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: PM3_STR, PM2_SUP, PP3, PP4

Variant summary: CFTR c.4193T>G (p.Ile1398Ser) results in a non-conservative amino acid change located in the AAA+ ATPase domain 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 8e-06 in 250670 control chromosomes. To our knowledge, c.4193T>G has been not been reported in the literature reporting primary evidence in individuals affected with Cystic Fibrosis. However, one database (sickkids) reports its presence in 25 years old twins with pancreatic insufficiency (sweat chloride levels of 66 mmol/l and 56 mmol/l, respectively) in compound heterozygosity with CFTR c.1522_1524delTTT (p.Phe508del). In addition, one individual with a clinical diagnosis of CF, tested for CFTR gene sequencing at our laboratory carried this variant and another pathogenic CFTR allele (c.3909C>G/p.Asn1303Lys). The phase of these variants is not available. 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

CFTR c.4193T>G has been previously identified in multiple individuals with features of cystic fibrosis who also have a second CF-associated variant, although the phase of these variants is not known. This variant (rs397508692) is rare (<0.1%) in a large population dataset (gnomAD: 2/250670 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar (Variation ID: 53914). Two bioinformatic tools queried predict that this amino acid substitution would be damaging, and the isoleucine residue at this position is evolutionarily conserved across most species assessed. In addition, bioinformatic analysis predicts that this variant may affect normal exon 26 (legacy exon 23) splicing, although this has not been confirmed experimentally to our knowledge. We consider the clinical significance of CFTR c.4193T>G to be uncertain at this time

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1398 of the CFTR protein (p.Ile1398Ser). This variant is present in population databases (rs397508692, gnomAD 0.002%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 34782259). ClinVar contains an entry for this variant (Variation ID: 53914). 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.