ClinVar Genomic variation as it relates to human health

CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information.

This sequence change replaces phenylalanine with tyrosine at codon 575 of the CFTR protein (p.Phe575Tyr). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and tyrosine. This variant is present in population databases (rs773569201, ExAC 0.002%). This missense change has been observed in individual(s) with recurrent pancreatitis (PMID: 17003641). ClinVar contains an entry for this variant (Variation ID: 619674). 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: "Tolerated"; PolyPhen-2: "Probably 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 CFTR c.1724T>A; p.Phe575Tyr variant (rs773569201) is reported in the literature in multiple individuals affected with pancreatitis and unspecified CFTR-related disorders who also carried pathogenic variant F508del and was confirmed in trans in at least one case (Keiles 2006, McCague 2019). This variant along with R117H has also been reported in an individual with borderline sweat chloride levels who was receiving treatment for CFTR-related disorders (Sontag 2005). This variant is reported in ClinVar (Variation ID: 619674) and is found in the non-Finnish European population with an allele frequency of 0.003% (3/113216 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein demonstrated activity of ~17% of wildtype (McCague 2019, Raraigh 2018). Computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on available information, this variant is considered to be likely pathogenic- mild. References: Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. McCague AF et al. Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis. Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126. PMID: 30888834. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. Sontag MK et al. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr. 2005 Sep;147(3 Suppl):S83-8. PMID: 16202790.

The p.F575Y variant (also known as c.1724T>A), located in coding exon 13 of the CFTR gene, results from a T to A substitution at nucleotide position 1724. The phenylalanine at codon 575 is replaced by tyrosine, an amino acid with highly similar properties. This variant was first reported in an infant with borderline sweat tests in conjunction with p.R117H; however, phase information was not provided (Sontag MK, et al. J. Pediatr. 2005 Sep; 147(3 Suppl):S83-8). In addition, this variant was identified in an individual with pancreatitis in trans with p.F508del (Keiles S, et al. Pancreas. 2006 Oct; 33(3):221-7). Experimental studies show that this alteration reduces CFTR function compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: CFTR c.1724T>A (p.Phe575Tyr) results in a conservative amino acid change located in the ATP-binding domain (IPR009147) 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 1.6e-05 in 250402 control chromosomes (gnomAD). c.1724T>A has been reported in the compound heterozygous state in at least 4 patients diagnosed with recurrent pancreatitis and unspecified CFTR-Related disease phenotypes, who carried the common pathogenic variant p.Phe508del in trans (Keiles_2006, McCague_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant has approximately 15-20% of wild-type activity as assessed in vitro (Raraigh_2018). The CFTR2 database reports that this variant has varying consequences and that some patients with this variant and another CF-causing variant have CF while others do not. The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 29805046, 30888834). ClinVar contains an entry for this variant (Variation ID: 619674). Based on the evidence outlined above, the variant was classified as likely pathogenic.