rs28934904
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3PM2_SupportingPS4PM1PS2
This summary comes from the ClinGen Evidence Repository: The p.Arg133Cys (NM_004992) variant in MECP2 has been reported as an assumed de novo occurrence in at least 4 individuals with Rett Syndrome (PMID:10814718, PMID:10991688, PMID:12707946) (PS2_very-strong). The p.Arg133Cys variant has been observed in at least 4 other individuals with Rett Syndrome (PMID:10814718, PMID:10991688, PMID:12707946, PMID:17387578, PMID:16473305) (PS4). The p.Arg133Cys variant occurs in the well-characterized (Methyl-DNA binding [MDB]: aa 90-162) functional domain of the MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg133Cys variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary the p.Arg133Cys variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS2_very-strong, PS4, PM1, PP3, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211250/MONDO:0010726/016
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.433C>T | p.Arg145Cys | missense_variant | 3/3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.397C>T | p.Arg133Cys | missense_variant | 4/4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.433C>T | p.Arg145Cys | missense_variant | 3/3 | 1 | NM_001110792.2 | ENSP00000395535 | ||
MECP2 | ENST00000303391.11 | c.397C>T | p.Arg133Cys | missense_variant | 4/4 | 1 | NM_004992.4 | ENSP00000301948 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:22Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2009 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Sep 08, 2020 | - - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.R133C in MECP2 (NM_004992.4) has been previously reported in individuals affected with Rett Syndrome (Sheikh et al, 2016). Experimental studies reveal damaging effect on protein structure and function (Sheikh et al, 2016; Brown et al, 2016). The variant has been submitted to ClinVar as Pathogenic.The p.R133C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R133C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 133 of MECP2 is conserved in all mammalian species. The nucleotide c.397 in MECP2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Apr 30, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 16, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Aug 01, 2023 | This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP5;PP3;PM2;PS4;PS2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Feb 21, 2019 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | May 10, 2022 | The p.Arg133Cys (NM_004992) variant in MECP2 has been reported as an assumed de novo occurrence in at least 4 individuals with Rett Syndrome (PMID: 10814718, PMID: 10991688, PMID: 12707946) (PS2_very-strong). The p.Arg133Cys variant has been observed in at least 4 other individuals with Rett Syndrome (PMID: 10814718, PMID: 10991688, PMID: 12707946, PMID: 17387578, PMID: 16473305) (PS4). The p.Arg133Cys variant occurs in the well-characterized (Methyl-DNA binding [MDB]: aa 90-162) functional domain of the MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg133Cys variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary the p.Arg133Cys variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS2_very-strong, PS4, PM1, PP3, PM2_supporting). - |
Pathogenic, criteria provided, single submitter | research | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Feb 12, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 02, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2, PM5 moderated, PM6 moderated, PP1 supporting, PP3 supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.397C>T;p.(Arg133Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11809; OMIM: 300005.0001; PMID: 20301670; 12746406; 27929079; 28394482; 26175308; 23810759) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 27929079; 26647311; 23260135; 26418480) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (MBD) - PM1. This variant is not present in population databases (rs28934904, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID:547103) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 10508514; 23810759) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 28394482) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Sep 16, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | research | Pediatric Department, Xiangya Hospital, Central South University | - | - - |
Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Aug 14, 2023 | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria.Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as Pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome, or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 30, 2024 | PS3, PS4, PM2, PM5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Oct 03, 2016 | - - |
not provided Pathogenic:14
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2023 | Recurrent pathogenic variant that accounts for 4-7% of MECP2 pathogenic variants (PMID: 18174548); Published functional studies demonstrate that mutant R133C MeCP2 protein accumulates at chromocenters (in vivo) at a different, statistically significant, extent than the wild type protein (PMID: 21831886); 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 (PMID: 18332345, 12746406, 18337588, 16122633; RettBASE); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22368975, 10508514, 11738866, 26064184, 23421866, 31139143, 10852707, 23270700, 11738879, 12843318, 11058114, 26418480, 26647311, 26795593, 27255190, 12746406, 18337588, 16122633, 16314321, 27929079, 25533962, 16077729, 28135719, 26175308, 11738864, 28394482, 29655203, 30536762, 29915382, 31535341, 31647993, 31623504, 32631363, 32472557, 33860439, 32005694, 12030010, 31130284, 33098801, 35872528, 35599849, 34271245, 31440721, 31069529, 35074918, 18332345, 18174548, 21831886) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Mar 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 18, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 23, 2022 | In the published literature, this variant has been reported in multiple individuals with Rett syndrome (PMID: 12567420 (2003), 18332345 (2008), 26647311 (2016)). Although this variant has been reported in individuals with classical Rett syndrome, it appears to be associated with a milder clinical phenotype when compared to other disease-associated variants in this gene (PMID: 15057977 (2004), 18332345 (2008), 26175308 (2016)). A functional study reported this variant caused impaired DNA binding (PMID: 17101771 (2007), 26647311 (2016)), 34324427 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2022 | This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with Rett syndrome and neonatal encephalopathy. It also appears to occur de novo in multiple individuals. Although this variant has been reported in individuals with classical Rett syndrome, it appears to be associated with milder clinical phenotype when compared to other disease associated variants in this gene (PMID: 18332345, 26175308,15057977). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused impaired binding to DNA (PMID: 17101771, 34324427, 26647311). The variant is located in a region that is considered important for protein function and/or structure. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Apr 03, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 29, 2017 | - - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 133 of the MECP2 protein (p.Arg133Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 11738879, 16473305, 22368975, 23421866, 26418480). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 10852707, 11058114, 11738866, 12843318, 21831886, 26647311). For these reasons, this variant has been classified as Pathogenic. - |
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2022 | The c.397C>T (p.R133C) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 397, causing the arginine (R) at amino acid position 133 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, 1999). Subsequently, this mutation has been described in numerous individuals with Rett syndrome (Philippe, 2006; Bao, 2013; Zhang, 2017). 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, 2003). 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, 2000; Free, 2001). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Rett syndrome, zappella variant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2009 | - - |
Angelman syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Apr 20, 2020 | - - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
MECP2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 05, 2024 | The MECP2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Cys. This variant has been reported in over 25 publications to be causative for Rett syndrome; in some individuals, the variant was reported to occur de novo (see, for example, Amir et al. 1999. PubMed ID: 10508514; Bebbington et al. 2008. PubMed ID: 18332345; reported as c.421C>T, Stojanovic et al. 2019. PubMed ID: 31623504). Patients with this variant may present with a milder phenotype, which is consistent with in vitro functional studies and occurrence in male subjects (Leonard et al. 2003. PubMed ID: 12746406; Sheikh et al. 2016. PubMed ID: 27929079). An alternative nucleotide change affecting the same amino acid (p.Arg133Gly) has also been reported in an individual with Rett syndrome (Bienvenu et al. 2002. PubMed ID: 12180070). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jul 16, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at