ClinVar

Description

The CFTR c.3737C>T; p.Thr1246Ile variant (rs397508600) is reported in the literature in the compound heterozygous state with a different pathogenic variant in individuals affected with cystic fibrosis, a CFTR-related disorder, or borderline sweat chloride levels with no other significant symptoms (Claustres 2000, El-Seedy 2012, Goubau 2009, Masica 2015, Sermet-Gaudelus 2010, Sosnay 2017). This variant is reported in ClinVar (Variation ID: 53799), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1246 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses of the variant protein demonstrate 13% of wild-type function, consistent with an intermediate effect (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic with variable clinical consequences. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR, White TB, Farrell PM, et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2.