ClinVar Genomic variation as it relates to human health

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD

Variant summary: CFTR c.3872A>G (p.Gln1291Arg) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these splicing predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250580 control chromosomes (gnomAD). c.3872A>G has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis (e.g. Doerk_1994, Lucarelli_2015). These data indicate that the variant is very likely to be associated with disease. Functional assays using CFTR deficient Bronchial Epithelial cells showed the variant had 62.3% residual activity, with the authors concluding the variant had varying clinical consequences (Rareigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 7525450, 25910067, 29805046). Four ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Q1291R variant (also known as c.3872A>G), located in coding exon 23 of the CFTR gene, results from an A to G substitution at nucleotide position 3872. The glutamine at codon 1291 is replaced by arginine, an amino acid with highly similar properties. This variant was identified in conjunction with p.F508del in an individual with pancreatic insufficient cystic fibrosis (CF) (Dörk T et al. Hum. Genet., 1994 Nov;94:533-42). In a cohort of individuals with CF and CFTR-related disorders, this variant was detected in the homozygous state; however, clinical information was not provided (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403). This variant was also detected in conjunction with p.F508del in an individual with abnormal newborn screening, equivocal sweat chloride results, and an abnormal nasal potential difference (Sermet-Gaudelus I et al. Thorax, 2010 Jun;65:539-44). It was the only variant identified in an individual with congenital bilateral absence of the vas deferens (Bienvenu T et al. Hum. Genet., 1995 Jun;95:698-702). Analysis of a rectal biopsy from an individual with this variant demonstrated aberrant splicing from the Q1291R allele due to use of a cryptic splice site and resulting in the inclusion of 29 base pairs and predicted to create a premature stop codon (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7). Functional analysis of this variant in CFBE cells demonstrated 62% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). The p.Q1291R alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). 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, the clinical significance of this alteration remains unclear.