The p.Asp156Gly variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with phenotype consistent with Rett syndrome (PMID 11309679, 11241840) (PM6_strong). The p.Asp156Gly variant in MECP2 has been observed in at least 2 other individuals with clinical features of Rett syndrome (PMID 11309679, 11241840) (PS4_moderate). The p.Asp156Gly variant occurs in the well-characterized methyl-binding domain (MBD) functional domain of MECP2 (PMID 1326358, 23770565) (PM1). A pathogenic missense variant (p.Asp156Glu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 11524741, 15737703, 26984561, 27354166, 12843318, 26418480, internal database - Invitae) (PM5). The p.Asp156Gly variant in MECP2 is absent from gnomAD (PM2_supporting). Chromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Asp156Gly variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM5, PS3_supporting, PM2_supporting, PP3).