rs28934904

Positions:

• chrX-154031431-G-A
• chrX-154031431-G-C
• chrX-154031431-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PM2_Supporting PS4 PM1 PS2

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: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:45 U:1 O:1
• Conservation: PhyloP100: 9.46

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:45 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:22 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.0	D;D;.;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Uncertain	0.022	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.95		Loss of MoRF binding (P = 0.0236);.;Loss of MoRF binding (P = 0.0236);.;Loss of MoRF binding (P = 0.0236);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28934904; hg19: chrX-153296882;