ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.2978A>G (p.Asp993Gly) 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. The variant allele was found at a frequency of 4e-06 in 251120 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2978A>G has been reported in the literature as a compound heterozygous genotype in an individual affected with Cystic Fibrosis (Sofia_2008) and in trans with F508del in an individual with moderate pulmonary symptoms (Staphylococcus infections) and an episode of pancreatitis in childhood, but who had negative sweat chloride test results (SickKids CFTR database). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30134826). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 993 of the CFTR protein (p.Asp993Gly). This variant is present in population databases (rs777904861, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.