ClinVar Genomic variation as it relates to human health

This sequence change replaces tyrosine with histidine at codon 1381 of the CFTR protein (p.Tyr1381His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 18782298). ClinVar contains an entry for this variant (Variation ID: 53900). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.

Variant summary: CFTR c.4141T>C (p.Tyr1381His) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Three 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 249708 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4141T>C has been reported in the literature in two individuals who also carried Delta F508: one was a CF patient, the other was a healthy carrier with normal sweat chloride levels (Sharma_2009, Terlizzi_2019). These data do not allow any conclusion about variant significance. 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: 19897426, 18782298, 31005549). Three submitters have cited 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.Y1381H variant (also known as c.4141T>C), located in coding exon 26 of the CFTR gene, results from a T to C substitution at nucleotide position 4141. The tyrosine at codon 1381 is replaced by histidine, an amino acid with similar properties. This variant was identified in conjunction with p.F508del in two individuals; one individual was reported to have cystic fibrosis while the other was healthy with normal sweat chloride levels (Sharma N et al. Ann Hum Genet, 2009 Jan;73:26-33; Terlizzi V et al. J Cyst Fibros, 2019 07;18:484-490). This amino acid position is not well conserved in available 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.