ClinVar

Description

Variant summary: CFTR c.1744A>T (p.Thr582Ser) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250028 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1744A>T has been reported in an individual with bronchiectasis as well as an individual with CBAVD, however, both individuals were pancreatic sufficient, had sweat chloride levels greater than 60 mmol/L, and a second CFTR allele was not identified in either case (Cystic Fibrosis Mutation Database). Additionally, in the literature, the variant has been reported in the heterozygous state in infertile patients (Chamayou_2019, Chamayou_2020), but was also reported in controls (Morea_2005). These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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: 15463919, 32357917, 31848897, 35913788, 25880441, 16126774, 25735457, 26277102). Two other submitters have provided clinical-significance assessments for this variant in ClinVar (evaluation after 2014) and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.