ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.504C>G (p.Asp168Glu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001110792.2(MECP2):c.504C>G (p.Asp168Glu)
Variation ID: 95196 Accession: VCV000095196.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154031360 (GRCh38) [ NCBI UCSC ] X: 153296811 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 10, 2015 Apr 6, 2024 Mar 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001110792.2:c.504C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Asp168Glu missense NM_004992.4:c.468C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Asp156Glu missense NM_001316337.2:c.189C>G NP_001303266.1:p.Asp63Glu missense NM_001369391.2:c.189C>G NP_001356320.1:p.Asp63Glu missense NM_001369392.2:c.189C>G NP_001356321.1:p.Asp63Glu missense NM_001369393.2:c.189C>G NP_001356322.1:p.Asp63Glu missense NM_001369394.2:c.189C>G NP_001356323.1:p.Asp63Glu missense NM_001386137.1:c.-129+36C>G intron variant NM_001386138.1:c.-129+36C>G intron variant NM_001386139.1:c.-129+36C>G intron variant NC_000023.11:g.154031360G>C NC_000023.10:g.153296811G>C NG_007107.3:g.110744C>G LRG_764:g.110744C>G LRG_764t1:c.504C>G LRG_764p1:p.Asp168Glu LRG_764t2:c.468C>G LRG_764p2:p.Asp156Glu AJ132917.1:c.468C>G - Protein change
- D156E, D168E, D63E
- Other names
- p.D156E:GAC>GAG
- NM_001110792.2(MECP2):c.504C>G
- p.Asp168Glu
- Canonical SPDI
- NC_000023.11:154031359:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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MECP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1831 | 2154 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 30, 2022 | RCV000081204.25 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2024 | RCV000169946.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV000815972.14 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Rett's disorder
Affected status: yes
Allele origin:
unknown
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Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics
Accession: SCV000223858.1
First in ClinVar: Jun 10, 2015 Last updated: Jun 10, 2015 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247969.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
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Suma Genomics
Accession: SCV001847692.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
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Pathogenic
(Nov 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002601737.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Clinical Features:
Hypotonia (present) , Global developmental delay (present) , Myopathy (present) , Poor gross motor coordination (present)
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Pathogenic
(Mar 08, 2024)
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criteria provided, single submitter
Method: curation
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Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Centre for Population Genomics, CPG
Accession: SCV004808972.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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 3.0, this variant is classified as pathogenic. At least the following criteria are met: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 15737703, 16473305, 12075485, 27354166, 20728410, 19722030, 23103540, 30781346, 26984561, 31645865, 19652677, 11524741, 21982064, 16672765,ClinVar Variation ID: 95196). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 15737703) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). (less)
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Pathogenic
(Jan 31, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000230259.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jun 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002526736.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS4, PS2_MOD, PS1_MOD, PM1, PM5, PM2_SUP, PP3
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Pathogenic
(Aug 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000191037.15
First in ClinVar: Nov 01, 2014 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that the D156E variant results in impaired heterochromatin binding, reduced transcriptional repression, and destabilization of the MeCP2 protein (Kudo et al., … (more)
Published functional studies demonstrate that the D156E variant results in impaired heterochromatin binding, reduced transcriptional repression, and destabilization of the MeCP2 protein (Kudo et al., 2003; Kucukkal et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19722030, 26418480, 29655203, 32472557, 10805343, 21831886, 12843318, 26984561, 12075485, 11524741) (less)
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Pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Severe neonatal-onset encephalopathy with microcephaly
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000956455.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 156 of the MECP2 … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 156 of the MECP2 protein (p.Asp156Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 11524741, 12075485, 15737703, 16473305, 16672765, 19722030, 22182064, 26984561, 27354166). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 95196). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318, 26418480). This variant disrupts the p.Asp156 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been observed in individuals with MECP2-related conditions (PMID: 11309679, 15737703, 18021529, 22182064), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 26, 2016)
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no assertion criteria provided
Method: research
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Rett syndrome
Affected status: unknown
Allele origin:
de novo
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RettBASE
Accession: SCV000188113.3
First in ClinVar: Aug 15, 2014 Last updated: Jan 30, 2017 |
Number of individuals with the variant: 16
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study. | Halbach N | American journal of medical genetics. Part A | 2016 | PMID: 27354166 |
MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning. | Zahorakova D | Journal of human genetics | 2016 | PMID: 26984561 |
Impact of Rett Syndrome Mutations on MeCP2 MBD Stability. | Kucukkal TG | Biochemistry | 2015 | PMID: 26418480 |
What does the nature of the MECP2 mutation tell us about parental origin and recurrence risk in Rett syndrome? | Zhang J | Clinical genetics | 2012 | PMID: 22182064 |
Genotype-phenotype correlation in Brazillian Rett syndrome patients. | Lima FT | Arquivos de neuro-psiquiatria | 2009 | PMID: 19722030 |
[Application of long range polymerase chain reaction and DNA direct sequencing in diagnosis of Rett syndrome]. | Li MR | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2007 | PMID: 18021529 |
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 |
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 |
Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain. | Kudo S | Journal of medical genetics | 2003 | PMID: 12843318 |
Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. | Huppke P | Neuropediatrics | 2002 | PMID: 12075485 |
Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation. | Yamada Y | Human mutation | 2001 | PMID: 11524741 |
MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. | Trappe R | American journal of human genetics | 2001 | PMID: 11309679 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MECP2 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/76634b44-1ead-4b51-bc2a-9f4e85ac232f | - | - | - | - |
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Text-mined citations for rs61748408 ...
HelpRecord last updated Jun 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.