ClinVar Genomic variation as it relates to human health

Variant summary: The variant identified by MLPA or other technology involves the deletion of exons 3 and part of exon 4 (i.e. the last exon) in the MECP2 gene. A presumed nomenclature of c.(26+1_27-1)_(1018_1253)del has been designated for the purposes of this classification. While this deletion is not expected to cause nonsense mediated decay (NMD), since the exact breakpoints are not known it is predicted to either create a large in-frame deletion, or a frameshift resulting in truncated protein, a known mechanism of disease. The variant was absent in 16120 control chromosomes (gnomAD database, structural variants dataset). Deletion variants, consistent with the coordinates of c.(26+1_27-1)_(1018_1253)del, has been reported in the literature in several individuals affected with Rett Syndrome (e.g. Schollen_2003, Laccone_2004, Vidal_2019), and in most of these patients the breakpoints within exon 4 were localized in a 'deletion prone region' (DPR; from c.1057 to c.1207) of the coding sequence (Laccone_2004, Vidal_2019). These data indicate that the variant is very likely to be associated with disease. At least one of these publications analyzed the transcript level effect of a deletion found in a patient (i.e. c.27-3929_c.1184del), and found that a part of intron 2, exon 3, intron 3, and the proximal portion of exon 4 were deleted, which were congruent with the deletion breakpoints that had been defined in the genomic DNA (Laccone_2004). At least one clinical diagnostic laboratory has submitted clinical-significance assessments for a similar variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.