ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.509C>T (p.Thr170Met) (rs28934906)

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Total submissions: 36
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000133129 SCV000191038 pathogenic not provided 2021-07-30 criteria provided, single submitter clinical testing 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); Also identified in males with severe neonatal-onset encephalopathy and in females who did not meet clinical criteria for Rett syndrome but had overlapping clinical features, including pervasive developmental disorder or clinical features suggestive of Angelman syndrome (Suter et al., 2014; Kleefstra et al., 2005; Villard et al., 2000); In vitro functional studies indicate that T158M impairs normal protein function (Yusufzai et al., 2000; Kudo et al., 2003; Agarwal et al., 2011; Lyst et al., 2013; Sheikh et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31031587, 12030010, 12843318, 21831886, 11071498, 28920956, 31535341, 31095231, 30945278, 30868116, 29655203, 30564305, 26175308, 28135719, 17236109, 17881312, 16077729, 25533962, 23921973, 12719401, 26418480, 26647311, 26795593, 23770565, 11058114, 10508514, 18337588, 18174548, 23421866, 14560307, 24511209, 23270700, 19442733, 19217433, 11738866, 11392517, 11738879, 10852707, 27929079)
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000012580 SCV000223837 pathogenic Rett syndrome criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000012580 SCV000247971 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000012580 SCV000255791 pathogenic Rett syndrome 2012-07-25 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012580 SCV000282491 pathogenic Rett syndrome 2015-09-29 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000133129 SCV000331102 pathogenic not provided 2015-10-02 criteria provided, single submitter clinical testing
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
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000012580 SCV000537706 pathogenic Rett syndrome 2016-06-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507589 SCV000604152 pathogenic not specified 2018-09-14 criteria provided, single submitter clinical testing The MECP2 c.473C>T; p.Thr158Met variant (rs28934906), is reported in the literature in multiple individuals affected with classical Rett syndrome (see link to RettBASE and references therein). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11811), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 158 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr158Met variant is considered to be pathogenic. References: Link to RettBASE (http://mecp2.chw.edu.au/cgi-bin/mecp2/search/process-search.cgi)
Invitae RCV000170110 SCV000645667 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2020-10-10 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.
Ambry Genetics RCV000623451 SCV000740723 pathogenic Inborn genetic diseases 2014-09-24 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000012580 SCV000781705 pathogenic Rett syndrome 2016-11-01 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
Ambry Genetics RCV000715117 SCV000845943 pathogenic History of neurodevelopmental disorder 2020-05-29 criteria provided, single submitter clinical testing The p.T158M pathogenic mutation (also known as c.473C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 473. The threonine at codon 158 is replaced by methionine, an amino acid with similar properties. As one of the most common Rett syndrome mutations, this mutation accounts for 10-13% of MECP2 mutations and has been seen in many individuals with classic Rett syndrome as well as in mildly affected individuals with preserved speech (Amir RE, et al. Nat. Genet. 1999;23(2):185-8.; Archer HL, et al. J. Med. Genet. 2006;43(5):451-6; Bebbington A, et al. J. Med. Genet. 2010;47(4):242-8; Archer H et al. J. Med. Genet., 2007 Feb;44:148-52; Huppke P et al. Hum. Mol. Genet., 2000 May;9:1369-75; The Deciphering Developmental Disorders Study. Nature. 2017 02;542(7642):433-438.; Guo H et al. Mol. Autism. 2018 Dec;9:64.; Tsang MH et al. Epilepsia Open. 2019 Mar;4(1):63-72.). This mutation has been documented in severely affected males, as well as in unaffected females with confirmed skewed X-chromosome inactivation that favors the expression of the normal allele (Villard L, et al. Neurology 2000;55(8):1188-93). In one study, in vitro functional analyses indicated that this mutation had intermediate affinity to heterochromatin and moderate effects on transcriptional repressive activity (Kudo S, J. et al. Med. Genet. 2003;40(7):487-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics,Fulgent Genetics RCV000763199 SCV000893818 pathogenic Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; Mental retardation, X-linked, syndromic 13; Rett syndrome; Autism, susceptibility to, X-linked 3 2018-10-31 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000012580 SCV000999345 pathogenic Rett syndrome criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000133129 SCV001246092 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000012580 SCV001426150 likely pathogenic Rett syndrome 2018-03-09 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000012580 SCV001428510 pathogenic Rett syndrome 2018-08-21 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000133129 SCV001447435 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000133129 SCV001450313 pathogenic not provided 2016-02-22 criteria provided, single submitter clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000012580 SCV001478268 pathogenic Rett syndrome criteria provided, single submitter clinical testing
Baylor Genetics RCV000012580 SCV001524903 pathogenic Rett syndrome 2020-02-17 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000012580 SCV000257511 pathogenic Rett syndrome 2014-05-21 no assertion criteria provided clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000133129 SCV000804259 pathogenic not provided 2015-04-03 no assertion criteria provided clinical testing
GeneReviews RCV000012580 SCV000998923 pathogenic Rett syndrome 2019-09-16 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000763199 SCV001450670 pathogenic Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; Mental retardation, X-linked, syndromic 13; Rett syndrome; Autism, susceptibility to, X-linked 3 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000133129 SCV001929477 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000133129 SCV001952757 pathogenic not provided no assertion criteria provided clinical testing

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