ClinVar Genomic variation as it relates to human health

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3, PM5, PP3, PP4

This sequence change replaces isoleucine with threonine at codon 444 of the CFTR protein (p.Ile444Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with congenital bilateralabsence of the vas deferens (CBAVD) (PMID: 21520337). 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 disruptive. 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.

Observed with a pathogenic variant on the opposite allele (in trans) or with another variant for which phase was unknown in multiple patients with congenital absence of vas deferens in the published literature and in a reputable database (Claustres 2017, Akinsal 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29484681, 21520337)

Variant summary: CFTR c.1331T>C (p.Ile444Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003239) 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 2.9e-05 in 242776 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1331T>C has been reported at a heterozygous state, without second variant in CFTR in several individuals affected with congenital absence of vas deferens (example, Steiner_2011, Akinsal_2018, Gaikwad_2020). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 29484681, 34145097, 21520337). ClinVar contains an entry for this variant (Variation ID: 551988). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.I444T variant (also known as c.1331T>C), located in coding exon 10 of the CFTR gene, results from a T to C substitution at nucleotide position 1331. The isoleucine at codon 444 is replaced by threonine, an amino acid with similar properties. This variant was detected in the heterozygous state in multiple individuals with congenital absence of the vas deferens (CAVD); however, a second mutation was not identified (Steiner B et al. Hum Mutat, 2011 Aug;32:912-20; Akinsal EC et al. Andrologia, 2018 Feb; Gaikwad A et al. Indian J Med Res, 2020 Dec;152:575-583). This amino acid position is highly 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.