical splice-donor site and interferes with normal CFTR mRNA splicing. This variant has been shown to maintain the translation reading frame of the CFTR mRNA; however, skipping of exon 13 (also known as exon 12) removes a portion of the gene important for its function (PMID: 1284540 (1992)). In the published literature, this variant has been reported in individuals with Cystic Fibrosis (PMID: 1284540 (1992), 23974870 (2013), 23276700 (2013), 26708955 (2016), 28544683 (2017), and 32429104 (2020)). The variant is described in online databases as being pathogenic and CF-causing (CFTR2 (https://cftr2.org/)). The frequency of this variant in the general population, 0.00016 (8/50402 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 25, 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: SCV001579893.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 13 of the CFTR gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 13 of the CFTR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs121908748, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 1284540, 18456578, 22658665, 23974870). This variant is also known as 1898+1G>A. ClinVar contains an entry for this variant (Variation ID: 7168). Studies have shown that disruption of this splice site results in skipping of exon 13 (also known as exon 12), but is expected to preserve the integrity of the reading-frame (PMID: 1284540). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 1992)
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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: SCV000027789.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In 2 patients with cystic fibrosis (CF; 219700), Strong et al. (1992) used chemical mismatch cleavage and subsequent DNA sequencing to identify a splice mutation … (more)
In 2 patients with cystic fibrosis (CF; 219700), Strong et al. (1992) used chemical mismatch cleavage and subsequent DNA sequencing to identify a splice mutation at the 5-prime end of intron 12 of the CFTR gene. A G-to-A transition at position 1 of the donor-splice site resulted in skipping of exon 12. The mutation was found in compound heterozygous state with the delF508 mutation (602421.0001) in a 39-year-old white male and a 9-year-old female with typical pulmonary and gastrointestinal changes of CF. Both were pancreatic insufficient. The male had a history of liver disease requiring splenorenal shunt for portal hypertension at age 14 years. (less)
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Pathogenic
(-)
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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: SCV001741143.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(May 20, 2019)
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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: SCV001190631.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Pathogenic
(-)
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955262.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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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: SCV001976170.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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GeneReviews
Accession: SCV001622800.2
First in ClinVar: May 23, 2021 Last updated: Oct 01, 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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Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients. | Petrova NV | Genes | 2020 | PMID: 32429104 |
Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. | Soltysova A | The clinical respiratory journal | 2018 | PMID: 28544683 |
The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. | Schrijver I | The Journal of molecular diagnostics : JMD | 2016 | PMID: 26708955 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
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 empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. | Ooi CY | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2012 | PMID: 22658665 |
Rapid detection of the ACMG/ACOG-recommended 23 CFTR disease-causing mutations using ion torrent semiconductor sequencing. | Elliott AM | Journal of biomolecular techniques : JBT | 2012 | PMID: 22468138 |
A high frequency of the Cystic Fibrosis 2184insA mutation in Western Ukraine: genotype-phenotype correlations, relevance for newborn screening and genetic testing. | Makukh H | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2010 | PMID: 20659818 |
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 population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. | Watson MS | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371902 |
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. | McKone EF | Lancet (London, England) | 2003 | PMID: 12767731 |
A splicing mutation (1898 + 1G-->T) in the CFTR gene causing cystic fibrosis. | Crawford J | Human mutation | 1995 | PMID: 7537147 |
Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene. | Cuppens H | Genomics | 1993 | PMID: 7508414 |
Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. | Strong TV | Human mutation | 1992 | PMID: 1284540 |
https://cftr2.org | - | - | - | - |
https://cftr2.org/mutation/scientific/1898%252B1G-%253EA/ | - | - | - | - |
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Text-mined citations for rs121908748 ...
HelpRecord last updated Jun 10, 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.