ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.271G>A (p.Gly91Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Although this variant alters a conserved nucleotide located in the exonic-splice region, 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250610 control chromosomes. c.271G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with features of Cystic Fibrosis (example, Claustres_2000, Feldmann_2003, Sarles_2014, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Han_2018). The most pronounced variant effect results in approximately 1.6% of normal residual CFTR function. One clinical diagnostic laboratory and two databases (CFTR-2 and CFTR-France) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.