Variant summary: The MECP2 c.808C>T (p.Arg270X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg294X, p.Ser360X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant lies in the transcription repression domain (TRD) and one of the major functions of MECP2 is repression of transcription mediated by its TRD. Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression. Additionally, this variant is a known common pathogenic variant that has been reported in numerous classic Rett Syndrome patients in the literature and has been classified by multiple clinical labs and databases as pathogenic. This variant was found in 1/86029 control chromosomes at a frequency of 0.0000116. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(46)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
46
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter)
Variation ID: 11815 Accession: VCV000011815.95
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 154031020 (GRCh38) [ NCBI UCSC ] X: 153296471 (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 Nov 23, 2014 Oct 20, 2024 May 7, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001110792.2:c.844C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Arg282Ter nonsense NM_004992.4:c.808C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Arg270Ter nonsense NM_001316337.2:c.529C>T NP_001303266.1:p.Arg177Ter nonsense NM_001369391.2:c.529C>T NP_001356320.1:p.Arg177Ter nonsense NM_001369392.2:c.529C>T NP_001356321.1:p.Arg177Ter nonsense NM_001369393.2:c.529C>T NP_001356322.1:p.Arg177Ter nonsense NM_001369394.2:c.529C>T NP_001356323.1:p.Arg177Ter nonsense NM_001386137.1:c.139C>T NP_001373066.1:p.Arg47Ter nonsense NM_001386138.1:c.139C>T NP_001373067.1:p.Arg47Ter nonsense NM_001386139.1:c.139C>T NP_001373068.1:p.Arg47Ter nonsense NC_000023.11:g.154031020G>A NC_000023.10:g.153296471G>A NG_007107.3:g.111084C>T LRG_764:g.111084C>T LRG_764t1:c.844C>T LRG_764p1:p.Arg282Ter LRG_764t2:c.808C>T LRG_764p2:p.Arg270Ter AJ132917.1:c.808C>T - Protein change
- R270*, R282*, R177*, R47*
- Other names
-
NP_004983.1:p.Arg270*
p.R270*:CGA>TGA
NM_001110792.2(MECP2):c.844C>T
p.Arg282Ter
- Canonical SPDI
- NC_000023.11:154031019:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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 |
1896 | 2224 | |
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 (24) |
criteria provided, multiple submitters, no conflicts
|
Nov 30, 2023 | RCV000012586.54 | |
| Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2022 | RCV000081212.60 | |
|
Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 12, 2014 | RCV000146359.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2017 | RCV000515283.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 24, 2017 | RCV000624100.7 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 28, 2023 | RCV000169940.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 30, 2020 | RCV001196907.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 19, 2021 | RCV001705588.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 7, 2024 | RCV004540996.3 |
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. |
More information
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
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Rett's disorder
Affected status: yes
Allele origin:
unknown
|
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics
Accession: SCV000223840.1
First in ClinVar: Jun 10, 2015 Last updated: Jun 10, 2015 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Feb 12, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000193642.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(Sep 30, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698544.1
First in ClinVar: Mar 03, 2018 Last updated: Mar 03, 2018 |
Comment:
Variant summary: The MECP2 c.808C>T (p.Arg270X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense … (more)
Variant summary: The MECP2 c.808C>T (p.Arg270X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg294X, p.Ser360X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant lies in the transcription repression domain (TRD) and one of the major functions of MECP2 is repression of transcription mediated by its TRD. Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression. Additionally, this variant is a known common pathogenic variant that has been reported in numerous classic Rett Syndrome patients in the literature and has been classified by multiple clinical labs and databases as pathogenic. This variant was found in 1/86029 control chromosomes at a frequency of 0.0000116. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 08, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885680.1
First in ClinVar: Sep 01, 2018 Last updated: Sep 01, 2018 |
Comment:
The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the … (more)
The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle J et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000; 9(7):1119-29. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9. (less)
|
|
|
Pathogenic
(May 10, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230264.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 7
Sex: mixed
|
|
|
Pathogenic
(Sep 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967749.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic … (more)
The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic male with clinical feature s of Rett syndrome (Cheadle et al. 2000, Topcu et al. 2002, Temudo et al. 2007, Knight et al. 2013, Maortua et al. 2013, Cuddapah et al. 2014, Pidcock et al. 20 16) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 270. This alteration occurs within th e last exon and is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yu sufzai and Wollfe 2000, Delepine et al. 2013). In summary, this variant meets cr iteria to be classified as pathogenic for Rett syndrome in an X-linked manner ba sed upon case counts, de novo occurrence, absence from controls, predicted impac t on protein and functional evidence. ACMG/AMP Criteria applied: PS4, PS2, PM6_S , PM2, PVS1_Strong, PS3_Moderate. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149827.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Sep 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448873.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(Jan 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autism, susceptibility to, X-linked 3
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367541.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
|
|
|
Pathogenic
(Dec 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV001527167.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in one … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in one patient with autism [PMID 28831199] and multiple patients in Baylor Genetics with neurodevelopmental phenotypes (less)
|
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: curation
|
Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
Centre for Population Genomics, CPG
Accession: SCV004101577.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
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 … (more)
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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). (ClinVar Accession: SCV002768332.1 , PMID 10854091, PMID 10854091). 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)
|
|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
unknown
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV004102713.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
|
|
Pathogenic
(Nov 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004171246.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Clinical Features:
Strabismus (present) , Delayed speech and language development (present) , Intellectual disability (present) , Hypotonia (present) , Global developmental delay (present) , Motor delay (present) … (more)
Strabismus (present) , Delayed speech and language development (present) , Intellectual disability (present) , Hypotonia (present) , Global developmental delay (present) , Motor delay (present) , Absent speech (present) , Sleep abnormality (present) (less)
|
|
|
Pathogenic
(Oct 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017246.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe neonatal-onset encephalopathy with microcephaly
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544624.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg270*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg270*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 217 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 individual(s) with Rett syndrome (PMID: 10854091, 11241840, 16473305, 17089071, 18174548, 23270700; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11815). 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, 23238081). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jul 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000537198.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016
Comment:
p.Arg270*
|
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked intellectual disability-psychosis-macroorchidism syndrome
Syndromic X-linked intellectual disability Lubs type Autism, susceptibility to, X-linked 3 Severe neonatal-onset encephalopathy with microcephaly Rett syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611282.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781709.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
unknown
|
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999372.1
First in ClinVar: Dec 01, 2019 Last updated: Dec 01, 2019 |
Number of individuals with the variant: 1
Clinical Features:
EEG abnormality (present) , Motor delay (present) , Autistic disorder of childhood onset (present) , Intellectual disability, profound (present) , Loss of ability to walk … (more)
EEG abnormality (present) , Motor delay (present) , Autistic disorder of childhood onset (present) , Intellectual disability, profound (present) , Loss of ability to walk (present) , Loss of speech (present) , Progressive microcephaly (present) , Motor deterioration (present) , Seizures (present) (less)
|
|
|
Pathogenic
(Jan 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449677.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Syndromic X-linked intellectual disability Lubs type
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934452.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318910.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region.. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011815, PMID:10767337). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Attention deficit hyperactivity disorder (present) , Autistic behavior (present) , Global developmental delay (present) , Motor stereotypies (present) , Strabismus (present)
|
|
|
Pathogenic
(Mar 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002107116.2
First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.808C>T;p.(Arg270*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product … (more)
The c.808C>T;p.(Arg270*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11058114; 23238081) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11815; PMID: 18174548; PMID: 16473305; PMID: 23270700; PMID: 10854091; PMID: 17089071) - PS4. This variant is not present in population databases (rs61750240- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 11241840) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(May 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV002598531.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768332.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome (MIM#312750). (I) 0110 - This gene is known to be predominantly associated with X-linked dominant disease. However, X-linked recessive disease has also been reported. In addition, both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein [(premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Rett syndrome (ClinVar, RettBASE, VCGS). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000191047.12
First in ClinVar: Nov 01, 2014 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587) (less)
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Pathogenic
(Mar 31, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428769.2
First in ClinVar: Aug 17, 2020 Last updated: May 20, 2023 |
Comment:
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP, PP4
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|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004046997.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop_gained (c.844C>T) variant is most commonly reported in heterozygous state in patients affected with Rett syndrome (Moog, U. et. al., 2003; Laccone F et. … (more)
The stop_gained (c.844C>T) variant is most commonly reported in heterozygous state in patients affected with Rett syndrome (Moog, U. et. al., 2003; Laccone F et. al., 2001) but has also been reported in individuals with atypical Rett syndrome (RettBASE). This variant is clearly defined as a Rett syndrome causative allele that accounts for ~7% of disease-causing variants (Percy A.K. et. al., 2007; Philippe C. et. al., 2006) and has been shown to arise de novo in individuals affected with Rett syndrome (Laccone F et. al., 2001). Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Tubulointerstitial fibrosis (present) , Macroorchidism (present) , Intellectual disability (present) , Developmental stagnation (present) , Delayed speech and language development (present)
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Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: research
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004123070.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
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Pathogenic
(Feb 24, 2022)
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criteria provided, single submitter
Method: clinical testing
|
MECP2-Related Disorders
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004814155.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The MECP2 c.844C>T p.(Arg282Ter) nonsense variant, also known as c.808C>T p.(Arg270Ter), occurs in the last exon of the gene, and the resulting transcript may escape … (more)
The MECP2 c.844C>T p.(Arg282Ter) nonsense variant, also known as c.808C>T p.(Arg270Ter), occurs in the last exon of the gene, and the resulting transcript may escape nonsense-mediated mRNA decay. However, the premature truncation, which occurs in the transcriptional repression domain, has also been shown to disrupt a conserved AT-hook domain that functions in DNA binding (Baker et al. 2013). This variant has been identified in individuals with a phenotype consistent with Rett syndrome or other MECP2-related disorder, including in some individuals in whom the variant occurred de novo (Laccone et al. 2001; Philippe et al. 2006; Yan et al. 2019; Liu et al. 2020; Martinez-Granero et al. 2021). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013). Transgenic mice expressing the variant in the absence of wildtype MECP2 recapitulated features of the clinical phenotype observed in human patients, including reduced lifespan, brain atrophy, and neurological signs (Baker et al. 2013). Based on the available evidence, the c.844C>T p.(Arg282Ter) variant is classified as pathogenic for MECP2-related disorders. (less)
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Pathogenic
(Mar 24, 2017)
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criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741795.4
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The p.R270* pathogenic mutation (also known as c.808C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at … (more)
The p.R270* pathogenic mutation (also known as c.808C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 808. This changes the amino acid from an arginine to a stop codon within coding exon 3. This common recurrent MECP2 mutation is located in the TRD-NLS (transcription repression domain-nuclear localization signal) region and has been shown to cause a more severe phenotype compared to other MECP2 mutations (Cardoza B et al. Seizure, 2011 Oct;20:646-9; Kifayathullah LA et al. Cytogenet Genome Res. 2010;129(4):290-297). In addition, this mutation has been reported in both males (several with XXY karyotypes) and females with classic Rett syndrome (Reichow B et al. J Autism Dev Disord, 2015 Oct;45:3377-83; De Bona Cet al. Eur J Hum Genet. 2000;8(5):325-330; Cheadle JP et al. Hum Mol Genet. 2000;9(7):1119-1129). Another study found that this mutation is unable to repress transcription, a major function of MeCP2 protein (Yusufzai TM et al. Nucleic Acids Res. 2000;28(21):4172-4179). 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. (less)
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Pathogenic
(May 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
MECP2-related disorder
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV005200999.1
First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024 |
Comment:
PVS1, PS2, PS4, PM2
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Pathogenic
(Oct 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001150513.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
MECP2: PVS1, PS2, PM2
Number of individuals with the variant: 6
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Pathogenic
(Mar 11, 2008)
|
no assertion criteria provided
Method: literature only
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RETT SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000032821.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 03, 2018 |
Comment on evidence:
In 3 of 31 patients with Rett syndrome (RTT; 312750), Huppke et al. (2000) identified an 808C-T transition in the MECP2 gene, resulting in a … (more)
In 3 of 31 patients with Rett syndrome (RTT; 312750), Huppke et al. (2000) identified an 808C-T transition in the MECP2 gene, resulting in a premature stop codon (arg270-to-ter; R270X) in exon 3. Bienvenu et al. (2000) found the same mutation in 5 of 46 Rett syndrome patients studied. De Bona et al. (2000) identified the R270X mutation in 4 unrelated individuals with Rett syndrome, indicating that it represents a hotspot. Topcu et al. (2002) reported a boy with features of classic Rett syndrome and a normal karyotype, with somatic mosaicism for the truncating R270X mutation. The mutation abolished an NlaIV restriction site, and densitometric scanning of the restriction fragments revealed that the allele ratio was approximately 36 to 64 for the mutant-to-normal allele. Topcu et al. (2002) speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism. In 524 females with Rett syndrome and an identified MECP2 mutation, Jian et al. (2005) prospectively analyzed mortality data and found significant differences in survival among the 8 most common mutations; survival among cases with the R270X mutation was reduced compared to all the other mutations (p = 0.01). By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R270X and R255X (300005.0021) were associated with the most severe phenotype. (less)
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Pathogenic
(Nov 21, 2016)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778230.1
First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
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Pathogenic
(Apr 03, 2015)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Additional submitter:
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000804250.1
First in ClinVar: Sep 01, 2018 Last updated: Sep 01, 2018 |
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965916.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001979370.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Apr 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927896.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Pathogenic
(Dec 05, 2013)
|
no assertion criteria provided
Method: curation
|
Encephalopathy, neonatal severe
Affected status: yes
Allele origin:
unknown
|
RettBASE
Accession: SCV000188246.2
First in ClinVar: Aug 15, 2014 Last updated: Apr 22, 2015 |
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Not Rett synd. - Progressive encephalopathy of neonatal onset
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|
|
Pathogenic
(Dec 05, 2013)
|
no assertion criteria provided
Method: curation
|
Rett syndrome
Affected status: yes
Allele origin:
unknown,
de novo
|
RettBASE
Accession: SCV000222439.1
First in ClinVar: Apr 24, 2015 Last updated: Apr 24, 2015 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Atypical
Observation 2:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Atypical
Observation 3:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Atypical
Observation 4:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Atypical
Observation 5:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Atypical
Observation 6:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Atypical
Observation 7:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Atypical
Observation 8:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Atypical
Observation 9:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 10:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 11:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 12:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 13:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Classical
Observation 14:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Classical
Observation 15:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Classical
Observation 16:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 17:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 18:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Not known
Comment on evidence:
Rett syndrome - Classical
Observation 19:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Not known
Comment on evidence:
Rett syndrome - Classical
Observation 20:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Not known
Comment on evidence:
Rett syndrome - Classical
Observation 21:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 22:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 23:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 24:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 25:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 26:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 27:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 28:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 29:
Number of individuals with the variant: 1
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 30:
Number of individuals with the variant: 1
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 31:
Number of individuals with the variant: 1
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 32:
Number of individuals with the variant: 1
Comment on evidence:
Rett syndrome - Classical
Observation 33:
Number of individuals with the variant: 1
Comment on evidence:
Rett syndrome - Classical
Observation 34:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 35:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 36:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 37:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 38:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 39:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 40:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 41:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 42:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 43:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 44:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 45:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 46:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 47:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 48:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Congenital onset
Observation 49:
Number of individuals with the variant: 1
Sex: male
Tissue: Blood, hair
Comment on evidence:
Rett syndrome - Male variant
Observation 50:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 51:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 52:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 53:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 54:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 55:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: brain
Comment on evidence:
Rett syndrome - Not certain
Observation 56:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 57:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 58:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 59:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 60:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 61:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 62:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 63:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Not certain
Observation 64:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood or fibroblasts
Comment on evidence:
Rett syndrome - classical
Observation 65:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: not known
Comment on evidence:
Rett syndrome - classical
Observation 66:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 67:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Atypical
Observation 68:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 69:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 70:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 71:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 72:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 73:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 74:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 75:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 76:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 77:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 78:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 79:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: not stated
Comment on evidence:
Rett syndrome - classical
Observation 80:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: not stated
Comment on evidence:
Rett syndrome - classical
Observation 81:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 82:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 83:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 84:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 85:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphoblastoid cell lines
Comment on evidence:
Rett syndrome - not certain
Observation 86:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphoblastoid cell lines
Comment on evidence:
Rett syndrome - not certain
Observation 87:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Classical
Observation 88:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Classical
Observation 89:
Number of individuals with the variant: 1
Sex: female
Tissue: lymphocytes
Comment on evidence:
Rett syndrome - Classical
Observation 90:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 91:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 92:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 93:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 94:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 95:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 96:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 97:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 98:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 99:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 100:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 101:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 102:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 103:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 104:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - classical
Observation 105:
Number of individuals with the variant: 1
Comment on evidence:
Rett syndrome - Not certain
Observation 106:
Number of individuals with the variant: 1
Comment on evidence:
Rett syndrome - Not certain
Observation 107:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 108:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 109:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 110:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 111:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 112:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - atypical
Observation 113:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 114:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 115:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 116:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 117:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 118:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 119:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 120:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 121:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 122:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 123:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 124:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 125:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 126:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 127:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 128:
Number of individuals with the variant: 1
Comment on evidence:
Rett syndrome - Not certain
Observation 129:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 130:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 131:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 132:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 133:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 134:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 135:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 136:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 137:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 138:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 139:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 140:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 141:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 142:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 143:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 144:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 145:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 146:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 147:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 148:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 149:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 150:
Number of individuals with the variant: 1
Comment on evidence:
Rett syndrome - Not certain
Observation 151:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 152:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 153:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 154:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 155:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 156:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 157:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 158:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 159:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 160:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 161:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 162:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 163:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 164:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 165:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 166:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 167:
Number of individuals with the variant: 1
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 168:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Not certain
Observation 169:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Not certain
Observation 170:
Number of individuals with the variant: 1
Sex: female
Tissue: Not known
Comment on evidence:
Rett syndrome - Not certain
Observation 171:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 172:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 173:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 174:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 175:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 176:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 177:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 178:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 179:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 180:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Not certain
Observation 181:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Not certain
Observation 182:
Number of individuals with the variant: 1
Family history: No
Tissue: blood
Comment on evidence:
Rett syndrome - Not certain
Observation 183:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 184:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 185:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 186:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 187:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 188:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 189:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 190:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 191:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 192:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 193:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 194:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 195:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 196:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 197:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 198:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 199:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 200:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 201:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 202:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 203:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 204:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 205:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 206:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 207:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 208:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 209:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 210:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 211:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 212:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 213:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 214:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 215:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 216:
Number of individuals with the variant: 1
Family history: Yes
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 217:
Number of individuals with the variant: 1
Family history: Yes
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 218:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 219:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 220:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 221:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 222:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 223:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 224:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 225:
Number of individuals with the variant: 1
Family history: No
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 226:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 227:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 228:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
Observation 229:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 230:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 231:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
|
|
|
Pathogenic
(Oct 03, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Rett syndrome
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000574735.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929888.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Rett syndrome
Affected status: yes
Allele origin:
de novo
|
Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV004032207.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
|
|
|
Pathogenic
(Jan 29, 2020)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare
Accession: SCV004175154.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Clinical Features:
delayed speech and language development (present) , seizure (present) , behavioral abnormality (present) , hypotonia (present) , abnormal facial shape (present) , developmental regression (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: South East Asian
Geographic origin: Bangladesh
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Rett syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000998926.2
First in ClinVar: Nov 17, 2019 Last updated: Oct 01, 2022 |
|
|
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Comment:
Comment:
The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle J et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000; 9(7):1119-29. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9.
Comment:
The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic male with clinical feature s of Rett syndrome (Cheadle et al. 2000, Topcu et al. 2002, Temudo et al. 2007, Knight et al. 2013, Maortua et al. 2013, Cuddapah et al. 2014, Pidcock et al. 20 16) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 270. This alteration occurs within th e last exon and is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yu sufzai and Wollfe 2000, Delepine et al. 2013). In summary, this variant meets cr iteria to be classified as pathogenic for Rett syndrome in an X-linked manner ba sed upon case counts, de novo occurrence, absence from controls, predicted impac t on protein and functional evidence. ACMG/AMP Criteria applied: PS4, PS2, PM6_S , PM2, PVS1_Strong, PS3_Moderate.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in one patient with autism [PMID 28831199] and multiple patients in Baylor Genetics with neurodevelopmental phenotypes
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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). (ClinVar Accession: SCV002768332.1 , PMID 10854091, PMID 10854091). 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 sequence change creates a premature translational stop signal (p.Arg270*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 217 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 individual(s) with Rett syndrome (PMID: 10854091, 11241840, 16473305, 17089071, 18174548, 23270700; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11815). 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, 23238081). For these reasons, this variant has been classified as Pathogenic.
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region.. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011815, PMID:10767337). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The c.808C>T;p.(Arg270*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11058114; 23238081) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11815; PMID: 18174548; PMID: 16473305; PMID: 23270700; PMID: 10854091; PMID: 17089071) - PS4. This variant is not present in population databases (rs61750240- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 11241840) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome (MIM#312750). (I) 0110 - This gene is known to be predominantly associated with X-linked dominant disease. However, X-linked recessive disease has also been reported. In addition, both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein [(premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Rett syndrome (ClinVar, RettBASE, VCGS). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587)
Comment:
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP, PP4
Comment:
The stop_gained (c.844C>T) variant is most commonly reported in heterozygous state in patients affected with Rett syndrome (Moog, U. et. al., 2003; Laccone F et. al., 2001) but has also been reported in individuals with atypical Rett syndrome (RettBASE). This variant is clearly defined as a Rett syndrome causative allele that accounts for ~7% of disease-causing variants (Percy A.K. et. al., 2007; Philippe C. et. al., 2006) and has been shown to arise de novo in individuals affected with Rett syndrome (Laccone F et. al., 2001). Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The MECP2 c.844C>T p.(Arg282Ter) nonsense variant, also known as c.808C>T p.(Arg270Ter), occurs in the last exon of the gene, and the resulting transcript may escape nonsense-mediated mRNA decay. However, the premature truncation, which occurs in the transcriptional repression domain, has also been shown to disrupt a conserved AT-hook domain that functions in DNA binding (Baker et al. 2013). This variant has been identified in individuals with a phenotype consistent with Rett syndrome or other MECP2-related disorder, including in some individuals in whom the variant occurred de novo (Laccone et al. 2001; Philippe et al. 2006; Yan et al. 2019; Liu et al. 2020; Martinez-Granero et al. 2021). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013). Transgenic mice expressing the variant in the absence of wildtype MECP2 recapitulated features of the clinical phenotype observed in human patients, including reduced lifespan, brain atrophy, and neurological signs (Baker et al. 2013). Based on the available evidence, the c.844C>T p.(Arg282Ter) variant is classified as pathogenic for MECP2-related disorders.
Comment:
The p.R270* pathogenic mutation (also known as c.808C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 808. This changes the amino acid from an arginine to a stop codon within coding exon 3. This common recurrent MECP2 mutation is located in the TRD-NLS (transcription repression domain-nuclear localization signal) region and has been shown to cause a more severe phenotype compared to other MECP2 mutations (Cardoza B et al. Seizure, 2011 Oct;20:646-9; Kifayathullah LA et al. Cytogenet Genome Res. 2010;129(4):290-297). In addition, this mutation has been reported in both males (several with XXY karyotypes) and females with classic Rett syndrome (Reichow B et al. J Autism Dev Disord, 2015 Oct;45:3377-83; De Bona Cet al. Eur J Hum Genet. 2000;8(5):325-330; Cheadle JP et al. Hum Mol Genet. 2000;9(7):1119-1129). Another study found that this mutation is unable to repress transcription, a major function of MeCP2 protein (Yusufzai TM et al. Nucleic Acids Res. 2000;28(21):4172-4179). 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.
Comment:
PVS1, PS2, PS4, PM2
Comment:
MECP2: PVS1, PS2, PM2
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: The MECP2 c.808C>T (p.Arg270X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg294X, p.Ser360X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant lies in the transcription repression domain (TRD) and one of the major functions of MECP2 is repression of transcription mediated by its TRD. Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression. Additionally, this variant is a known common pathogenic variant that has been reported in numerous classic Rett Syndrome patients in the literature and has been classified by multiple clinical labs and databases as pathogenic. This variant was found in 1/86029 control chromosomes at a frequency of 0.0000116. Taken together, this variant is classified as pathogenic.
Comment:
The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle J et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000; 9(7):1119-29. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9.
Comment:
The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic male with clinical feature s of Rett syndrome (Cheadle et al. 2000, Topcu et al. 2002, Temudo et al. 2007, Knight et al. 2013, Maortua et al. 2013, Cuddapah et al. 2014, Pidcock et al. 20 16) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 270. This alteration occurs within th e last exon and is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yu sufzai and Wollfe 2000, Delepine et al. 2013). In summary, this variant meets cr iteria to be classified as pathogenic for Rett syndrome in an X-linked manner ba sed upon case counts, de novo occurrence, absence from controls, predicted impac t on protein and functional evidence. ACMG/AMP Criteria applied: PS4, PS2, PM6_S , PM2, PVS1_Strong, PS3_Moderate.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in one patient with autism [PMID 28831199] and multiple patients in Baylor Genetics with neurodevelopmental phenotypes
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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). (ClinVar Accession: SCV002768332.1 , PMID 10854091, PMID 10854091). 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 sequence change creates a premature translational stop signal (p.Arg270*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 217 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 individual(s) with Rett syndrome (PMID: 10854091, 11241840, 16473305, 17089071, 18174548, 23270700; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11815). 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, 23238081). For these reasons, this variant has been classified as Pathogenic.
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region.. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011815, PMID:10767337). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The c.808C>T;p.(Arg270*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11058114; 23238081) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11815; PMID: 18174548; PMID: 16473305; PMID: 23270700; PMID: 10854091; PMID: 17089071) - PS4. This variant is not present in population databases (rs61750240- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 11241840) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome (MIM#312750). (I) 0110 - This gene is known to be predominantly associated with X-linked dominant disease. However, X-linked recessive disease has also been reported. In addition, both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein [(premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Rett syndrome (ClinVar, RettBASE, VCGS). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587)
Comment:
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP, PP4
Comment:
The stop_gained (c.844C>T) variant is most commonly reported in heterozygous state in patients affected with Rett syndrome (Moog, U. et. al., 2003; Laccone F et. al., 2001) but has also been reported in individuals with atypical Rett syndrome (RettBASE). This variant is clearly defined as a Rett syndrome causative allele that accounts for ~7% of disease-causing variants (Percy A.K. et. al., 2007; Philippe C. et. al., 2006) and has been shown to arise de novo in individuals affected with Rett syndrome (Laccone F et. al., 2001). Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The MECP2 c.844C>T p.(Arg282Ter) nonsense variant, also known as c.808C>T p.(Arg270Ter), occurs in the last exon of the gene, and the resulting transcript may escape nonsense-mediated mRNA decay. However, the premature truncation, which occurs in the transcriptional repression domain, has also been shown to disrupt a conserved AT-hook domain that functions in DNA binding (Baker et al. 2013). This variant has been identified in individuals with a phenotype consistent with Rett syndrome or other MECP2-related disorder, including in some individuals in whom the variant occurred de novo (Laccone et al. 2001; Philippe et al. 2006; Yan et al. 2019; Liu et al. 2020; Martinez-Granero et al. 2021). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013). Transgenic mice expressing the variant in the absence of wildtype MECP2 recapitulated features of the clinical phenotype observed in human patients, including reduced lifespan, brain atrophy, and neurological signs (Baker et al. 2013). Based on the available evidence, the c.844C>T p.(Arg282Ter) variant is classified as pathogenic for MECP2-related disorders.
Comment:
The p.R270* pathogenic mutation (also known as c.808C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 808. This changes the amino acid from an arginine to a stop codon within coding exon 3. This common recurrent MECP2 mutation is located in the TRD-NLS (transcription repression domain-nuclear localization signal) region and has been shown to cause a more severe phenotype compared to other MECP2 mutations (Cardoza B et al. Seizure, 2011 Oct;20:646-9; Kifayathullah LA et al. Cytogenet Genome Res. 2010;129(4):290-297). In addition, this mutation has been reported in both males (several with XXY karyotypes) and females with classic Rett syndrome (Reichow B et al. J Autism Dev Disord, 2015 Oct;45:3377-83; De Bona Cet al. Eur J Hum Genet. 2000;8(5):325-330; Cheadle JP et al. Hum Mol Genet. 2000;9(7):1119-1129). Another study found that this mutation is unable to repress transcription, a major function of MeCP2 protein (Yusufzai TM et al. Nucleic Acids Res. 2000;28(21):4172-4179). 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.
Comment:
PVS1, PS2, PS4, PM2
Comment:
MECP2: PVS1, PS2, PM2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| MECP2 Disorders. | Adam MP | - | 2019 | PMID: 20301670 |
| Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. | Li J | Molecular psychiatry | 2017 | PMID: 28831199 |
| Determinants of sleep disturbances in Rett syndrome: Novel findings in relation to genotype. | Boban S | American journal of medical genetics. Part A | 2016 | PMID: 27255190 |
| Functional outcomes in Rett syndrome. | Pidcock FS | Brain & development | 2016 | PMID: 26175308 |
| Brief report: systematic review of Rett syndrome in males. | Reichow B | Journal of autism and developmental disorders | 2015 | PMID: 26254891 |
| Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. | Cuddapah VA | Journal of medical genetics | 2014 | PMID: 24399845 |
| MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). | Maortua H | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23810759 |
| An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. | Baker SA | Cell | 2013 | PMID: 23452848 |
| Pubertal trajectory in females with Rett syndrome: a population-based study. | Knight O | Brain & development | 2013 | PMID: 23270700 |
| 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 |
| MeCP2 deficiency is associated with impaired microtubule stability. | Delépine C | FEBS letters | 2013 | PMID: 23238081 |
| Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis. | Todorov T | Mutation research | 2012 | PMID: 22525432 |
| Molecular diagnostic dilemmas in Rett syndrome. | Zvereff V | Brain & development | 2012 | PMID: 22277191 |
| Molecular screening of MECP2 gene in a cohort of Lebanese patients suspected with Rett syndrome: report on a mild case with a novel indel mutation. | Corbani S | Journal of intellectual disability research : JIDR | 2012 | PMID: 21954873 |
| Epilepsy in Rett syndrome: association between phenotype and genotype, and implications for practice. | Cardoza B | Seizure | 2011 | PMID: 21764336 |
| MeCP2 mutant protein is expressed in astrocytes as well as in neurons and localizes in the nucleus. | Kifayathullah LA | Cytogenetic and genome research | 2010 | PMID: 20625242 |
| Analysis of the parental origin of de novo MECP2 mutations and X chromosome inactivation in 24 sporadic patients with Rett syndrome in China. | Zhu X | Journal of child neurology | 2010 | PMID: 20207612 |
| Identification and characterization of novel sequence variations in MECP2 gene in Rett syndrome patients. | Monnerat LS | Brain & development | 2010 | PMID: 20031356 |
| Genotype-phenotype correlation in Brazillian Rett syndrome patients. | Lima FT | Arquivos de neuro-psiquiatria | 2009 | PMID: 19722030 |
| Investigating genotype-phenotype relationships in Rett syndrome using an international data set. | Bebbington A | Neurology | 2008 | PMID: 18332345 |
| Rett syndrome: North American database. | Percy AK | Journal of child neurology | 2007 | PMID: 18174548 |
| MECP2 mutations in Serbian Rett syndrome patients. | Djarmati A | Acta neurologica Scandinavica | 2007 | PMID: 17986102 |
| Abnormal movements in Rett syndrome are present before the regression period: a case study. | Temudo T | Movement disorders : official journal of the Movement Disorder Society | 2007 | PMID: 17914728 |
| 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 |
| The MECP2 gene mutation screening in Rett syndrome patients from Croatia. | Matijević T | Annals of the New York Academy of Sciences | 2006 | PMID: 17341617 |
| Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome. | Kim IJ | Experimental & molecular medicine | 2006 | PMID: 16672765 |
| Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. | Philippe C | European journal of medical genetics | 2006 | PMID: 16473305 |
| Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. | Archer HL | Journal of medical genetics | 2006 | PMID: 16183801 |
| p.R270X MECP2 mutation and mortality in Rett syndrome. | Jian L | European journal of human genetics : EJHG | 2005 | PMID: 16077729 |
| Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. | Fukuda T | Brain & development | 2005 | PMID: 15737703 |
| Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype. | Chae JH | Journal of child neurology | 2004 | PMID: 15526954 |
| Mutation analysis of MECP2 and determination of the X-inactivation pattern in Hungarian Rett syndrome patients. | Kárteszi J | American journal of medical genetics. Part A | 2004 | PMID: 15389714 |
| Fetal alcohol syndrome in association with Rett syndrome. | Zoll B | Genetic counseling (Geneva, Switzerland) | 2004 | PMID: 15287421 |
| Screening of MECP2 coding sequence in patients with phenotypes of decreasing likelihood for Rett syndrome: a cohort of 171 cases. | Kammoun F | Journal of medical genetics | 2004 | PMID: 15173251 |
| 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 |
| MECP2 mutations in Israel: implications for molecular analysis, genetic counseling, and prenatal diagnosis in Rett syndrome. | Yaron Y | Human mutation | 2002 | PMID: 12325033 |
| Spectrum of MECP2 mutations in Rett syndrome. | Bienvenu T | Genetic testing | 2002 | PMID: 12180070 |
| Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. | Huppke P | Neuropediatrics | 2002 | PMID: 12075485 |
| Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome. | Chae JH | Journal of child neurology | 2002 | PMID: 11913567 |
| Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. | Topçu M | European journal of human genetics : EJHG | 2002 | PMID: 11896459 |
| Mutation analysis in Rett syndrome. | Milunsky JM | Genetic testing | 2001 | PMID: 11960578 |
| Rett syndrome in Spain: mutation analysis and clinical correlations. | Monrós E | Brain & development | 2001 | PMID: 11738885 |
| Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in Rett patients with preserved speech. | Yamashita Y | Brain & development | 2001 | PMID: 11738864 |
| Spectrum of MECP2 mutations in Rett syndrome. | Lee SS | Brain & development | 2001 | PMID: 11738860 |
| Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation. | Yamada Y | Human mutation | 2001 | PMID: 11524741 |
| DHPLC analysis of the MECP2 gene in Italian Rett patients. | Nicolao P | Human mutation | 2001 | PMID: 11462237 |
| MeCP2 mutations in children with and without the phenotype of Rett syndrome. | Hoffbuhr K | Neurology | 2001 | PMID: 11402105 |
| Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome. | Inui K | Brain & development | 2001 | PMID: 11376998 |
| MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern. | Nielsen JB | European journal of human genetics : EJHG | 2001 | PMID: 11313756 |
| MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. | Trappe R | American journal of human genetics | 2001 | PMID: 11309679 |
| 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 |
| Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions. | Laccone F | Human mutation | 2001 | PMID: 11241840 |
| MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. | Imessaoudene B | Journal of medical genetics | 2001 | PMID: 11238684 |
| A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients. | Bourdon V | Human genetics | 2001 | PMID: 11214906 |
| 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 |
| Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in patients with Rett syndrome. | Obata K | Journal of medical genetics | 2000 | PMID: 10991688 |
| 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 |
| MECP2 mutations account for most cases of typical forms of Rett syndrome. | Bienvenu T | Human molecular genetics | 2000 | PMID: 10814719 |
| Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. | Huppke P | Human molecular genetics | 2000 | PMID: 10814718 |
| Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. | Cheadle JP | Human molecular genetics | 2000 | PMID: 10767337 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5328443a-6e83-4ddd-a071-5ec86d9ae44c | - | - | - | - |
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Text-mined citations for rs61750240 ...
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Record last updated Nov 03, 2024
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