ClinVar Genomic variation as it relates to human health

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 84 of the CFTR protein (p.Tyr84His). This variant is present in population databases (rs745756794, gnomAD 0.003%). 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: 498176). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Variant summary: CFTR c.250T>C (p.Tyr84His) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250904 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although cited in the literature within settings of carrier screening of individuals with no prior family history of Cystic Fibrosis or in unaffected controls (e.g., Picci_2010, Rosendahl_2012), to our knowledge, this variant has not been reported among individuals affected with Cystic Fibrosis. However, c.250T>C has been reported in the literature as a carrier genotype in at-least one individual affected with infertility (e.g., Chamayou_2020). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis or CFTR-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32357917, 19897426, 22427236). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.Y84H variant (also known as c.250T>C), located in coding exon 3 of the CFTR gene, results from a T to C substitution at nucleotide position 250. The tyrosine at codon 84 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in two healthy control individuals (Picci L et al. J. Cyst. Fibros., 2010 Jan;9:29-35; Rosendahl J et al. Gut, 2013 Apr;62:582-92), and in one Sicilian male with infertility (Chamayou S et al. BMC Med Genet, 2020 05;21:89). This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The CFTR c.250T>C variant is predicted to result in the amino acid substitution p.Tyr84His. This variant has been reported in the heterozygous state in an individual with male infertility (Table 1, Chamayou et al. 2020. PubMed ID: 32357917). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.