ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.433C>T (p.Arg145Cys) (rs28934904)

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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081202 SCV000191035 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing R133C is a recurrent pathogenic variant that accounts for 4-7% of MECP2 pathogenic variants (Percy et al., 2007). This variant is often observed in females with the preserved speech variant of Rett syndrome, but has also been identified in females with classic and atypical Rett syndrome and in a male with hypotonia, developmental delay, and a movement disorder (RettBASE; Leonard et al., 2003; Neul et al., 2008; Bebbington et al., 2008; Masuyama et al., 2005). The R133C 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 alters a highly conserved position in the methyl-binding domain of the protein, and functional studies indicate that it impairs binding to methylated DNA (Yusufzai et al., 2000; Galvao et al., 2005).
Genetic Services Laboratory, University of Chicago RCV000030666 SCV000193634 pathogenic Rett syndrome 2013-07-16 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000030666 SCV000223850 pathogenic Rett syndrome criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081202 SCV000230257 pathogenic not provided 2016-10-03 criteria provided, single submitter clinical testing
Neurogenetics Laboratory - MEYER, AOU Meyer RCV000030666 SCV000494539 pathogenic Rett syndrome 2016-11-16 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000445570 SCV000537194 uncertain significance not specified 2015-07-16 criteria provided, single submitter clinical testing
Invitae RCV000460141 SCV000544618 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 133 of the MECP2 protein (p.Arg133Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs28934904, ExAC no frequency). This variant has been reported in 4-7% of individuals diagnosed with Rett syndrome (PMID: 23421866, 11738879, 26418480, 16473305, 22368975). It is typically associated with a later age of onset (>6 y/o) than other pathogenic variants in MECP2 (PMID: 23421866). ClinVar contains an entry for this variant (Variation ID: 11809). Experimental studies have shown that this missense variant reduces the affinity of MECP2 for methylated DNA, although the effect is less than for other MECP2 variants (PMID: 21831886, 10852707, 11058114, 12843318, 11738866). When expressed in mice, this variant is associated with intermediate survival between those expressing the wild-type protein and those with complete loss of the protein (PMID: 26647311). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000081202 SCV000604146 pathogenic not provided 2017-09-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030666 SCV000698538 pathogenic Rett syndrome 2016-09-29 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.397C>T (p.Arg133Cys) variant involves the alteration of a non-conserved nucleotide. Arg133 is located in the Methyl-CpG DNA binding domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This prediction was confirmed by one functional study showing MECP2 R133C resulted in the complete disruption of its ability to bind to methylated DNA (Yusufzai_2000). This variant has been reported as a de novo variant in numerous RTT patients, some of whom are reported to have a mild phenotype, and is one of the most common pathogenic variant in MECP2. This variant is absent in 87882 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624907 SCV000740730 pathogenic Inborn genetic diseases 2014-09-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000081202 SCV000842734 pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715531 SCV000846360 pathogenic History of neurodevelopmental disorder 2017-09-30 criteria provided, single submitter clinical testing The p.R133C pathogenic mutation (also known as c.397C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 397. The arginine at codon 133 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation (also referred to as c.471C>T) was originally identified as a de novo alteration in a sporadic case with Rett syndrome (Amir RE et al. Nat. Genet., 1999 Oct;23:185-8). Subsequently, this mutation has been described in numerous individuals with Rett syndrome (Philippe C et al. Eur J Med Genet, 2006 Jan-Feb;49:9-18; Bao X et al. Dev Med Child Neurol, 2013 Jun;55:553-8). p.R133C is one of the most common missense mutations in MECP2 and currently represents 4.7% of all MECP2 variants reported in the IRSA MECP2 Variation Database (RettBASE) (Christodoulou J et al. Hum. Mutat., 2003 May;21:466-72). This mutation is located in the highly conserved methyl-CpG binding domain of the MECP2 protein and impairs binding to methylated DNA in vitro (Yusufzai TM and Wolffe AP. Nucleic Acids Res., 2000 Nov;28:4172-9; Free A et al. J. Biol. Chem., 2001 Feb;276:3353-60). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation.
Mendelics RCV000030666 SCV001142093 pathogenic Rett syndrome 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081202 SCV001246093 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Strasbourg University Hospital RCV001257757 SCV001434569 pathogenic Intellectual disability 2020-04-20 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000081202 SCV001447106 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000081202 SCV001449965 pathogenic not provided 2019-03-26 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000030666 SCV001622394 pathogenic Rett syndrome 2021-02-12 criteria provided, single submitter research A heterozygous de novo missense variation in exon 3 of the MECP2 gene that results in the amino acid substitution of Cysteine for Arginine at codon 145 was detected. The observed variant c.433C>T (p.Arg145Cys) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
OMIM RCV000012578 SCV000032812 pathogenic Rett syndrome, zappella variant 2009-03-01 no assertion criteria provided literature only
OMIM RCV000030666 SCV000032813 pathogenic Rett syndrome 2009-03-01 no assertion criteria provided literature only
GeneReviews RCV000030666 SCV000041140 pathogenic Rett syndrome 2019-09-16 no assertion criteria provided literature only
RettBASE RCV000169934 SCV000188081 pathogenic Angelman syndrome 2013-12-05 no assertion criteria provided curation
RettBASE RCV000170107 SCV000222428 pathogenic Mental retardation, X-linked, syndromic 13 2013-12-05 no assertion criteria provided curation
RettBASE RCV000030666 SCV000222429 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000030666 SCV000257510 pathogenic Rett syndrome 2010-04-30 no assertion criteria provided clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000030666 SCV000574734 pathogenic Rett syndrome 2016-10-03 no assertion criteria provided clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000081202 SCV000804251 pathogenic not provided 2015-04-03 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000030666 SCV001149829 pathogenic Rett syndrome 2019-02-21 no assertion criteria provided clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000030666 SCV001738788 pathogenic Rett syndrome no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000081202 SCV001741949 pathogenic not provided no assertion criteria provided clinical testing

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