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

dbSNP: rs28934904

Total submissions: 46

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000030666	SCV002540680	pathogenic	Rett syndrome	2022-05-10	reviewed by expert panel	curation	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).
GeneDx	RCV000081202	SCV000191035	pathogenic	not provided	2021-03-10	criteria provided, single submitter	clinical testing	Recurrent pathogenic variant that accounts for 4-7% of MECP2 pathogenic variants (Percy et al., 2007); 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 (Agarwal et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22368975, 10508514, 11738866, 26064184, 23421866, 18332345, 31139143, 10852707, 23270700, 11738879, 12843318, 11058114, 21831886, 26418480, 26647311, 26795593, 27255190, 18174548, 12746406, 18337588, 16122633, 16314321, 27929079, 25533962, 16077729, 28135719, 26175308, 11738864, 28394482, 29655203, 30536762, 29915382, 31535341, 31647993, 31623504, 32631363, 12030010, 31130284, 33098801)
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
Eurofins Ntd Llc (ga)	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 Children's Health, Delaware	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	2024-01-17	criteria provided, single submitter	clinical testing	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.
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	2022-05-23	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000624907	SCV000846360	pathogenic	Inborn genetic diseases	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
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000030666	SCV001149829	pathogenic	Rett syndrome	2019-02-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics 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 and Genomics, 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.
Revvity Omics, Revvity	RCV000081202	SCV002017248	pathogenic	not provided	2020-03-18	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000030666	SCV002059304	pathogenic	Rett syndrome	2020-09-08	criteria provided, single submitter	clinical testing
DASA	RCV000030666	SCV002061267	pathogenic	Rett syndrome	2022-01-05	criteria provided, single submitter	clinical testing	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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273925	SCV002558997	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000030666	SCV003807439	pathogenic	Rett syndrome	2022-03-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2, PM5 moderated, PM6 moderated, PP1 supporting, PP3 supporting
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000030666	SCV004022309	pathogenic	Rett syndrome	2023-08-01	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP5;PP3;PM2;PS4;PS2
Centre for Population Genomics, CPG	RCV000030666	SCV004098783	pathogenic	Rett syndrome	2023-08-14	criteria provided, single submitter	curation	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).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000030666	SCV004101513	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	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.
Genetics and Molecular Pathology, SA Pathology	RCV000030666	SCV004175641	pathogenic	Rett syndrome	2022-09-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000081202	SCV004220014	pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003984804	SCV004801154	pathogenic	Syndromic X-linked intellectual disability Lubs type	2024-03-14	criteria provided, single submitter	research
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	not provided	Rett syndrome		no assertion provided	literature only
RettBASE	RCV000169934	SCV000188081	pathogenic	Angelman syndrome	2013-12-05	no assertion criteria provided	curation
RettBASE	RCV000170107	SCV000222428	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	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
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
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000081202	SCV001927841	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081202	SCV001951591	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000081202	SCV001971593	pathogenic	not provided		no assertion criteria provided	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000030666	SCV004032208	pathogenic	Rett syndrome		no assertion criteria provided	research