ClinVar Miner

Submissions for variant NM_004992.3(MECP2):c.473C>T (p.Thr158Met) (rs28934906)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507589 SCV000604152 pathogenic not specified 2017-04-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623451 SCV000740723 pathogenic Inborn genetic diseases 2014-09-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Ambry Genetics RCV000715117 SCV000845943 pathogenic History of neurodevelopmental disorder 2016-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Athena Diagnostics Inc RCV000012580 SCV000255791 pathogenic Rett syndrome 2012-07-25 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000012580 SCV000781705 pathogenic Rett syndrome 2016-11-01 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000133129 SCV000280901 pathogenic not provided 2015-10-22 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000012580 SCV000537706 pathogenic Rett syndrome 2016-06-08 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000012580 SCV000257511 pathogenic Rett syndrome 2014-05-21 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000133129 SCV000804259 pathogenic not provided 2015-04-03 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000133129 SCV000331102 pathogenic not provided 2015-10-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763199 SCV000893818 pathogenic Severe neonatal-onset encephalopathy with microcephaly; MECP2 duplication syndrome; Mental retardation, X-linked, syndromic 13; Rett syndrome; Autism, susceptibility to, X-linked 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000133129 SCV000191038 pathogenic not provided 2018-10-29 criteria provided, single submitter clinical testing T158M is a recurrent missense substitution that accounts for 9-12% of MECP2 pathogenic variants and has been identified in females with both classic and atypical Rett syndrome (Percy et al., 2007; Neul et al., 2008; Bao et al., 2013; RettBASE). The T158M variant has also been reported in patients who did not meet clinical criteria for Rett syndrome, including a female with pervasive developmental disorder, males with severe neonatal-onset encephalopathy, and individuals with clinical features suggestive of Angelman syndrome (Suter et al., 2014; Kleefstra et al., 2005; Villard et al., 2000). This variant alters a highly conserved residue in the methyl-binding domain of the protein. Multiple studies indicate that T158M impairs normal protein function (Kudo et al., 2003; Agarwal et al., 2011). The presence of T158M is consistent with the diagnosis of Rett syndrome
Genetic Services Laboratory, University of Chicago RCV000012580 SCV000247971 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000012580 SCV000845272 pathogenic Rett syndrome 2018-08-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012580 SCV000282491 pathogenic Rett syndrome 2015-09-29 criteria provided, single submitter clinical testing
Invitae RCV000170110 SCV000645667 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 158 of the MECP2 protein (p.Thr158Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (rs28934906, ExAC no frequency). This variant has been reported in greater than 10% of individuals diagnosed with Rett syndrome and is considered one of the most common causes of the disease (PMID: 18337588, 23270700, 23421866, RettBASE). It is typically associated with earliest onset among pathogenic variants in MECP2 (PMID: 23421866). In at least one case, this variant was shown to arise de novo (PMID: 10508514). ClinVar contains an entry for this variant (Variation ID: 11811). Experimental studies have shown that this missense change partially reduces the affinity of MECP2 for methylated DNA (PMID: 10852707, 11058114, 11738866, 12843318, 21831886). When expressed in mice, this variant is associated with survival and severity comparable to the complete loss of the protein (PMID: 26647311). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000012580 SCV000537196 likely pathogenic Rett syndrome 2015-07-17 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000012580 SCV000223837 pathogenic Rett syndrome criteria provided, single submitter clinical testing
OMIM RCV000012580 SCV000032815 pathogenic Rett syndrome 2007-07-01 no assertion criteria provided literature only
OMIM RCV000170110 SCV000032816 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2007-07-01 no assertion criteria provided literature only
RettBASE RCV000169935 SCV000188121 pathogenic Autism, susceptibility to, X-linked 3 2014-02-26 no assertion criteria provided curation
RettBASE RCV000170109 SCV000222431 pathogenic Angelman syndrome 2014-02-26 no assertion criteria provided curation
RettBASE RCV000170110 SCV000222432 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2014-02-26 no assertion criteria provided curation
RettBASE RCV000012580 SCV000222433 pathogenic Rett syndrome 2014-02-26 no assertion criteria provided curation

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