ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Tyr275*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 10794365, 16963320). ClinVar contains an entry for this variant (Variation ID: 35890). For these reasons, this variant has been classified as Pathogenic.

Variant summary: CFTR c.825C>G (p.Tyr275X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249138 control chromosomes. c.825C>G has been reported in the literature in individuals affected with Classic Cystic Fibrosis (Bernardino 2000, McGinniss 2005, Claustres 2017, Dankert-Roelse 2018). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence, evaluating the basal and drug induced read-through levels of this premature termination codon, and reported less than 0.5% basal read-through activities and low levels of drug induced responses (Pranke 2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Y275* pathogenic mutation (also known as c.825C>G) located in coding exon 7 of the CFTR gene, results from a C to G substitution at nucleotide position 825. This changes the amino acid from a tyrosine to a stop codon within coding exon 7. This mutation was originally described newborn with severe disease who is also heterozygous for p.F508del (Bernardino AL et al. Genet Test. 2000;4:69-74). It was later reported in a 3 year old with positive sweat chlorides and classic CF presentation (McGinniss et al Hum Genet 2005; 118: 331-338) as well as in a newborn with elevated sweat chloride levels and a second disease causing allele (Dankert-Roelse JE et al. J. Cyst. Fibros., 2019 Jan;18:54-63). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.