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 stars
practice guideline

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no 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

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)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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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	PubMed (1) [See all records that cite this PMID]
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	PubMed (1) [See all records that cite this PMID]
SCV000071454	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000886222	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Nov 5, 2018)	unknown	clinical testing	Citation Link,
SCV001169430	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jan 29, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001173564	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 15, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 1284540, 32429104, 7508414, 7537147 Citation Link,
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	PubMed (1) [See all records that cite this PMID] Citation Link,
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	PubMed (2) [See all records that cite these PMIDs] 12767731, 23974870 Citation Link,
SCV001371812	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 29, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001579893	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18456578, 22658665, 23974870, 1284540, 28492532
SCV001622800	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 15371902, 20301428

Help

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.

PubMed [citation]

PMID:: 11280952

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.

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.

PubMed [citation]

PMID:: 28603918

See all PubMed Citations (14)

PMC

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.

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

PMC [article]

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.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£

#	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

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