Menu
GeneBe

rs28934907

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001110792.2(MECP2):c.352C>T(p.Arg118Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 25)

Consequence

MECP2
NM_001110792.2 missense

Scores

15
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27

Conservation

PhyloP100: 4.35
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001110792.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-154032267-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant X-154032268-G-A is Pathogenic according to our data. Variant chrX-154032268-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032268-G-A is described in Lovd as [Pathogenic]. Variant chrX-154032268-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.352C>T p.Arg118Trp missense_variant 2/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.316C>T p.Arg106Trp missense_variant 3/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.352C>T p.Arg118Trp missense_variant 2/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.316C>T p.Arg106Trp missense_variant 3/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
25

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:27
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:14
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, IndiaJan 23, 2023- -
Pathogenic, criteria provided, single submitterclinical testingProvincial Medical Genetics Program of British Columbia, University of British ColumbiaJan 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenOct 21, 2019- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 06, 2018Variant summary: MECP2 c.316C>T (p.Arg106Trp) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A functional study, Yusufzai_2000, found the variant to abolish selectivity for methylated DNA binding. The variant was absent in 87536 control chromosomes (ExAC). The variant, c.316C>T, has been reported in the literature in multiple individuals affected with Rett Syndrome (Wan_1999, Cheadle_2000, Buyse_2000, Vacca_2001, and Zahorakova_2007). These data indicate that the variant is very likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 1999- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHMar 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterOct 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 27, 2021The MECP2 c.352C>T (p.Arg118Trp) missense variant, also noted as p.Arg106Trp in the literature, is a common pathogenic variant and accounts for 2.79% of cases as per RettBASE (Christodoulou et al. 2003). Across a selection of the available literature, the p.Arg118Trp variant has been reported in a heterozygous state in at least 20 unrelated individuals affected with Rett syndrome, and the variant is typically associated with early onset disorder (Amir et al. 1999; Bebbington et al. 2008; Khalili et al. 2020). The variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggest the variant is rare. The Arg118 residue is located in the critical methyl-CpG binding domain and is shown to result in significantly reduced chromatin binding and decreased MECP2 accumulation at chromocenters compared to wildtype (Agarwal et al. 2011; Sheikh et al. 2016). Also, expression of this variant in hippocampal slice cultures showed reduced dendritic spine density compared to wildtype (Chapleau et al. 2009). This variant was identified in a de novo state. Based on the available evidence, the p.Arg118Trp variant is classified as pathogenic for Rett syndrome. -
Pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGDec 11, 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 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting).Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). 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). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4).Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). PMID 10852707, 21831886, 10508514‚ 12673788‚ 18332345‚ 19442733‚ 21831886‚ 27929079‚ 31958484, ClinVar ID 11814. -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 14, 2015Microcephaly; Developmental delay; Seizures; Frequent hand to face movements -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratoire de Génétique Moléculaire, CHU BordeauxApr 24, 2020- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Heidelberg UniversityOct 26, 2022- -
Pathogenic, no assertion criteria providedcurationRettBASEJun 12, 2013- -
not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 16, 2012It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with Rett syndrome (PMIDs: 27929079 (2022), 32472557 (2020), 23270700 (2013), 20231667 (2010), 20098342 (2010), 10508514 (1999)). Experimental studies have indicated that the variant is damaging to MECP2 protein function (PMIDs: 27929079 (2016), 21831886 (2011), 19442733 (2009), 12843318 (2003), 11738866 (2001)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 07, 2022Reported as a common pathogenic variant in association with Rett syndrome (Amir et al., 1999; Vilchis et al., 2014; RettBASE); Published functional studies suggest it significantly impairs the binding of methylated DNA (Ballestar et al., 2000); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24715477, 20098342, 23270700, 25789914, 19442733, 19217433, 25942534, 25900226, 20231667, 21831886, 11058114, 10852707, 25814391, 26017205, 26379794, 26418480, 26175308, 26278631, 25914188, 25779967, 25659951, 26108439, 26003587, 11738866, 12843318, 27929079, 16077729, 29631775, 30202406, 30564305, 29655203, 10508514, 31095231, 28920956, 32730690, 32369273, 31130284, 33258288, 32105570, 32472557) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2021- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 23, 2015- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 15, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 106 of the MECP2 protein (p.Arg106Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Rett syndrome (PMID: 10508514, 18332345, 20098342, 23270700, 23421866). ClinVar contains an entry for this variant (Variation ID: 11814). 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: 12843318, 19442733, 21831886). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJun 20, 2019This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals with Rett syndrome [PMID: 16077729, 11058114, 10508514, 10852707, 20098342] -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 25, 2019The MECP2 c.316C>T; p.Arg106Trp variant (rs28934907) has been reported in patients with Rett syndrome (Amir 1999, Psoni 2010). MECP2 protein containing the variant has a reduced binding affinity for methylated DNA (Ballestar 2000, Yusufzai 2000). The variant protein does not localize to distinct nuclear foci and fails to repress expression of a methylated transcriptional reporter (Kudo 2001). Hippocampal pyramidal neurons overexpressing the p.Arg106Trp variant protein have a lower density of mature dendritic spines after 48 hours of culture (Chapleau 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11814). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 106 is highly conserved and lies within the methyl-CpG binding domain. Computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Amir RE et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185-8. Ballestar E et al. Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. Biochemistry. 2000 Jun 20;39(24):7100-6. Chapleau CA et al. Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations. Neurobiol Dis. 2009 Aug;35(2):219-33. Kudo S et al. Functional analyses of MeCP2 mutations associated with Rett syndrome using transient expression systems. Brain Dev. 2001 Dec;23 Suppl 1:S165-73. Psoni S et al. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res. 2010 May;67(5):551-6. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 26, 2019The p.R106W pathogenic mutation (also known as c.316C>T and 390C>T), located in coding exon 2 of the MECP2 gene, results from a C to T substitution at nucleotide position 316. The arginine at codon 106 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was observed in two maternally related half-sisters with Rett syndrome; of note, their mother did not carry the p.R106W mutation indicating the presence of gonadal mosaicism (Amir RE et al. Nat. Genet., 1999 Oct;23:185-8). In another study, this mutation was identified in seven unrelated girls from the Australian Rett Syndrome Database, who had been diagnosed clinically or genetically with Rett syndrome (Knight O et al. Brain Dev., 2013 Nov;35:912-20) This mutation is located in the methyl-cytosine-binding domain (MBD) of the MECP2 protein and impairs its ability to bind and organize pericentric heterochromatin (Agarwal N et al. Hum. Mol. Genet., 2011 Nov;20:4187-95) and selectivity for methylated DNA (Ballestar E et al. Biochemistry, 2000 Jun;39:7100-6; Yusufzai TM et al. Nucleic Acids Res., 2000 Nov;28:4172-9). Two different alterations at the same position, p.R106G and p.R106Q, have been seen in three individuals from the French Cohort of Rett syndrome patients (Bienvenu T et al. Hum. Mol. Genet., 2000 May;9:1377-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021MECP2 NM_004992.3 exon 3 p.Arg106Trp (c.316C>T): This variant has been reported in the literature in several individuals with Rett syndrome (male and female), with multiple cases reported to be de novo (Amir 1999 PMID:10508514, Glaze 2010 PMID:20231667, Psoni 2010 PMID:20098342, Knight 2013 PMID:23270700, Vilchis 2014 PMID:24715477, Pidcock 2016 PMID:26175308, Shioda 2018 PMID:29631775, RettBASE). Literature suggests that this variant accounts for up to 4.4% of pathogenic variants in MECP2 (Philippe 2006 PMID:16473305, Neul 2008 PMID:18337588, Vilchis 2014 PMID:24715477, RettBASE). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:11814). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies support that this variant impacts the protein through impaired binding affinity to methylated CpGs (Kudo 2001 PMID:11738866, Kudo 2003 PMID:12843318, Agarwal 2011 PMID:21831886). In addition, expression studies of this variant in cultured neurons from postportum brain samples showed significant reduction in dendritic spine dennsity compared to wildtype (Chapleau 2009 PMID:19442733). However, these studies may not accurately represent in vivo biological function. Additionally, this variant is located in the methyl binding domain, where the majority of pathogenic variants in MECP2 have been identified (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic based on the data above. -
Autism, susceptibility to, X-linked 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3. -
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.68
D
BayesDel_noAF
Pathogenic
0.74
Cadd
Uncertain
24
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
1.0
D;.;D;D;D;D;D
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
M;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-7.6
D;D;.;.;.;.;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;.;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;.;D;D
Polyphen
1.0
D;D;.;.;.;.;.
Vest4
0.98
MutPred
0.94
Loss of disorder (P = 0.0132);.;Loss of disorder (P = 0.0132);.;Loss of disorder (P = 0.0132);.;.;
MVP
1.0
ClinPred
1.0
D
GERP RS
2.8
Varity_R
0.99
gMVP
0.98

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: rs28934907; hg19: chrX-153297719; COSMIC: COSV57654085; COSMIC: COSV57654085; API