The CFTR c.1680-886A>G variant is predicted to interfere with splicing. **Use**, which is predicted to interfere with splicing. This variant, also referred to as c.1679+1634A>G, c.1679+1.6kbA>G, or 1811+1.6kb A-->G, results in introduction of a 49bp exon between exons 12 and 13 and has previously been reported to be causative for Cystic Fibrosis (reported as a cryptic exon between exons 11 and 12 in Chillón et al. 1995 PubMed ID: 7534040; Sosnay et al. 2013. PubMed ID: 23974870; Steiner et al. 2011. PubMed ID: 21520337). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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.

Variant summary: The CFTR c.1679+1634A>G variant involves the alteration of a non-conserved intronic nucleotide and 4/5 splice prediction tools predict a significant impact on normal splicing (creation of a novel splicing donor site). cDNA studies proved the aberrant splicing (Chillon_1995). This variant is absent in 30882 control chromosomes (gnomAD). This variant has been reported in many affected individuals. Functional studies showed that individuals with genotype deltaF508/c.1679+1634A>G have only 1%-3% of normal CFTR mRNA. This loss of 97% of normal CFTR mRNA must be responsible for the pancreatic insufficiency and for the severe CF phenotype in these patients (Chillion_1995 and Sosnay_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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.

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

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.