ClinVar

Description

The p.I1148T variant (also known as c.3443T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide position 3443. The isoleucine at codon 1148 is replaced by threonine, an amino acid with similar properties. In two studies, this alteration was detected in cohorts of individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) at rates of 8.7% and 9% (Mak CM, et al. J. Hum. Genet. 2008 ; 53(1):55-63, Wang LH, et al. J. Hum. Genet. 2011; 56(9):660-5). In one functional study, authors showed that this alteration did not show a loss of expression of full length protein on western blot, but they explained that the alteration is present in a b-sheet, with its functional group facing toward the nucleotide binding pocket, and may therefore affect hydrophobicity (Luoma LM, et al. Hum. Mutat. 2010;31(5):569-77). This alteration has been detected in both the heterozygous and homozygous state in several chromosomes from individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) (Gu S, et al. PLoS ONE 2013;8(7):e66526, Loudianos G, et al. Eur. J. Hum. Genet.;6(5):487-91, Dedoussis GV, et al. Ann. Hum. Genet. 2005;69(Pt 3):268-74, Panagiotakaki E, et al. Am. J. Med. Genet. A 2004;131(2):168-73, Vrabelova S, et al. Mol. Genet. Metab. ; 86(1-2):277-85, Panichareon B, et al. Eur J Med Genet ; 54(2):103-7). This variant was previously reported in the SNPDatabase as rs60431989, but was not reported in the 1000 Genomes Project or the NHLBI Exome Sequencing Project (ESP) population-based cohorts. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.