ClinVar Genomic variation as it relates to human health

This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_STR, PP3

Variant summary: CFTR c.3896C>T (p.Thr1299Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249246 control chromosomes (gnomAD). c.3896C>T has been reported in the literature in multiple individuals affected with cystic fibrosis (e.g. Liechti-Gallati_1999, Rock_2005, Alonso_2007, Ooi_2015, Minso_2020, Gonska_2021), including patients who carried a 2nd pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10439967, 16202788, 17331079, 25963003, 33020115, 34814176). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic (n=1) or VUS (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The CFTR c.3896C>T; p.Thr1299Ile variant (rs397508634), is reported in the literature in individuals with a suspected diagnosis of cystic fibrosis, including with the common pathogenic F508del variant on the opposite chromosome (Alonso 2007, Liechti-Gallati 1999, Ooi 2015, Rock 2005). This variant is reported in ClinVar (Variation ID: 53844), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 1299 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Thr1299Ile variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007 Mar;71(Pt 2):194-201. Liechti-Gallati S et al. Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. Eur J Hum Genet. 1999 Jul;7(5):590-8. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. Rock MJ et al. Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing. J Pediatr. 2005 Sep;147(3 Suppl):S73-7.