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rs61751362

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001110792.2(MECP2):c.916C>T(p.Arg306Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R306R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

MECP2
NM_001110792.2 stop_gained

Scores

3
3
3

Clinical Significance

Pathogenic reviewed by expert panel P:39O:1

Conservation

PhyloP100: 3.16
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 129 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154030948-G-A is Pathogenic according to our data. Variant chrX-154030948-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11819.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030948-G-A is described in Lovd as [Pathogenic]. Variant chrX-154030948-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.916C>T p.Arg306Ter stop_gained 3/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.880C>T p.Arg294Ter stop_gained 4/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.916C>T p.Arg306Ter stop_gained 3/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.880C>T p.Arg294Ter stop_gained 4/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
23
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:39Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:20
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 11, 2008- -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11960578, 15737703, 19722030, 21982064). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 11241840). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011819/ PMID: 10767337/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyDec 16, 2020ACMG codes:PVS1,PS3,PS4,PM2,PP5 -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The stop gained p.R294* in MECP2 (NM_004992.3) has been reported multiple times in females affected with Rett syndrome and is also present in the Rett database (Boban et al; Wen Z et al). It has shown to promote apoptosis of identified neurons in vivo (Williams A et al). It has been submitted to the ClinVar database as Pathogenic. The p.R294* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelMar 26, 2021The p.Arg294* variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Arg294* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with Rett syndrome (PMID: 15737703, 11960578, 19722030, 21982064, RettBASE) (PS4). A transcription assay performed in Xenopus oocytes has shown that this variant impacts protein function (PMID 11058114) (PS3_supporting). The p.Arg294* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg294* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting). -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The c.880C>T;p.(Arg294*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 11819; PMID: 31535341; 28465761; 26800272; 23270700; 16473305; 18332345; 11241840; 15737703; 19722030; 29046627) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history(PMID: 23810759) - PS2. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11058114; 26604147) - PS3_moderate. This variant is not present in population databases (rs61751362, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 01, 2017This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with global delays and hypotonia -
Pathogenic, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -
Likely pathogenic, criteria provided, single submitterliterature onlyCenter for Human Genetics, University of LeuvenJan 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
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 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). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). -
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CitySep 26, 2019- -
Pathogenic, criteria provided, single submitterclinical testingCourtagen Diagnostics Laboratory, Courtagen Life SciencesJan 19, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 28, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterDec 03, 2019- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 31, 2017Variant summary: The MECP2 c.880C>T (p.Arg294X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1079C>A/p.Ser360X)). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87847 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional study proved mutant protein R294X with loss of function (Yusufzai_ 2000). Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 12, 2015- -
not provided Pathogenic:11
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMar 28, 2018- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 16, 2018The MECP2 c.880C>T; p.Arg294Ter variant (rs61751362) is reported in the medical literature in individuals with classical Rett syndrome and atypical Rett syndrome (see link to RettBASE below and references therein, Cheadle 2000, Pidcock 2016, Wen 2017, Wang 2016). Additionally, the variant protein is reported to have lowered expression, to have slightly reduced stability, and to be unable to repress transcription (Wen 2017, Yusufzai 2000). The variant is reported in the ClinVar database (Variation ID: 11819). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein. Considering available information, this variant is classified as pathogenic. References: Link to RettBase variants: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle JP et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000 Apr 12;9(7):1119-29. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wen Z et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism. 2017 Aug 3;8:43. Wang T et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun. 2016 Nov 8;7:13316. Yusufzai TM and Wolffe AP. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 26, 2021Common recurrent variant that accounts for approximately 7% of MECP2 pathogenic variants (Percy et al., 2007); Observed in females with both classic and atypical Rett syndrome, often associated with a milder clinical presentation, and has been identified in a male with progressive microcephaly, developmental regression, and a movement disorder (RettBASE; Neul et al., 2008; Lundvall et al., 2006); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 193 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it is defective in promoting nucleosome-nucleosome bridging (Yusufzai et al., 2000; Nikitina et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11058114, 26604147, 10991688, 17660293, 23270700, 27159028, 27824329, 10767337, 27255190, 29321033, 28785396, 29421650, 29595472, 29056246, 16077729, 26175308, 17420824, 11738864, 18337588, 17236109, 18174548, 30693677, 30564305, 30536762, 31209962, 31535341, 32105570, 32472557, 32005694, 33994118, 12030010, 31130284, 31031587) -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 28, 2018This variant causes the premature termination of MECP2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with Rett syndrome (PMID: 11241840 (2001), 23270700 (2013), 31535341 (2020)). In addition, a functional study reported this variant resulted in a damaging effect on protein function (PMID: 11058114 (2000)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 19, 2013- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalFeb 07, 2019- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
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:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021This variant has been reported in the literature in numerous individuals with Rett syndrome, including males, and as de novo in at least 1 individual with autism spectrum disorder (ASD) (Selected publications: Cheadler 2000 PMID:10767337, Yamashita 2001 PMID:11738864, Jian 2005 PMID:16077729, Lundvall 2006 PMID:17236109, Stachon 2007 PMID:17420824, Wen 2017 PMID:28785396). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:11819). Functional studies support that this variant will impact the protein, suggesting repression of transcription and instability (Yusufzai 2000 PMID:11058114). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or abnormal protein. Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However, the vast majority of pathogenic variants in this gene (including this variant) are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. Loss of function has been established for this gene, but missense variants have been described as pathogenic as well (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 21, 2022- -
Autism, susceptibility to, X-linked 3 Pathogenic:1Other:1
risk factor, no assertion criteria providedliterature onlyOMIMMar 11, 2008- -
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change creates a premature translational stop signal (p.Arg294*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 193 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 11241840, 15737703, 16473305, 17236109, 18332345, 19722030, 23270700). ClinVar contains an entry for this variant (Variation ID: 11819). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 26604147, 27442528, 28785396). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 14, 2024- -
MECP2-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-This variant is also known as c.880C>T (p.Arg294Ter) due to use of an alternate transcript. This nonsense variant found in exon 4 of 4 is predicted to result in truncation of the MeCP2 protein. This variant has been previously reported in individuals with MECP2-related disorders (PMID:16473305, 11241840, 15737703, 19722030, 11960578, 21982064). Functional studies have shown that the c.916C>T (p.Arg306Ter) variant destabilizes the MeCP2 protein and expression of the truncated protein in-vitro results in increased apoptosis levels (PMID: 11058114, 27442528, 28785396). The c.916C>T (p.Arg306Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.916C>T (p.Arg306Ter) variant is classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 05, 2021The c.880C>T (p.R294*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position 880. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 294. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 38% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in many females with classic Rett syndrome. In addition, several studies show that this pathogenic variant is associated with a milder phenotype including, but not limited to: a later age at diagnosis (5-6 years of age), delayed onset of regression, later onset of stereotypical behaviors, more retention of words and hand function, and ambulatory ability (Cheadle, 2000; Fieremans, 2016; Pidcock, 2016; Wen, 2017; Colvin, 2004; Fehr, 2010). The p.R294* amino acid is located within the transcription repression domain, which normally binds methylated DNA in the context of chromatin, leading to long-term transcriptional repression (Hite, 2009). Functional analysis demonstrated that the p.R294* alteration retains DNA binding capabilities at levels comparable to those of the wild-type protein, but failed to repress DNA transcription (Yusufzai, 2000). Based on the available evidence, this alteration is classified as pathogenic. -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc TauliApr 26, 2021PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.58
Cadd
Pathogenic
37
Dann
Uncertain
1.0
DEOGEN2
Benign
0.093
T
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.36
T
MetaRNN
Uncertain
0.60
D
MutationTaster
Benign
1.0
A;A
Sift4G
Pathogenic
0.0
D
Vest4
0.54
MVP
0.95
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs61751362; hg19: chrX-153296399; API