ClinVar

Description

The CFTR c.3154T>G; p.Phe1052Val variant (rs150212784) has been reported in patients diagnosed with cystic fibrosis (Brancolini 1995, Lakeman 2008, Mercier 1993, Onay 1998, Sosnay 2013) and CFTR-related disorders (Gallati 2009, Pelletier 2010, Puechal 2011, Tzetis 2007), and associated with varying clinical consequences (CFTR2 database). Functional studies indicate that the variant protein has normal maturation and conductance (Sosnay 2013, Van Goor 2014), but altered channel kinetics (Cotten 1996, Seibert 1996). The variant is reported in ClinVar (Variation ID: 35865). It is found in the general population with an overall allele frequency of 0.06% (177/281760 alleles, including 1 homozygote) in the Genome Aggregation Database. The phenylalanine at codon 1052 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.948). Based on available information, this variant is considered to be pathogenic with a variable presentation of clinical phenotypes. References: CFTR2 database: http://cftr2.org/ Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995; 96(3):312-8. Cotten J et al. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996; 271(35):21279-84. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008;12(1):25-35. Mercier B et al. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993; 16(1):296-7. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998; 102(2):224-30. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011; 70(4):653-9. Seibert F et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996; 271(25):15139-45. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007; 71(5):451-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36.