ClinVar

Description

The p.H412Y variant (also known as c.1234C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1234. The histidine at codon 412 is replaced by tyrosine, an amino acid with similar properties. This variant was first described in two unrelated adults with moderate to severe aplastic anemia. In cells transfected with this variant, telomerase activity decreased to approximately 50% of wild type, whereas other alterations studied resulted in activity levels of <1% of wild type (Yamaguchi H et al. N. Engl. J. Med., 2005 Apr;352:1413-24). In addition, this variant was found in an individual with pulmonary fibrosis, pulmonary hypertension and a telomere length 25% shorter than healthy individuals and this individual's father with idiopathic pulmonary fibrosis (Marchand-Adam S et al. Am. J. Respir. Crit. Care Med., 2013 Aug;188:402-4). In another study, this variant was detected in trans with the p.P704S alteration in the TERT gene in an individual with osteoporosis, short telomeres, and normal peripheral blood cell counts. This individual&rsquo;s son was homozygous for the p.P704S alteration and presented with characteristic features of dyskeratosis congenita. Functional analysis of the the p.H412Y variant demonstrated a reduced telomerase activity of 36% of wild type (Du HY et al. Blood, 2008 Feb;111:1128-30). Additional functional studies showed that the p.H412Y variant resulted in a 15% decrease in activity in vitro (Alder JK et al. Proc. Natl. Acad. Sci. U.S.A., 2008 Sep;105:13051-6), whereas another study showed no change in activity or processivity in vitro or in human cell lines (Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on available evidence to date, the clinical significance of this alteration remains unclear.