ClinVar Genomic variation as it relates to human health

This sequence change affects a donor splice site in intron 14 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs141158996, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7683952, 9239681, 12815607, 20059485, 23974870). This variant is also known as 2622+1G>A. ClinVar contains an entry for this variant (Variation ID: 7175). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Variant summary: The CFTR c.2490+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict the variant to abolish the canonical splice donor site. This variant was found in 2/109598 control chromosomes at a frequency of 0.0000182, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been cited in numerous classic CF patients in the literature in trans with pathogenic variants, including deltaF508. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.

The CFTR c.2490+1G>A variant (rs141158996), also known as 2622+1G>A, has been identified in many individuals affected with pancreatic insufficient forms of cystic fibrosis (see link for CFTR2 database, Audrezet 1993, Dorfman 2010, Krenkova 2013, Scotet 2003, Sosnay 2013) and at least one individual with congenital bilateral absence of the vas deferens (De Braekeleer 1996). It is also reported as pathogenic in ClinVar (Variation ID: 7175). This variant abolishes the splice donor site of intron 13 and is predicted to alter splicing (Alamut v.2.11). Based on available information, this variant is considered pathogenic. References: Link to CFTR2 database: https://cftr2.org/ Audrezet M et al. Identification of 12 novel mutations in the CFTR gene. Hum Mol Genet. 1993 Jan;2(1):51-4. De Braekeleer M et al. Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 1996 Sep;2(9):669-77. Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 May;77(5):464-73. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. Scotet V et al. Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. Hum Mutat. 2003 Jul;22(1):105. Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.

The c.2490+1G>A intronic pathogenic mutation (also known as 2622+1G>A) results from a G to A one nucleotide after coding exon 14 of the CFTR gene. This mutation was first described in an affected two-year-old with cystic fibrosis, including pancreatic insufficiency and pulmonary disease, in conjunction with p.F508del (Audrézet MP et al. Hum. Mol. Genet., 1993 Jan;2:51-4). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and an increased rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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 pathogenic.

The CFTR c.2490+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as c.2622+1G>A, has been repeatedly documented as pathogenic in individuals with cystic fibrosis (Audrezet et al. 1993. PubMed ID: 7683952; Scotet et al. 2003. PubMed ID: 12815607; Sosnay et al. 2013, PubMed ID: 23974870; https://cftr2.org/mutation/scientific/2622%252B1G-%253EA). Multiple clinical diagnostic labs have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7175/). This variant is reported in 0.0021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.