ClinVar Genomic variation as it relates to human health

The p.Lys1080Gln variant in CFTR has not been previously reported in individuals with pulmonary disease, but has been identified in 3/116974 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7 66126240). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, the clini cal significance of the p.Lys1080Gln variant is uncertain. ACMG/AMP Criteria app lied: PM2.

This sequence change replaces lysine with glutamine at codon 1080 of the CFTR protein (p.Lys1080Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs766126240, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 32003094). ClinVar contains an entry for this variant (Variation ID: 517253). 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 p.K1080Q variant (also known as c.3238A>C), located in coding exon 20 of the CFTR gene, results from an A to C substitution at nucleotide position 3238. The lysine at codon 1080 is replaced by glutamine, an amino acid with some similar properties. A recent functional study on a different amino acid substitution at this same position, p.K1080R, showed reduced amounts of protein maturing in the ER but ultimately normal levels of CFTR protein trafficking to the cell surface (Lee et al. Mol Cell Biol. 2014;34(14):2554-65). The p.K1080Q variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is conserved in all available species, except lamprey. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.K1080Q remains unclear.

Variant summary: CFTR c.3238A>C (p.Lys1080Gln) results in a conservative amino acid change in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251086 control chromosomes. c.3238A>C has been reported in the literature in at-least two individuals affected with Cystic Fibrosis (Kilinc_2020, Lui_2017). These data indicate that the variant may be associated with disease. 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: 32003094, 28344137). ClinVar contains an entry for this variant (Variation ID: 517253). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The CFTR c.3238A>C variant is predicted to result in the amino acid substitution p.Lys1080Gln. This variant has been reported along with the c.1521_1523del (p.Phe508del) pathogenic variant in two apparently unrelated individuals with CFTR-related disorder (Lui et al. 2017. PubMed ID: 28344137; Kilinc et al. 2020. PubMed ID: 32003094). This variant was also documented in a cohort of individuals with chronic obstructive pulmonary disease (Table S1, Saferali et al. 2022. PubMed ID: 34996830). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.