ClinVar Genomic variation as it relates to human health

The CFTR c.2079T>G variant is predicted to result in the amino acid substitution p.Phe693Leu. This variant has been reported with a minor allele frequency as high as 0.12% in African populations including one homozygous individual (http://gnomad.broadinstitute.org/variant/7-117232300-T-G), and has been reported as likely benign and a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/194336/). The c.2079T>G variant has been reported in a CFTR database with the patient presenting with severe asthma (http://www.genet.sickkids.on.ca/MutationDetailPage.external?sp=1209). A different nucleotide substitution, c.2077T>C, resulting in the same amino acid change (p.Phe693Leu) has been reported in a patient with pancreatic insufficiency (http://www.genet.sickkids.on.ca/MutationDetailPage.external?sp=343). This variant has been reported individuals with cystic fibrosis (Groman et al. 2002. PubMed ID: 12167682; Mutesa et al. 2008. PubMed ID: 19017867), pancreatic insufficient cystic fibrosis (Boyne et al. 2000. PubMed ID: 10970190), and healthy individuals (Vankeerberghen et al. 1998. PubMed ID: 9736778). Functional studies have shown that the p.Phe693Leu variant did not significantly affect chloride transport when compared to wild-type CFTR channels (Vankeerberghen et al. 1998. PubMed ID: 9736778). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant summary: CFTR c.2079T>G (p.Phe693Leu) results in a non-conservative amino acid change located in the regulator domain (IPR025837) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 253336 control chromosomes (gnomAD and Monaghan_2004), predominantly at a frequency of 0.0009 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (7.9e-05 vs 0.013), allowing no conclusion about variant significance. c.2079T>G has been reported in the literature in compound heterozygosity with the 5T variant in an individual affected with Non-Classic Cystic Fibrosis and with p.F508del in a compound heterozygous individual with transient hypertrypsinaemia (e.g. Groman_2002, Boyne_2000). It has also been reported as an uninformative genotype (zygosity/second allele not specified) in an individual affected with Cystic Fibrosis, in the heterozygous state in two individuals with CF-like disease who also harbored variants in the SCNN1G and/or SCNN1B genes as well as in a healthy individual in compound heterozygosity with a pathogenic variant (e.g. Vankeerberghen_1998, Schrijver_2005b, Mutesa_2009). In addition, another variant (c.2077T>C) which leads to the same amino acid change as c.2079T>G, has been reported in a CF patient with an alternative cause for the disease phenotype (e.g. Ferec_1995). These reports do not allow any strong conclusions to be made regarding an association between c.2079T>G and disease. In a functional study, the variant did not significantly affect chloride transport ability in comparison to WT, suggesting it has little to no impact on protein function (Vankeerberghen_1998). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=7) and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The p.F693L variant (also known as c.2079T>G), located in coding exon 14 of the CFTR gene, results from a T to G substitution at nucleotide position 2079. The phenylalanine at codon 693 is replaced by leucine, an amino acid with highly similar properties. This alteration was observed in an individual with cystic fibrosis-like disease; however, a second CFTR alteration was not documented (Mutesa L et al. Chest, 2009 May;135:1233-42). This alteration was also identified in conjunction with p.F508del in an individual with pancreatic insufficient cystic fibrosis; however, the phase was not provided (Boyne J et al. J Med Genet. 2000;37(7):543-7). An in vitro functional study found that this variant did not significantly affect chloride transportation or the maturation of the protein (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.