ClinVar Genomic variation as it relates to human health

NM_000492.3(CFTR):c.1477C>T(Q493*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 18456578. Classification of NM_000492.3(CFTR):c.1477C>T(Q493*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã

The CFTR c.1477C>T; p.Gln493Ter variant (rs77101217) has been reported in cystic fibrosis patients, often associated with pancreatic insufficiency (CFTR2 database, Kerem 1990, Ooi 2012, Sosnay 2013). This variant is also reported in ClinVar (Variation ID: 7107). It is only found on six alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Kerem BS et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. PMID: 2236053. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870.

The p.Q493* pathogenic mutation (also known as c.1477C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1477. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was originally described in an individual with cystic fibrosis (clinical criteria were not provided) and pancreatic insufficiency (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). This mutation was also observed in conjunction with the (TG)12-5T variant in a male with congenital bilateral absence of the vas deferens (CBAVD); however, phase was not determined (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). This mutation is associated with pancreatic insufficiency, pulmonary disease, and elevated sweat chloride levels (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Variant summary: The variant of interest causes a nonsense change involving a conserved nucleotide resulting in a predicted truncated CFTR protein, a known mechanism for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121326 (1/60663), which does not exceed the predicted maximum expected allele frequency for a pathogenic CFTR variant of 1/77. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable clinical laboratories/databases cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.

The CFTR c.1477C>T (p.Gln493Ter) stop-gained variant has been reported in at least four studies and is found in a total of six affected individuals including four compound heterozygotes, one complex heterozygote, and one presumed heterozygote (Kerem et al. 1990; Kristidis et al. 1992; Feuillet-Fieux et al. 2011; Steiner et al. 2011). Three of the compound heterozygotes have a clinical diagnosis of cystic fibrosis and pancreatic insufficiency and have the p.Phe508del variant as their second variant (Kristidis et al. 1992). Steiner et al. (2011) reported on a compound heterozygote with a diagnosis of congenital bilateral absence of the vas deferens. Feuillet-Fieux et al. (2011) identified a complex heterozygous individual, with a clinical diagnosis of cystic fibrosis based on sweat chloride values who had no other pulmonary or intestinal symptoms, who carried three other variants on the maternal allele and the p.Gln493Ter variant on the paternal allele. The p.Gln493Ter variant was absent from 2456 controls and is reported at a frequency of 0.000047 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the evidence available, the p.Gln493Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

This sequence change creates a premature translational stop signal (p.Gln493*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs77101217, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 1376016, 2236053, 12815607, 21184098, 21858268, 23974870). ClinVar contains an entry for this variant (Variation ID: 7107). For these reasons, this variant has been classified as Pathogenic.

Variant interpreted as Pathogenic and reported on 09-23-2020 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.