NM_000492.4(CFTR):c.1766+1G>A AND Cystic fibrosis
- Germline classification:
- Pathogenic (11 submissions)
- Last evaluated:
- Mar 3, 2004
- Review status:
- 4 stars out of maximum of 4 starspractice guideline
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000007588.34
Allele description [Variation Report for NM_000492.4(CFTR):c.1766+1G>A]
NM_000492.4(CFTR):c.1766+1G>A
- Gene:
- CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 7q31.2
- Genomic location:
- Preferred name:
- NM_000492.4(CFTR):c.1766+1G>A
- Other names:
- 1898+1G>A; 1898+1G->A
- HGVS:
- NC_000007.14:g.117590440G>A
- NG_016465.4:g.129657G>A
- NM_000492.4:c.1766+1G>AMANE SELECT
- LRG_663t1:c.1766+1G>A
- LRG_663:g.129657G>A
- NC_000007.13:g.117230494G>A
- NG_016465.3:g.129657G>A
- NM_000492.3(CFTR):c.1766+1G>A
- NM_000492.3:c.1766+1G>A
This HGVS expression did not pass validation- Nucleotide change:
- IVS12, G-A, +1
- Links:
- Genetic Testing Registry (GTR): GTR000500233; OMIM: 602421.0064; dbSNP: rs121908748
- NCBI 1000 Genomes Browser:
- rs121908748
- Molecular consequence:
- NM_000492.4:c.1766+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Condition(s)
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000027789 | OMIM | no assertion criteria provided | Pathogenic (Jan 1, 1992) | germline | literature only | |
SCV000071398 | American College of Medical Genetics and Genomics (ACMG) - The ACMG recommended carrier screening panel | practice guideline (Guideline for cystic fibrosis carrier screening) | pathogenic (Mar 3, 2004) | germline | curation | |
SCV000071454 | CFTR2 - CFTR2 | reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) | Pathogenic (Mar 17, 2017) | germline | research | |
SCV000886222 | Mendelics | criteria provided, single submitter (Mendelics Assertion Criteria 2017) | Pathogenic (Nov 5, 2018) | unknown | clinical testing | |
SCV001169430 | CFTR-France | criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) | Pathogenic (Jan 29, 2018) | germline | curation | |
SCV001173564 | Ambry Genetics | criteria provided, single submitter (Ambry Variant Classification Scheme 2023) | Pathogenic (Dec 15, 2022) | germline | clinical testing | |
SCV001193951 | Myriad Genetics, Inc. | criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) | Pathogenic (Nov 20, 2019) | unknown | clinical testing | |
SCV001363800 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Apr 1, 2019) | germline | clinical testing | |
SCV001371812 | Johns Hopkins Genomics, Johns Hopkins University | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 29, 2020) | germline | clinical testing | |
SCV001579893 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Dec 25, 2023) | germline | clinical testing | |
SCV001622800 | GeneReviews | no classification provided | not provided | unknown | literature only |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | research, curation |
not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
not provided | unknown | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, literature only |
Citations
PubMed
Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.
Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ; Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG. American College of Medical Genetics..
Genet Med. 2001 Mar-Apr;3(2):149-54. No abstract available.
- PMID:
- 11280952
Claustres M, Thèze C, des Georges M, Baux D, Girodon E, Bienvenu T, Audrezet MP, Dugueperoux I, Férec C, Lalau G, Pagin A, Kitzis A, Thoreau V, Gaston V, Bieth E, Malinge MC, Reboul MP, Fergelot P, Lemonnier L, Mekki C, Fanen P, Bergougnoux A, et al.
Hum Mutat. 2017 Oct;38(10):1297-1315. doi: 10.1002/humu.23276. Epub 2017 Jun 28.
- PMID:
- 28603918
PMC
Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW.
Genetics in Medicine. 2004 Sep-Oct; 6(5): 387-391
- PMCID:
- PMC3110945
- PMID:
- 15371902
- DOI:
- 10.1097/01.GIM.0000139506.11694.7C
Details of each submission
From OMIM, SCV000027789.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | literature only | PubMed (1) |
Description
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.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From American College of Medical Genetics and Genomics (ACMG) - The ACMG recommended carrier screening panel, SCV000071398.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
Description
Converted during submission to Pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From CFTR2 - CFTR2, SCV000071454.4
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Mendelics, SCV000886222.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From CFTR-France, SCV001169430.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Ambry Genetics, SCV001173564.5
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (4) |
Description
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.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Myriad Genetics, Inc., SCV001193951.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363800.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
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.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Johns Hopkins Genomics, Johns Hopkins University, SCV001371812.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV001579893.4
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (5) |
Description
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.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From GeneReviews, SCV001622800.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | literature only | PubMed (2) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Oct 26, 2024