The p.V1108L variant (also known as c.3322G>C), located in coding exon 20 of the CFTR gene, results from a G to C substitution at nucleotide position 3322. The valine at codon 1108 is replaced by leucine, an amino acid with highly similar properties. This alteration was reported in a 37 year old with CBAVD and no other clinical manifestations of cystic fibrosis; he was also heterozygous for the 11-5T variant, phase not reported (Grangeia A, Genet. Med. 2007 Mar; 9(3):163-72). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: CFTR c.3322G>C (p.Val1108Leu) results in a 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 1.6e-05 in 250936 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3322G>C has been reported in the literature as a non-informative genotype (second allele not-specified) or in cis with a pathogenic CFTR allele in individuals with features of CBAVD or chronic bronchitis (COPDGene study cohort) (example, Grangeia_2007, Steiner_2011, Pagin_2016, Safareli_2022). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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: 17413420, 26900683, 34996830, 21520337, 26277102, 29216686). ClinVar contains an entry for this variant (Variation ID: 53719). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1108 of the CFTR protein (p.Val1108Leu). This variant is present in population databases (rs397508542, gnomAD 0.004%). This missense change has been observed in individual(s) with a CFTR-related disorder and congenital absence of the vas deferens (PMID: 17413420, 28603918). ClinVar contains an entry for this variant (Variation ID: 53719). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 CFTR c.3322G>C; p.Val1108Leu variant (rs397508542; ClinVar Variation ID: 53719) is reported in the literature in an individual affected with congenital absence of the vas deferens who also carried a pathogenic-mild CFTR variant (Grangeia 2007), and has been observed in individuals with CFTR-associated conditions, but where the existence of a second allele was not specified (Pagin 2016, Saferali 2022, de Souza 2018). However, it has also been confirmed in cis with severe variants (Steiner 2011 and Claustres 2017). This variant is only observed on four alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.758). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. PMID: 28603918. de Souza DAS et al. Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling. Andrology. 2018 Jan;6(1):127-135. PMID: 29216686 Grangeia A et al. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007;9(3):163-172. PMID: 17413420 Pagin A et al. Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis. PLoS One. 2016 Feb 22;11(2):e0149426. PMID: 26900683 Saferali A et al. CFTR variants are associated with chronic bronchitis in smokers. Eur Respir J. 2022 Aug 10;60(2):2101994. PMID: 34996830 Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. PMID: 21520337.