NM_000492.4(CFTR):c.1680-886A>G AND Cystic fibrosis

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 17, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000046417.23

Allele description [Variation Report for NM_000492.4(CFTR):c.1680-886A>G]

NM_000492.4(CFTR):c.1680-886A>G

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.1680-886A>G

Other names:

1811+1.6kbA->G; c.1679+1634A>G; 1812-886A>G; p.?

HGVS:

NC_000007.14:g.117589467A>G
NG_016465.4:g.128684A>G
NG_056131.3:g.2422A>G
NM_000492.4:c.1680-886A>GMANE SELECT
LRG_663t1:c.1680-886A>G
LRG_663:g.128684A>G
NC_000007.13:g.117229521A>G
NM_000492.3:c.1680-886A>G

Links:

dbSNP: rs397508266

Molecular consequence:

NM_000492.4:c.1680-886A>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000071568	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,
SCV000074430	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2026)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23974870, 25122143, 7534040, 28492532
SCV001137480	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001169393	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]
SCV002711001	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 12, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15994263, 18456578 Citation Link,
SCV003927249	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12414835, 7534040, 25741868
SCV007332257	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Mar 12, 2025)	germline	clinical testing	Citation Link

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	unknown	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

Citations

PubMed

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.

Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.

Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.

PubMed [citation]

PMID:: 23974870
PMCID:: PMC3874936

Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy.

Audrézet MP, Munck A, Scotet V, Claustres M, Roussey M, Delmas D, Férec C, Desgeorges M.

Genet Med. 2015 Feb;17(2):108-16. doi: 10.1038/gim.2014.113. Epub 2014 Aug 14. Erratum in: Genet Med. 2015 Jan;17(1):93. doi: 10.1038/gim.2014.137..

PubMed [citation]

PMID:: 25122143

See all PubMed Citations (9)

Details of each submission

From CFTR2 - CFTR2, SCV000071568.4

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000074430.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change falls in intron 12 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 23974870, 25122143). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1679+1.6kbA>G or c.1811+1.6kbA>G. ClinVar contains an entry for this variant (Variation ID: 53338). Studies have shown that this variant results in an insertion of 49 bp from intron 12 into the transcript, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7534040). 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 Mendelics, SCV001137480.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR-France, SCV001169393.1

#	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, SCV002711001.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.1680-886A>G (also known as c.1679+1634A>G and 1811+1.6kbA>G) pathogenic mutation results from an A to G substitution 886 nucleotides upstream from coding exon 13 of the CFTR gene. This pathogenic mutation creates a significant reduction in the amount of CFTR mRNA and individuals identified with this alteration in trans with another severe pathogenic alteration were demonstrated to have pancreatic insufficiency (Chillon M et al. Am J Hum Genet. 1995;56:623-629). This pathogenic mutation was further described in 11 compound heterozygotes and 2 homozygous individuals, all who presented with elevated sweat chloride levels, severe pulmonary manifestations, and pancreatic insufficiency (Reboul MP et al. J Med Genet. 2002;39(11):e73). Based on the supporting evidence, this alteration is interpreted 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 Johns Hopkins Genomics, Johns Hopkins University, SCV003927249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Disease-causing CFTR variant. 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV007332257.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CFTR c.1680-886A>G variant (rs397508266) (also known as 1811+1.6kb A>G) has been reported in patients diagnosed with classic cystic fibrosis and pancreatic insufficiency (Chillon 1995, Reboul 2002, Sosnay 2013). This variant is absent from the Genome Aggregation Database(v2.1.1), indicating it is not a common polymorphism. This is an intronic variant and computational analyses (Alamut Visual Plus v.1.12) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Functional analyses demonstrate the loss of wildtype splicing and the aberrant inclusion of 49bp in intron 11, leading to instability of the resulting transcript (Chillon 1995). Based on available information, this variant is considered to be pathogenic. References: Chillon M et al. A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811+1.6kbA-->G, produces a new exon: high frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype. Am J Hum Genet. 1995 Mar;56(3):623-9. Reboul MP et al. Splice mutation 1811+1.6kbA>G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients. J Med Genet. 2002 Nov;39(11):e73. 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.

#	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

Last Updated: Feb 15, 2026

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