ClinVar Genomic variation as it relates to human health

The CFTR variant, c.365A>G; p.Tyr122Cys, has been described individuals suspected to have mild cystic fibrosis (CF) (de Cid 2010, SickKids database). This variant is reported as uncertain significance in ClinVar (Variation ID: 411120), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 122 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, a different variant at this residue, c.364T>C; p.Tyr122His, has been described in an individual affected with congenital bilateral absence of the vas deferens (CBAVD) (Radpour 2006). Due to limited information, the clinical significance of the p.Tyr122Cys variant is uncertain at this time. References: Link to SickKids database for Tyr122Cys: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1624 de Cid R et al.Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas. 2010 Mar;39(2):209-15. Radpour R et al. Two novel missense and one novel nonsense CFTR mutations in Iranian males with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 2006 12(11):717-21.

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the CFTR protein (p.Tyr122Cys). This variant is present in population databases (rs377295859, gnomAD 0.005%). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 19812525). ClinVar contains an entry for this variant (Variation ID: 411120). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.Y122C variant (also known as c.365A>G), located in coding exon 4 of the CFTR gene, results from an A to G substitution at nucleotide position 365. The tyrosine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in the homozygous state in an individual with chronic pancreatitis (de Cid R et al. Pancreas, 2010 Mar;39:209-15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

Variant summary: CFTR c.365A>G (p.Tyr122Cys) 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 251088 control chromosomes. c.365A>G has been reported in the literature in the homozygous state in at least one individual affected with chronic pancreatitis (deCid_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 28.05% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 25087612, 19812525). ClinVar contains an entry for this variant (Variation ID: 411120). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.