Description
The MECP2 c.844C>T p.(Arg282Ter) nonsense variant, also known as c.808C>T p.(Arg270Ter), occurs in the last exon of the gene, and the resulting transcript may escape nonsense-mediated mRNA decay. However, the premature truncation, which occurs in the transcriptional repression domain, has also been shown to disrupt a conserved AT-hook domain that functions in DNA binding (Baker et al. 2013). This variant has been identified in individuals with a phenotype consistent with Rett syndrome or other MECP2-related disorder, including in some individuals in whom the variant occurred de novo (Laccone et al. 2001; Philippe et al. 2006; Yan et al. 2019; Liu et al. 2020; Martinez-Granero et al. 2021). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013). Transgenic mice expressing the variant in the absence of wildtype MECP2 recapitulated features of the clinical phenotype observed in human patients, including reduced lifespan, brain atrophy, and neurological signs (Baker et al. 2013). Based on the available evidence, the c.844C>T p.(Arg282Ter) variant is classified as pathogenic for MECP2-related disorders.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | unknown | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
