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rs61750241

Variant summary

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

The NM_001110792.2(MECP2):c.842del(p.Gly281AlafsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 23)

Consequence

MECP2
NM_001110792.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:33

Conservation

PhyloP100: 7.37
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. There are 138 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154031021-GC-G is Pathogenic according to our data. Variant chrX-154031021-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 95202.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154031021-GC-G is described in Lovd as [Pathogenic]. Variant chrX-154031021-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.842del p.Gly281AlafsTer20 frameshift_variant 3/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.806del p.Gly269AlafsTer20 frameshift_variant 4/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.842del p.Gly281AlafsTer20 frameshift_variant 3/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.806del p.Gly269AlafsTer20 frameshift_variant 4/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:33
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:14
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Children's Mercy Hospital and Clinics-- -
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 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). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenDec 09, 2017- -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalMay 03, 2016- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 30, 2018Variant summary: MECP2 c.806delG (p.Gly269AlafsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.880C>T, p.Arg294X; c.1079C>A, p.Ser360X). The variant was absent in 177658 control chromosomes (gnomAD). c.806delG has been reported in the literature in numerous individuals affected with Rett Syndrome (Li_2007, Miltenberger-Miltenyi_2003), including one family in which the variant segregated with disease (Wan_1999). Additionally, one male mutation carrier was affected with encephalopathy (Leuzzi_2004). At least one publication reports experimental evidence evaluating an impact on protein function which shows this truncation variant disrupts MECP2 protein activity (Yusufzai_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The frame shift (c.842del) variant has been reported as a de novo occurrence and in at least 2 individuals with Rett syndrome (Zahorakova et. al., 2016; De et. al., 2000). Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000). The p.Gly281AlafsTer20 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing.(Le et. al., 2018). The observed variant is found to be present in last exon. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelMar 09, 2021The p.Gly269Alafs*20 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). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, PM2_supporting). -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2007- -
Pathogenic, criteria provided, single submitterclinical testingSeattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's HospitalAug 25, 2020This is a recurrent variant, reported in multiple individuals with Rett Syndrome (NBK1497, PMID: 10577905, PMID: 10854091, PMID: 12111643, PMID: 17089071, PMID: 27354166 and others. Note: this variant has historically been described as V288X). -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterApr 13, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 15, 2013- -
Pathogenic, no assertion criteria providedcurationRettBASEJun 12, 2013- -
not provided Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncAug 21, 2020The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 12, 2013- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLaboratoire Génétique Moléculaire, CHRU TOURSMay 04, 2021- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 26, 2021Reported multiple times in association with Rett syndrome in females and neonatal progressive encephalopathy in males (Wan et al., 1999; Moog et al, 2003; Kankirawatana et al., 2006; Le et al., 2018); Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31216405, 30081849, 31095231, 30945278, 30536762, 29655203, 30405208, 10577905, 16832102, 15557528, 22497713, 11058114, 12615169) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:4
Pathogenic, no assertion criteria providedcurationRettBASEJun 12, 2013- -
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2007- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 06, 2024This sequence change creates a premature translational stop signal (p.Gly269Alafs*20) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 218 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 and childhood-onset mitochondrial respiratory complex deficiency (PMID: 1057790, 10854091, 12111643, 16473305, 17089071, 26741492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 95202). 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). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 26, 2019The c.806delG pathogenic mutation, located in coding exon 3 of the MECP2 gene, results from a deletion of one nucleotide at nucleotide position 806, causing a translational frameshift with a predicted alternate stop codon (p.G269Afs*20). This mutation has been identified in multiple females with classic Rett syndrome and several males with neonatal progressive encephalopathy (Wan M et al. Am. J. Hum. Genet., 1999 Dec;65:1520-9; Cheadle JP et al. Hum. Mol. Genet., 2000 Apr;9:1119-29; De Bona C et al. Eur. J. Hum. Genet., 2000 May;8:325-30; Leuzzi V et al. Neurology, 2004 Nov;63:1968-70). Of note, this mutation has also been called c.803delG, c.880delG, and p.V288* in the literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2014- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 17, 2019The MECP2 c.806delG; p.Gly269fs variant (rs61750241) has been reported in multiple individuals affected with Rett syndrome (De Bona 2000, Pan 2002, Philippe 2006). It has also been reported in an individual with childhood-onset mitochondrial respiratory complex deficiency but not in either parent, suggesting a de novo origin in this individual (Kohda 2016). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 95202), and it 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 deletes a single nucleotide, resulting in a frameshift and a premature termination codon in the last exon of the MECP2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated MECP2 protein. Functional analysis of the truncated variant protein indicates an inability to repress transcription through its transcriptional repression domain (Yusufzai 2000). Based on available information, this variant is considered pathogenic. References: De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000 May;8(5):325-30. Kohda M et al. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. Pan H et al. MECP2 gene mutation analysis in Chinese patients with Rett syndrome. Eur J Hum Genet. 2002 Aug;10(8):484-6. Philippe C et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb;49(1):9-18. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsApr 22, 2023- -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 19, 2019ACMG classification criteria: PVS1, PS3, PS4, PM2, PP1 -
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 ChicagoDec 08, 2021MECP2 NM_004992.3 exon 4 p.Gly269Alafs*20 (c.806delG): This variant has been reported in the literature in several individuals (both male and female) with a clinical diagnosis or features of Rett syndrome, segregating with disease in 3 affected family members and identified as likely de novo in at least 3 individuals (Wan 1999 PMID:10577905, De Bona 2000 PMID:10854091, Pan 2002 PMID:12111643, Leuzzi 2004 PMID:15557528, Philippe 2006 PMID:16473305, Falsaperla 2012 PMID:22497713). This variant has also been identified in 1 individual with childhood onset mitochondrial respiratory chain complex deficiency as de novo (Kohda 2016 PMID:26741492). This variant is not present in large control databases. This variant is present in ClinVar with several labs classifying this variant as pathogenic (Variation ID:95202). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Functional studies support a deleterious effect of this variant, specifically the inability to repress transcription (Yusufzai 2000 PMID:11058114). This variant is a deletion of 1 nucleotide at position 806 which results in a premature stop codon 20 amino acids downstream from this location and is predicted to result in a truncated, abnormal protein. This variant occurs in exon 4 which is the last exon of this gene; due to its position it is possible that this protein may escape nonsense mediated decay, but will still result in a truncated protein. Loss of function has been established as a mechanism of disease for this gene; in addition, the vast majority of pathogenic variants in this gene are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic. -
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
Pathogenic, no assertion criteria providedcurationRettBASEJun 12, 2013- -
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 31, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs61750241; hg19: chrX-153296472; API