ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.535C>T (p.Arg179Trp) (rs61748420)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000193537 SCV000247973 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000498300 SCV000589567 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The R167W variant in the MECP2 gene has been reported previously in association with intellectual disability and language impairment in multiple hemizygous males from unrelated families (Gomot et al., 2003; Bianciardi et al., 2016; Sheikh et al., 2016). Impaired social interactions, behavioral issues, obesity, and tremors have also been reported in association with the hemizygous presence of the R167W variant (Gomot et al., 2003; Bianciardi et al., 2016; Sheikh et al., 2016). Heterozygous carrier females with resting tremors have been reported (Gomot et al., 2003). The R167W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R167W 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. Functional studies show the R167W mutant protein is defective, as when expressed in mouse myoblast cells, chromocenter clustering reduced in size and increased in number (Sheikh et al., 2016). We interpret R167W as a pathogenic variant.
Invitae RCV000688107 SCV000815707 likely pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 167 of the MECP2 protein (p.Arg167Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with X-linked intellectual disability in the hemizygous male individuals in a family (PMID: 11309367, 14598336). It has also been reported in male individuals and a family with X-linked intellectual disability, as well as in heterozygous, unaffected females (PMID: 27929079, 26490184, 26350204). ClinVar contains an entry for this variant (Variation ID: 143603). Experimental studies have shown that this missense change results in a protein that causes alterations in chromatin organization (PMID: 27929079). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000193537 SCV001164193 uncertain significance Rett syndrome 2017-11-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000498300 SCV001246090 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
RettBASE RCV000133142 SCV000188134 uncertain significance Mental retardation, X-linked, syndromic 13 2011-02-15 no assertion criteria provided curation

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