ClinVar Genomic variation as it relates to human health

The CFTR c.253G>C; p.Gly85Arg variant, is reported as a rare CFTR variant in Africa and Asia (Abubakar Bobbo 2023), as well as Belgium populations (De Wachter 2017); however, published clinical information is limited. This variant is also reported in ClinVar (Variation ID: 2567868). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.956). Additionally, a different variant at this codon (p.Gly85Glu) is a well-established pathogenic variant (see ClinVar Variation ID: 7143), suggesting the glycine 85 residue is critical for protein function. Based on available information, this variant is considered to be likely pathogenic. References: Abubakar Bobbo K et al. A comprehensive review of cystic fibrosis in Africa and Asia. Saudi J Biol Sci. 2023 Jul;30(7):103685. PMID: 37313453. De Wachter E et al. What can the CF registry tell us about rare CFTR-mutations? A Belgian study. Orphanet J Rare Dis. 2017 Aug 22;12(1):142. PMID: 28830496.

The p.G85R variant (also known as c.253G>C), located in coding exon 3 of the CFTR gene, results from a G to C substitution at nucleotide position 253. The glycine at codon 85 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in the Belgian CF registry in an individual who had a sweat chloride >60 mmol/L (De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The CFTR c.253G>C variant is predicted to result in the amino acid substitution p.Gly85Arg. This variant has been reported in an individual in the Belgian Cystic Fibrosis Registry; however, the presence of an additional variant was not specified (De Wachter et al. 2017. PubMed ID: 28830496). It is absent in a large population database, indicating it is rare. Alternative nucleotide changes affecting the same amino acid (p.Gly85Glu, p.Gly85Val) have been reported in individuals with cystic fibrosis (Kerem et al. 1997. PubMed ID: 9271620; Casals et al. 1997. PubMed ID: 9439669). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.