ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.504C>G (p.Asp168Glu) (rs61748408)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081204 SCV000191037 pathogenic not provided 2017-10-02 criteria provided, single submitter clinical testing The D156E pathogenic variant in the MECP2 gene has been reported multiple times in association with Rett syndrome (Yamada et al., 2001; Huppke et al., 2002; Lima et al., 2009; RettBASE). The D156E variant is not observed in large population cohorts (Lek et al., 2016). The D156E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this variant alters a conserved residue in the methyl CpG binding domain, and in vitro functional assays indicate that D156E severely impairs heterochromatin binding and transcriptional repression (Kudo et al., 2003).
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000169946 SCV000223858 pathogenic Rett syndrome criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081204 SCV000230259 pathogenic not provided 2013-01-31 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000169946 SCV000247969 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000815972 SCV000956455 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 156 of the MECP2 protein (p.Asp156Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Rett syndrome (PMID: 11524741, 27354166, 12075485,  19722030, 16672765, 16473305) including multiple de novo observations (PMID: 15737703, 22182064, 26984561). ClinVar contains an entry for this variant (Variation ID: 95196). Experimental studies have shown that this missense change impairs heterochromatin binding and transcriptional repression (PMID: 12843318) and destabilizes the MECP2 protein (PMID: 26418480) This variant disrupts the p.Asp156 amino acid residue in MECP2. Other variants that disrupt this residue have been observed in affected individuals (PMID: 15737703, 18021529, 11309679, 22182064), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
RettBASE RCV000169946 SCV000188113 pathogenic Rett syndrome 2016-04-26 no assertion criteria provided research

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