ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.3458T>A (p.Val1153Glu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250860 control chromosomes. c.3458T>A has been reported in the literature in individuals affected with Congenital absence of vas deferens and Cystic Fibrosis (Dork_1997, Ratbi_2007, Pagin_2016, McCague_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 18.7% of normal activity (Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 30888834, 26900683, 29805046, 17329263). ClinVar contains an entry for this variant (Variation ID: 53747). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The CFTR c.3458T>A (p.Val1153Glu) missense variant has been reported in four individuals, including in a compound heterozygous state with an intron variant in one individual with congenital bilateral absence of the vas deference (CBAVD), and in a heterozygous state without a second identified variant in one individual with cystic fibrosis, in one individual with CBAVD, and in one individual with allergic bronchopulmonary aspergillosis (Dörk et al. 1997; Padoan et al. 2002; Ratbi et al. 2007; Lebecque et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Residue Val1153 is located in transmembrane domain 12 of the CFTR channel, and expressing an alanine substitution at this residue in patch excised inside-out macropatches and single-channel patches from Xenopus oocytes resulted in altered pore properties and suggested that residue 1153 is located toward the intracellular side of the channel pore (Cui et al. 2012). Evidence for this variant is limited, and individuals with this variant in different molecular states have been reported with variable CFTR-related phenotypes. Therefore, the p.Val1153Glu variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces valine with glutamic acid at codon 1153 of the CFTR protein (p.Val1153Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is present in population databases (rs397508567, ExAC 0.008%). This missense change has been observed in individuals with congenital absence of the vas deferens and/or suspected cystic fibrosis (PMID: 9272157, 17329263, 26900683, 29805046). ClinVar contains an entry for this variant (Variation ID: 53747). 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 (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). 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.V1153E variant (also known as c.3458T>A), located in coding exon 21 of the CFTR gene, results from a T to A substitution at nucleotide position 3458. The valine at codon 1153 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been detected as compound heterozygous with other CFTR variants in individuals with congenital bilateral absence of the vas deferens (CBAVD), as well as asymptomatic individuals (Dörk T et al. Hum Genet, 1997 Sep;100:365-77; Steiner B et al. Hum Mutat, 2011 Aug;32:912-20; Claustres M et al. Hum Mutat, 2017 10;38:1297-1315; Pagin A et al. PLoS One, 2016 Feb;11:e0149426). This variant has also been detected in the heterozygous state in individuals with CBAVD or allergic bronchopulmonary aspergillosis (ABPA) who did not have a second variant identified (Ratbi I et al. Hum Reprod, 2007 May;22:1285-91; Lebecque P et al. Thorax, 2011 Jun;66:540-1). Functional analysis of this variant in CFBE cells demonstrated 18% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). This amino acid position is well 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.