ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The CFTR c.1163C>T; p.Thr388Met variant (rs143860237) is reported in the literature in an individual with asthma (Tzetis 2001) and an individual with congenital bilateral absence of the vas deferens (Dayangac 2004). It is reported in ClinVar (Variation ID: 495887), and is observed in the general population at an overall frequency of 0.015% (43/282316 alleles) in the Genome Aggregation Database. The threonine at codon 388 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.601). Due to limited information, the clinical significance of the p.Thr388Met variant is uncertain at this time. REFERENCES Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. PMID: 15070876. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001 Mar;108(3):216-21. PMID: 11354633.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 388 of the CFTR protein (p.Thr388Met). This variant is present in population databases (rs143860237, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis, congenital bilateral absence of the vas deferens, or asthma (PMID: 11354633, 15070876, 26708955). This variant is also known as c.1295C>T. ClinVar contains an entry for this variant (Variation ID: 495887). 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 methionine 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.

The p.T388M variant (also known as c.1163C>T), located in coding exon 9 of the CFTR gene, results from a C to T substitution at nucleotide position 1163. The threonine at codon 388 is replaced by methionine, an amino acid with similar properties. This variant was first reported in an individual with cystic fibrosis (CF) and pancreatic insufficiency (Zielenski J et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids; 5-23-96); however, a second CFTR alteration was not identified. This variant was also reported in one individual with asthma, normal sweat chloride levels, and no classic symptoms of CF (Tzetis M et al. Hum. Genet. 2001 Mar; 108(3):216-21). In addition, this variant has been seen in individuals with a clinical diagnosis of congenital bilateral absence of the vas deferens (CBAVD) who did not have a second CFTR alteration (Dayangaç D et al. Hum. Reprod. 2004 May; 19(5):1094-100; Akinsal EC et al. Andrologia, 2018 Feb). This amino acid position is well conserved in available vertebrate species; however, methionine is the reference amino acid in other 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.1163C>T (p.Thr388Met) results in a non-conservative amino acid change in 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 0.00016 in 250946 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00016 vs 0.013), allowing no conclusion about variant significance. c.1163C>T has been reported in the literature as heterozygous in individuals affected with CFTR-Related Diseases including CF, CBAVD/CUAVD, asthma, and in children with positive newborn screening, without strong evidence for causality (example, Schrijver_2016, Dayangac_2004, Akinsal_2018, Tzetis_2001, Bozdogan_2021). These reports do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 86.1% 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: 26990548, 29484681, 33572515, 15070876, 29589582, 26708955, 11354633, 38388235). ClinVar contains an entry for this variant (Variation ID: 495887). Based on the evidence outlined above, the variant was classified as uncertain significance.

The CFTR c.1163C>T variant is predicted to result in the amino acid substitution p.Thr388Met. In the heterozygous state, this variant has been reported in a patient with asthma or COPD (Tzetis et al. 2001. PubMed ID: 11354633; Table S1, Saferali et al. 2022. PubMed ID: 34996830), and has also been reported in a patient with congenital bilateral absence of the vas deferens (CBAVD) (Dayangaç et al. 2004. PubMed ID: 15070876). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.