ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.3121A>C (p.Lys1041Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain 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 4.1e-05 in 245616 control chromosomes (gnomAD); all occurrences were observed in the Latino subpopulation. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (4.1e-05 vs 0.0063), allowing no conclusion about variant significance. c.3121A>C has been reported in a non-peer reviewed abstract in an individual affected with Cystic Fibrosis (Nelemi_2017). This report does not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk/CF/CFTR-related disorder. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Li_2018). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1041 of the CFTR protein (p.Lys1041Gln). This variant is present in population databases (rs769448889, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 439492). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29475947). 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 frequency of this variant in the general population, 0.00029 (10/34494 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a functional study which suggests the Lys1041 residue may be important for CFTR protein chloride channel function (PMID: 29475947 (2018), 25944907 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

The p.K1041Q variant (also known as c.3121A>C), located in coding exon 19 of the CFTR gene, results from an A to C substitution at nucleotide position 3121. The lysine at codon 1041 is replaced by glutamine, an amino acid with similar properties. In one study, this variant showed a decrease in chloride conductance to 80% of wild type (Li MS et al. J. Biol. Chem., 2018 Apr;293:5649-5658). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.

The CFTR c.3121A>C variant is predicted to result in the amino acid substitution p.Lys1041Gln. Functional studies of the p.Lys1041Gln variant suggest this variant impacts protein function (Li et al. 2018. PubMed ID: 29475947). This variant is reported in 0.029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.