This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1130 of the CFTR protein (p.Gly1130Ala). This variant is present in population databases (rs397508550, gnomAD 0.006%). This missense change has been observed in individual(s) with CFTR-related conditions and/or congenital absence of vas deferens (PMID: 15070876, 31005549, 32357917, 34140271). ClinVar contains an entry for this variant (Variation ID: 53730). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.G1130A variant (also known as c.3389G>C), located in coding exon 21 of the CFTR gene, results from a G to C substitution at nucleotide position 3389. The glycine at codon 1130 is replaced by alanine, an amino acid with similar properties. This alteration has been described in patients with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with other pathogenic mutation in CFTR; however, phase of the alterations was not specified (Dayangaç D et al. Hum Reprod, 2004 May;19:1094-100; Ocak Z et al. Turk J Med Sci, 2014;44:347-51). This alteration has also been reported in infertility cohorts (Morea A et al. Mol Hum Reprod, 2005 Aug;11:607-14; Chamayou S et al. BMC Med Genet, 2020 05;21:89), and in conjunction with a with pathogenic mutation in CFTR in an individual with no clinical diagnosis of cystic fibrosis and intermediate sweat chloride levels (Terlizzi V et al. J Cyst Fibros, 2019 07;18:484-490). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance.

Variant summary: CFTR c.3389G>C (p.Gly1130Ala) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 3.1e-05 in 292134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3389G>C has been reported in the literature in individuals affected with Congenital bilateral absense of the vas deferens (CBAVD) or infertility (Dayangac_2004, Havasi_2010, Ocak_2014, Chamayou_2020) and in an individual with intermediate sweat chloride levels but no diagnosis of Cystic fibrosis (Terlizzi_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15070876, 16126774, 20100616, 25536748, 31005549, 32357917, 34140271, 39855646). ClinVar contains an entry for this variant (Variation ID: 53730). Based on the evidence outlined above, the variant was classified as uncertain significance.