The 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).
NM_001110792.2(MECP2):c.842del (p.Gly281fs)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Rett syndrome
Classification is based on the expert panel submission
Mar 2021 by
ClinGen Rett and Angelman-like Disorders Variant Curation E…
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001110792.2(MECP2):c.842del (p.Gly281fs)
Variation ID: 95202 Accession: VCV000095202.85
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: Xq28 X: 154031022 (GRCh38) [ NCBI UCSC ] X: 153296473 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 22, 2015 Feb 23, 2026 Mar 9, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001110792.2:c.842del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Gly281fs frameshift NM_001110792.2:c.842delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004992.4:c.806del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Gly269fs frameshift NM_001316337.2:c.527del NP_001303266.1:p.Gly176fs frameshift NM_001369391.2:c.527del NP_001356320.1:p.Gly176fs frameshift NM_001369392.2:c.527del NP_001356321.1:p.Gly176fs frameshift NM_001369393.2:c.527del NP_001356322.1:p.Gly176fs frameshift NM_001369394.2:c.527del NP_001356323.1:p.Gly176fs frameshift NM_001386137.1:c.137del NP_001373066.1:p.Gly46fs frameshift NM_001386138.1:c.137del NP_001373067.1:p.Gly46fs frameshift NM_001386139.1:c.137del NP_001373068.1:p.Gly46fs frameshift NM_004992.3(MECP2):c.806delG NM_004992.3:c.806delG NC_000023.11:g.154031025del NC_000023.10:g.153296476del NG_007107.3:g.111082del LRG_764:g.111082del LRG_764t1:c.842del LRG_764p1:p.Gly281fs LRG_764t2:c.806del LRG_764p2:p.Gly269fs AJ132917.1:c.806delG - Protein change
- G176fs, G269fs, G281fs, G46fs
- Other names
-
NM_001110792.2(MECP2):c.842del
p.Gly281fs
- Canonical SPDI
- NC_000023.11:154031021:CCCC:CCC
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MECP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2133 | 2483 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2023 | RCV000081211.65 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Mar 24, 2025 | RCV000170113.18 | |
| Pathogenic (15) |
reviewed by expert panel
|
Mar 9, 2021 | RCV000168691.41 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 28, 2025 | RCV000169939.23 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 7, 2020 | RCV000624370.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 31, 2017 | RCV000850572.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 17, 2019 | RCV001000009.15 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2019 | RCV002251971.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003227637.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 22, 2023 | RCV003333025.2 | |
|
X-linked MECP2-related disorders
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 11, 2025 | RCV006555428.1 |
| click to load more conditions click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 09, 2021)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Rett syndrome
(X-linked inheritance)
|
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001711986.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
show
The 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). (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 01, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome |
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781707.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 30, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919617.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
show
Variant 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 31, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Severe neonatal-onset encephalopathy with microcephaly
Syndromic X-linked intellectual disability Lubs type X-linked intellectual disability-psychosis-macroorchidism syndrome Rett syndrome |
Baylor Genetics
Accession: SCV000992788.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 21, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Athena Diagnostics
Accession: SCV000842737.2
First in ClinVar: Oct 19, 2018 Last updated: Jan 26, 2021 |
Comment:
show
The 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Apr 22, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Syndromic X-linked intellectual disability Lubs type |
Baylor Genetics
Accession: SCV004040645.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Oct 07, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Inborn genetic diseases |
Ambry Genetics
Accession: SCV000846671.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
show
The c.806delG (p.G269Afs*20) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a deletion of one nucleotide at position 806, causing a translational frameshift with a predicted alternate stop codon after 20 amino acids. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts ~40% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). The c.806delG (p.G269Afs*20) alteration has been identified previously in a woman with motor coordination difficulties, mild learning disability, and skewed X chromosome inactivation, as well as her sister and daughter who were affected with classic Rett syndrome, and her son who died from congenital encephalopathy (Wan, 1999). De novo c.806delG (p.G269Afs*20) alterations have also been identified in two male patients with progressive encephalopathy characterized by neonatal onset severe hypotonia, apneic episodes, respiratory failure, and microcephaly; one boy additionally had a movement disorder characterized by irregular brief jerks (Leuzzi, 2004; Kankirawatana, 2006). One patient died at 36 months of age (Leuzzi, 2004), and the other patient died at 27 months of age (Kankirawatana, 2006). Based on the available evidence, this alteration is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett's disorder |
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics
Accession: SCV000223843.1
First in ClinVar: Jun 10, 2015 Last updated: Jun 10, 2015 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 15, 2013)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome |
Genetic Services Laboratory, University of Chicago
Accession: SCV000247997.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome |
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004042687.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 22, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413457.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome
Severe neonatal-onset encephalopathy with microcephaly Syndromic X-linked intellectual disability Lubs type Autism, susceptibility to, X-linked 3 X-linked intellectual disability-psychosis-macroorchidism syndrome Rett syndrome Rett syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003924220.2
First in ClinVar: May 20, 2023 Last updated: May 03, 2025 |
Comment:
show
MECP2 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 17, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885679.2
First in ClinVar: Oct 19, 2018 Last updated: Feb 09, 2020 |
Comment:
show
The 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(May 04, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Laboratoire Génétique Moléculaire, CHRU TOURS
Accession: SCV001760578.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Dec 19, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
See cases
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523392.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Neurodevelopmental abnormality (present) , Limb joint contracture (present) , Developmental regression (present) , Movement disorder (present)
Geographic origin: Brazil
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Severe neonatal-onset encephalopathy with microcephaly |
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559121.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Jul 26, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000190966.11
First in ClinVar: Nov 01, 2014 Last updated: Mar 04, 2023 |
Comment:
show
Reported 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) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome
(X-linked inheritance)
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047986.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Neurodevelopmental delay (present) , Myopathy (present)
Comment on clinical features:
Baby of Ashwini was referred for genetic evaluation in view of the following: Clinical symptoms: Developmental delay, social smile present and motor delay under evaluation. Antenatal and birth history: FTLSCS, CIAB. Clinical suspicion: Congenital Myopathy/HIE/GDD
|
|
|
Pathogenic
(Dec 09, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome
(X-linked inheritance)
|
Institute of Human Genetics Munich, TUM University Hospital
Accession: SCV000680285.2
First in ClinVar: Feb 08, 2018 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Zygosity: 1 Single Heterozygote
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Apr 13, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Rett syndrome |
MGZ Medical Genetics Center
Accession: SCV002581580.2
First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025
Comment:
ACMG criteria applied: PVS1, PS4_VSTR, PM2_SUP
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(Mar 24, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
X-linked intellectual disability-psychosis-macroorchidism syndrome
(X-linked inheritance)
|
Institute of Human Genetics Munich, TUM University Hospital
Accession: SCV006302612.5
First in ClinVar: Aug 03, 2025 Last updated: Sep 22, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Hypotonia (present) , Respiratory distress (present) , Apnea (present) , Failure to thrive (present)
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Pathogenic
(Dec 04, 2024)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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Rett syndrome |
3billion
Accession: SCV006585170.1
First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025 |
Comment:
show
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000095202 /PMID: 10577905 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Method: exome sequencing
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Pathogenic
(Oct 01, 2020)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500678.33
First in ClinVar: Mar 14, 2021 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
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Pathogenic
(Apr 28, 2025)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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Severe neonatal-onset encephalopathy with microcephaly |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544619.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026 |
Comment:
show
This 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 gene product 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
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Pathogenic
(Aug 25, 2020)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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Rett syndrome |
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Accession: SCV002525692.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
show
This 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). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Global developmental delay (present) , Developmental regression (present) , Secondary microcephaly (present) , Motor deterioration (present)
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Pathogenic
(Aug 14, 2023)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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Rett syndrome
(X-linked inheritance)
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Centre for Population Genomics, CPG
Accession: SCV004098850.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
show
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 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). (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
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Pathogenic
(Nov 12, 2013)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000230256.6
First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 2
Zygosity: 2 Single Heterozygotes
Sex: mixed
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Pathogenic
(Nov 11, 2025)
N
Not contributing to aggregate classification
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criteria provided, single submitter
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X-linked MECP2-related disorders
(X-linked inheritance)
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Variantyx, Inc.
Accession: SCV007494943.1
First in ClinVar: Feb 23, 2026 Last updated: Feb 23, 2026 |
Comment:
show
This is a frameshift variant in the MECP2 gene (OMIM: 300005). Pathogenic variants in this gene have been associated with X-linked MECP2-related disorders. This variant likely occurred de novo in the current proband and in individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 26984561, 10854091) (PS2_Very_Strong). This variant introduces a premature termination codon in exon 4 out of 4 and is expected to result in loss of function, which is a known disease mechanism for MECP2 in this disorder (PMID: 30081849) (PVS1). This variant has been reported in several unrelated affected individuals (PMID: 32472557) (PS4) and is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for X-linked MECP2-related disorders. (less)
Observation: 1
Collection method: clinical testing
Allele origin: maternal
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: maternal
Affected status: unknown
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Pathogenic
(May 03, 2016)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Rett syndrome |
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804883.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Pathogenic
(Jan 01, 2007)
N
Not contributing to aggregate classification
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no assertion criteria provided
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RETT SYNDROME |
OMIM
Accession: SCV000032817.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, Wan et al. (1999) identified a 1-bp deletion (806delG) in the … (more)
In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, Wan et al. (1999) identified a 1-bp deletion (806delG) in the MECP2 gene, resulting in a val288-to-ter (V288X) substitution in the transcription repression domain. The same mutation was found in her sister and daughter, who were affected with classic Rett syndrome (RTT; 312750), and in her hemizygous son, who died from congenital encephalopathy (300673). Leuzzi et al. (2004) reported a 28-month-old boy with the 806delG mutation. The patient's mother did not carry the mutation, suggesting germline mosaicism or a de novo mutation. After a normal pregnancy and cesarean section, the patient was markedly hypotonic with weak suction and vomiting. He showed chaotic ocular movements, masticatory automatisms, and brief seizure-like episodes. Brain MRI was normal. Examination at age 10 months showed microcephaly, severe developmental delay, axial hypotonia, limb rigidity, hyperreflexia, lack of purposeful hand movements, and poor eye contact. In addition, he had paroxysmal myoclonic movements of the upper limbs that were unresponsive to conventional antiepileptic drugs. Neurophysiologic investigations showed arrhythmic multifocal myoclonus that was of cortical origin, although not associated with cortical hyperexcitability. The findings were similar to those observed in patients with Rett syndrome and believed to result from reduced dendritic branching and circuitry derangement (Guerrini et al., 1998). Li et al. (2007) referred to this mutation as G269fs. (less)
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Pathogenic
(Jan 01, 2007)
N
Not contributing to aggregate classification
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no assertion criteria provided
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ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION |
OMIM
Accession: SCV000032818.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, Wan et al. (1999) identified a 1-bp deletion (806delG) in the … (more)
In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, Wan et al. (1999) identified a 1-bp deletion (806delG) in the MECP2 gene, resulting in a val288-to-ter (V288X) substitution in the transcription repression domain. The same mutation was found in her sister and daughter, who were affected with classic Rett syndrome (RTT; 312750), and in her hemizygous son, who died from congenital encephalopathy (300673). Leuzzi et al. (2004) reported a 28-month-old boy with the 806delG mutation. The patient's mother did not carry the mutation, suggesting germline mosaicism or a de novo mutation. After a normal pregnancy and cesarean section, the patient was markedly hypotonic with weak suction and vomiting. He showed chaotic ocular movements, masticatory automatisms, and brief seizure-like episodes. Brain MRI was normal. Examination at age 10 months showed microcephaly, severe developmental delay, axial hypotonia, limb rigidity, hyperreflexia, lack of purposeful hand movements, and poor eye contact. In addition, he had paroxysmal myoclonic movements of the upper limbs that were unresponsive to conventional antiepileptic drugs. Neurophysiologic investigations showed arrhythmic multifocal myoclonus that was of cortical origin, although not associated with cortical hyperexcitability. The findings were similar to those observed in patients with Rett syndrome and believed to result from reduced dendritic branching and circuitry derangement (Guerrini et al., 1998). Li et al. (2007) referred to this mutation as G269fs. (less)
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Pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
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not provided |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742681.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Pathogenic
(Jun 12, 2013)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Encephalopathy, neonatal severe |
RettBASE
Accession: SCV000188244.3
First in ClinVar: Aug 15, 2014 Last updated: Apr 13, 2025 |
Observation:
3
Observation 1
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: male
Comment on evidence:
Not Rett synd. - Progressive encephalopathy of neonatal onset
Observation 2
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: male
Tissue: not known
Comment on evidence:
Not Rett synd. - progressive encephalopathy of neonatal onset
Observation 3
Collection method: curation
Allele origin: maternal
Affected status: yes
Number of individuals with the variant: 1
Family history: Yes
Sex: male
Tissue: Blood
Comment on evidence:
Not Rett synd. - Progressive encephalopathy of neonatal onset
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Pathogenic
(Jun 12, 2013)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Mental retardation, X-linked, syndromic 13
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RettBASE
Accession: SCV000222437.2
First in ClinVar: Apr 22, 2015 Last updated: Apr 13, 2025 |
Observation 1
Collection method: curation
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Family history: Yes
Sex: female
Tissue: Blood
Comment on evidence:
Not Rett synd. - X-linked mental retardation
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Pathogenic
(Jun 12, 2013)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Rett syndrome |
RettBASE
Accession: SCV000222438.2
First in ClinVar: Apr 24, 2015 Last updated: Apr 13, 2025 |
Observation:
46
Observation 1
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 2
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 3
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 4
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 5
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 6
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 7
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 8
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 9
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: lymphoblastoid cell lines
Comment on evidence:
Rett syndrome - not certain
Observation 10
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Not certain
Observation 11
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 12
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 13
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 14
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Tissue: blood
Comment on evidence:
Rett syndrome - Not certain
Observation 15
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - classical
Observation 16
Collection method: curation
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Family history: Yes
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 17
Collection method: curation
Allele origin: maternal
Affected status: yes
Number of individuals with the variant: 1
Family history: Yes
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 18
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 19
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 20
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 21
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 22
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 23
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 24
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 25
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - atypical
Observation 26
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 27
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 28
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 29
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 30
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 31
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 32
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 33
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 34
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 35
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 36
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 37
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 38
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 39
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 40
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 41
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 42
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 43
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 44
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 45
Collection method: curation
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 46
Collection method: curation
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
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not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956202.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Comment:
Comment:
Variant 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.
Comment:
The 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.
Comment:
The c.806delG (p.G269Afs*20) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a deletion of one nucleotide at position 806, causing a translational frameshift with a predicted alternate stop codon after 20 amino acids. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts ~40% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). The c.806delG (p.G269Afs*20) alteration has been identified previously in a woman with motor coordination difficulties, mild learning disability, and skewed X chromosome inactivation, as well as her sister and daughter who were affected with classic Rett syndrome, and her son who died from congenital encephalopathy (Wan, 1999). De novo c.806delG (p.G269Afs*20) alterations have also been identified in two male patients with progressive encephalopathy characterized by neonatal onset severe hypotonia, apneic episodes, respiratory failure, and microcephaly; one boy additionally had a movement disorder characterized by irregular brief jerks (Leuzzi, 2004; Kankirawatana, 2006). One patient died at 36 months of age (Leuzzi, 2004), and the other patient died at 27 months of age (Kankirawatana, 2006). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PM2, PS2_very_strong, PVS1
Comment:
MECP2 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.
Comment:
The 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.
Comment:
ACMG classification criteria: PVS1, PS3, PS4, PM2, PP1
Comment:
Reported 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)
Comment:
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.
Comment:
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000095202 /PMID: 10577905 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This 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 gene product 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.
Comment:
This 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).
Comment:
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 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).
Comment:
This is a frameshift variant in the MECP2 gene (OMIM: 300005). Pathogenic variants in this gene have been associated with X-linked MECP2-related disorders. This variant likely occurred de novo in the current proband and in individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 26984561, 10854091) (PS2_Very_Strong). This variant introduces a premature termination codon in exon 4 out of 4 and is expected to result in loss of function, which is a known disease mechanism for MECP2 in this disorder (PMID: 30081849) (PVS1). This variant has been reported in several unrelated affected individuals (PMID: 32472557) (PS4) and is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for X-linked MECP2-related disorders.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort. | Wen Y | Clinical genetics | 2020 | PMID: 32472557 |
| An electrochemiluminescence based assay for quantitative detection of endogenous and exogenously applied MeCP2 protein variants. | Steinkellner H | Scientific reports | 2019 | PMID: 31138832 |
| The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. | Jiao Q | Clinical genetics | 2019 | PMID: 30945278 |
| The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. | Neul JL | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2019 | PMID: 30536762 |
| Spectrum of MECP2 mutations in Vietnamese patients with RETT syndrome. | Le Thi Thanh H | BMC medical genetics | 2018 | PMID: 30081849 |
| Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. | Lindy AS | Epilepsia | 2018 | PMID: 29655203 |
| MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning. | Zahorakova D | Journal of human genetics | 2016 | PMID: 26984561 |
| A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. | Kohda M | PLoS genetics | 2016 | PMID: 26741492 |
| Spectrum of MECP2 gene mutations in a cohort of Indian patients with Rett syndrome: report of two novel mutations. | Das DK | Gene | 2013 | PMID: 23262346 |
| Apneic crises: a clue for MECP2 testing in severe neonatal hypotonia-respiratory failure. | Falsaperla R | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2012 | PMID: 22497713 |
| MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders. | Psoni S | Brain & development | 2012 | PMID: 21982064 |
| Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations. | Hadzsiev K | Journal of human genetics | 2011 | PMID: 21160487 |
| [Methyl-CpG-binding protein 2 gene and CDKL5 gene mutation in patients with Rett syndrome: analysis of 177 Chinese pediatric patients]. | Li MR | Zhonghua yi xue za zhi | 2009 | PMID: 19552836 |
| Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. | Zahorakova D | Journal of human genetics | 2007 | PMID: 17387578 |
| MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. | Li MR | Journal of human genetics | 2007 | PMID: 17089071 |
| Early progressive encephalopathy in boys and MECP2 mutations. | Kankirawatana P | Neurology | 2006 | PMID: 16832102 |
| Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. | Philippe C | European journal of medical genetics | 2006 | PMID: 16473305 |
| MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients. | Moog U | Brain & development | 2006 | PMID: 16376510 |
| Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation. | Leuzzi V | Neurology | 2004 | PMID: 15557528 |
| Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. | Schanen C | American journal of medical genetics. Part A | 2004 | PMID: 15057977 |
| Mutations and polymorphisms in the human methyl CpG-binding protein MECP2. | Miltenberger-Miltenyi G | Human mutation | 2003 | PMID: 12872250 |
| Mutation analysis in the MECP2 gene and genetic counselling for Rett syndrome. | Gill H | Journal of medical genetics | 2003 | PMID: 12746405 |
| MECP2 gene mutation analysis in Chinese patients with Rett syndrome. | Pan H | European journal of human genetics : EJHG | 2002 | PMID: 12111643 |
| DHPLC analysis of the MECP2 gene in Italian Rett patients. | Nicolao P | Human mutation | 2001 | PMID: 11462237 |
| Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females. | Vacca M | Journal of molecular medicine (Berlin, Germany) | 2001 | PMID: 11269512 |
| MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features. | Auranen M | Neurology | 2001 | PMID: 11245712 |
| Functional consequences of Rett syndrome mutations on human MeCP2. | Yusufzai TM | Nucleic acids research | 2000 | PMID: 11058114 |
| Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. | Buyse IM | American journal of human genetics | 2000 | PMID: 11055898 |
| Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome. | Amano K | Journal of human genetics | 2000 | PMID: 10944854 |
| Preserved speech variant is allelic of classic Rett syndrome. | De Bona C | European journal of human genetics : EJHG | 2000 | PMID: 10854091 |
| Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. | Wan M | American journal of human genetics | 1999 | PMID: 10577905 |
| Cortical reflex myoclonus in Rett syndrome. | Guerrini R | Annals of neurology | 1998 | PMID: 9546328 |
| Morphology of growing bone surfaces. | Rasmussen PJ | Scandinavian journal of dental research | 1975 | PMID: 1057790 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/106a168a-0ad6-45ba-b2f9-2a8b9774f3c8 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1e897fde-76a7-45dc-8f7f-6e1191668335 | - | - | - | - |
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Text-mined citations for rs61750241 ...
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Record last updated Apr 13, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.