ClinVar Genomic variation as it relates to human health

This CFTR variant (rs200899224) is rare (<0.1%) in large population datasets1,2 (gnomAD: 23/278104 total alleles; 0.00827%; no homozygotes). One submitter in ClinVar classifies the clinical significance of this variant as uncertain. This variant affects the first nucleotide of exon 10 (legacy exon 9), however bioinformatics tools do not predict that this variant will have a significant affect on exon 10 splicing. This has not been confirmed experimentally, to our knowledge. Of two bioinformatics tools queried, one predicts that this amino acid substitution would be probably damaging while the second predicts it would be tolerated. The glycine residue at this position is highly conserved across the species assessed. We consider the clinical significance of c.1210G>C uncertain at this time.

Variant summary: CFTR c.1210G>C (p.Gly404Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 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 8.9e-05 in 246874 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (8.9e-05 vs 0.013), allowing no conclusion about variant significance. c.1210G>C has been reported in the literature in a heterozygote following newborn screening (Skov_2020). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 404 of the CFTR protein (p.Gly404Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 495893). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.

The p.G404R variant (also known as c.1210G>C) is located in coding exon 10 of the CFTR gene. The glycine at codon 404 is replaced by arginine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 10. This variant was identified in a cohort of individuals undergoing CFTR sequencing; however, complete phenotype and genotype information was not provided (Ridge PG et al, 2013 Jan;3:3). This amino acid position is well 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.1210G>C; p.Gly404Arg variant (rs200899224), is reported in the literature in a cohort of individuals undergoing testing for cystic fibrosis (Ridge 2013), and in a newborn screen study (Skov 2020). This variant is also reported in ClinVar (Variation ID: 495893). It is observed in the general population with an overall allele frequency of 0.008% (23/278104 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.601). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ridge PG et al., Miller C, Bayrak-Toydemir P, Best DH, Mao R, Swensen JJ, Lyon E, Voelkerding KV. Cystic fibrosis testing in a referral laboratory: results and lessons from a six-year period. J Clin Bioinforma. 2013 Jan 23;3(1):3. PMID: 23343000. Skov M et al. Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years. Pediatr Pulmonol. 2020 Feb;55(2):549-555. PMID: 31682332.

The CFTR c.1210G>C variant is predicted to result in the amino acid substitution p.Gly404Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.