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rs28934904

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong

The NM_001110792.2(MECP2):c.433C>T(p.Arg145Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

MECP2
NM_001110792.2 missense

Scores

13
3
1

Clinical Significance

Pathogenic reviewed by expert panel P:43U:1O:1

Conservation

PhyloP100: 9.46

Links

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
?
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001110792.2
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 23.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-154031430-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 143559.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
?
Variant X-154031431-G-A is Pathogenic according to our data. Variant chrX-154031431-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154031431-G-A is described in Lovd as [Pathogenic]. Variant chrX-154031431-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.433C>T p.Arg145Cys missense_variant 3/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.397C>T p.Arg133Cys missense_variant 4/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.433C>T p.Arg145Cys missense_variant 3/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.397C>T p.Arg133Cys missense_variant 4/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:43Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:21Other:1
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanySep 08, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2009- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergAug 01, 2023This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP5;PP3;PM2;PS4;PS2 -
Pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGAug 14, 2023This 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, no assertion criteria providedclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsOct 03, 2016- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 29, 2016Variant 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 submitterclinical testingNeuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine-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 providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalApr 30, 2010- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Klinikum rechts der IsarFeb 21, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologySep 16, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 16, 2013- -
Pathogenic, criteria provided, single submitterclinical testingNeurogenetics Laboratory - MEYER, AOU MeyerNov 16, 2016- -
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, no assertion criteria providedclinical testingGénétique des Maladies du Développement, Hospices Civils de Lyon-- -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The 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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelMay 10, 2022The 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, no assertion criteria providedresearchPediatric Department, Xiangya Hospital, Central South University-- -
Pathogenic, criteria provided, single submitterresearchFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsFeb 12, 2021A 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 submitterclinical testingMolecular Genetics Laboratory, Children's Mercy Hospital and Clinics-- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinMar 02, 2022ACMG classification criteria: PS3 supporting, PS4 strong, PM2, PM5 moderated, PM6 moderated, PP1 supporting, PP3 supporting -
not provided Pathogenic:14
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 23, 2022In 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 29, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncMay 23, 2022This 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, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 10, 2021Recurrent 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) -
Pathogenic, no assertion criteria providedclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaApr 03, 2015- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalMar 26, 2019- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, Revvity OmicsMar 18, 2020- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 03, 2016- -
Inborn genetic diseases Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 08, 2014- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2017The 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. -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 17, 2022This 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. 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 submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -
Rett syndrome, zappella variant Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2009- -
Angelman syndrome Pathogenic:1
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingDiagnostic Laboratory, Strasbourg University HospitalApr 20, 2020- -
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 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
32
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28934904; hg19: chrX-153296882; API