ClinVar

Description

Variant summary: CFTR c.508C>T (p.Arg170Cys) results in a non-conservative amino acid change located in the first transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 252182 control chromosomes (gnomAD and publication data). This frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (5.6e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.508C>T, has been reported in compound heterozygous state in at least 2 patients affected with cystic fibrosis (Soltysova_2017, Erdogan_2021), and in heterozygous state (or without a 2nd variant specified) in individuals affected with suspected CF, alcohol-related pancreatitis, congenital absence of the vas deferens (Bernardino_2003, Casals_2004, Sharma_2014, Pagin_2016), but was also found in controls (Le Marechal_2001, Modiano_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, two different missense changes affecting the same amino acid (R170E and R170G) showed defect in transport to the Golgi complex (PMID: 33771570). The following publications have been ascertained in the context of this evaluation (PMID: 14526128, 15097853, 15126740, 19812525, 15536480, 16251901, 24958810, 11379874, 26900683, 28544683, 30592194, 34860163, 33771570). Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.