Variant summary: CFTR c.647G>A (p.Trp216X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246204 control chromosomes (gnomAD and publication). The variant, c.647G>A, has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, including one homozygote (Anzai_2003, Clain_2005, Claustres_2000, Kammesheidt_2006, Shen_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The CFTR c.647G>A; p.Trp216Ter variant (rs397508775), also known as c.779G>A in traditional nomenclature, is reported in the literature in a homozygous or compound heterozygous state in multiple individuals affected with cystic fibrosis (Clain 2005, Claustres 2000, Kammesheidt 2006, Shen 2016) or congenital bilateral absence of the vas deferens (Anzai 2003). This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 54033), and is only observed on one allele in the Genome Aggregation Database. 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: Anzai C et al. CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens. J Cyst Fibros. 2003 Mar;2(1):14-8. Clain J et al. Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype. Hum Mutat. 2005 Apr;25(4):360-71. 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):143-56. Kammesheidt A et al. Comprehensive genetic analysis of the cystic fibrosis transmembrane conductance regulator from dried blood specimens--implications for newborn screening. Genet Med. 2006 Sep;8(9):557-62. Shen Y et al. Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016 Apr;171:269-76.e1.

The c.647G>A variant in CFTR is a nonsense variant predicted to introduce a stop codon at amino acid 216. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 15776432, 16980811). Given the available evidence, this variant is classified as Pathogenic.

The p.W216* pathogenic mutation (also known as c.647G>A), located in coding exon 6 of the CFTR gene, results from a G to A substitution at nucleotide position 647. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This mutation has been identified in individuals with congenital absence of the vas deferens and cystic fibrosis (CF), including one homozygous individual with CF (Claustres M et al. Hum. Mutat., 2000;16:143-56; Anzai C et al. J. Cyst. Fibros., 2003 Mar;2:14-8; Kammesheidt A et al. Genet. Med., 2006 Sep;8:557-62; Shen Y et al. J. Pediatr., 2016 Apr;171:269-76.e1). 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.