ClinVar Genomic variation as it relates to human health

Converted during submission to Pathogenic.

NM_000492.3(CFTR):c.3528delC(K1177Sfs*15, aka 3659delC) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3528delC(K1177Sfs*15, aka 3659delC) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

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

The p.Lys1117SerfsX15 variant in CFTR (c.3528delC, also reported in the past as c.3659delC) is a well-established pathogenic variant in individuals with cystic fibrosis and is often associated with pancreatic insufficiency. It was classified as pathogenic on Mar 17, 2017 by the ClinGen-approved CFTR2 expert panel and is included in the ACMG Technical Standards and Guidelines for CFTR Mutation Testing (ClinVar Variation ID 35868) (Kerem 1990 PMID:2236053, Grody 2001 PMID:11280952, Sosnay 2013 PMID:23974870, Ooi 2012 PMID: 22658665). It has also been identified in 0.028% (36/128698) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1117 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis and other CFTR-related disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CFTR-related disorders. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting.

This sequence change creates a premature translational stop signal (p.Lys1177Serfs*15) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs762828343, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 15371902, 23974870). This variant is also known as c.3659delC . ClinVar contains an entry for this variant (Variation ID: 35868). For these reasons, this variant has been classified as Pathogenic.

The CFTR c.3528del, p.Lys1177SerfsTer15 variant (rs78984783), also known as 3659delC, is reported in the literature in numerous individuals affected with cystic fibrosis and is often associated with pancreatic insufficiency (Kerem 1990, Sosnay 2013, CFTR2 database). The variant is listed in ClinVar (Variation ID: 35868), and observed in the general population at a frequency of 0.016% (44/282148 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990; 87(21):8447-51. PMID: 2236053. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870.

The c.3528delC pathogenic mutation, located in coding exon 22 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 3528, causing a translational frameshift with a predicted alternate stop codon (p.K1177Sfs*15). This alteration was identified in an individual with cystic fibrosis in conjunction with p.G551D (Adam RJ et al. JCI Insight, 2016 Apr;1:e86183). This alteration is also associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 3659delC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

The CFTR c.3528delC variant is predicted to result in a frameshift and premature protein termination (p.Lys1177Serfs*15). This variant, also described as 3659delC, has previously been reported to be causative for cystic fibrosis (Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870; https://cftr2.org/). This variant is reported in 0.028% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.