ClinVar Miner

Submissions for variant NM_004992.3(MECP2):c.401C>G (p.Ser134Cys) (rs61748390)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000133095 SCV000247967 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000375578 SCV000329817 pathogenic not provided 2018-02-26 criteria provided, single submitter clinical testing The S134C missense variant in the MECP2 gene has been reported multiple times previously in association with Rett syndrome (Cheadle et al., 2000; RettBASE). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S134C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and different missense variants in the same codon (S134P, S134F) as well as multiple missense variants in nearby residues have been reported in association with Rett syndrome (Stenson et al., 2014; RettBASE), supporting the functional importance of this region of the protein. Additionally, functional studies suggest that the S134C variant reduces the ability of the MECP2 protein to bind and cluster heterochromatin (Agarwal et al., 2011). We interpret S134C as a pathogenic variant.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000133095 SCV000537175 likely pathogenic Rett syndrome 2015-07-07 criteria provided, single submitter clinical testing
Invitae RCV000698431 SCV000827093 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-11-22 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 134 of the MECP2 protein (p.Ser134Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Rett syndrome (PMID: 10814718, 11738864, 17089071, 12655490, 21160487, 11738883, 18337588), including several individuals in which the variant was found to be de novo (PMID: 10767337, 23696494, 22182064). ClinVar contains an entry for this variant (Variation ID: 143562). Experimental studies have shown that this missense change destabilizes the MBD domain of the MECP2 protein (PMID: 26418480). For these reasons, this variant has been classified as Pathogenic.
RettBASE RCV000133095 SCV000188085 pathogenic Rett syndrome 2011-11-01 no assertion criteria provided curation

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