ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.953G>A (p.Arg318His)
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.953G>A (p.Arg318His)
Variation ID: 143746 Accession: VCV000143746.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154030911 (GRCh38) [ NCBI UCSC ] X: 153296362 (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 Apr 24, 2015 Feb 28, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001110792.2:c.953G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Arg318His missense NM_004992.4:c.917G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Arg306His missense NM_001110792.1:c.953G>A NM_001316337.2:c.638G>A NP_001303266.1:p.Arg213His missense NM_001369391.2:c.638G>A NP_001356320.1:p.Arg213His missense NM_001369392.2:c.638G>A NP_001356321.1:p.Arg213His missense NM_001369393.2:c.638G>A NP_001356322.1:p.Arg213His missense NM_001369394.2:c.638G>A NP_001356323.1:p.Arg213His missense NM_001386137.1:c.248G>A NP_001373066.1:p.Arg83His missense NM_001386138.1:c.248G>A NP_001373067.1:p.Arg83His missense NM_001386139.1:c.248G>A NP_001373068.1:p.Arg83His missense NC_000023.11:g.154030911C>T NC_000023.10:g.153296362C>T NG_007107.3:g.111193G>A LRG_764:g.111193G>A LRG_764t1:c.953G>A LRG_764p1:p.Arg318His LRG_764t2:c.917G>A LRG_764p2:p.Arg306His P51608:p.Arg306His AJ132917.1:c.917G>A - Protein change
- R306H, R318H, R213H, R83H
- Other names
- NM_001110792.2(MECP2):c.953G>A
- p.Arg318His
- Canonical SPDI
- NC_000023.11:154030910:C:T
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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
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. |
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MECP2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1824 | 2145 |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2023 | RCV000133290.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2021 | RCV001778753.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2021 | RCV000256087.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2022 | RCV001857484.6 |
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
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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
(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: SCV000248006.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Likely pathogenic
(Jan 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome
Affected status: yes
Allele origin:
maternal
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NeuroMeGen, Hospital Clinico Santiago de Compostela
Accession: SCV000693793.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Aug 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV002016294.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
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Pathogenic
(Dec 14, 2022)
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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: SCV002120295.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg306 amino acid residue in MECP2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg306 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10991688, 14649554, 16473305, 23770565, 24511209, 24970834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 143746). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 23921973). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MECP2 protein (p.Arg306His). (less)
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Likely pathogenic
(Jun 30, 2015)
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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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Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000537171.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
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Pathogenic
(Mar 30, 2021)
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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: SCV000322254.8
First in ClinVar: Oct 09, 2016 Last updated: Jul 24, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate that the p.R306H variant abolishes binding of MECP2 to DNA (Heckman et al., 2014); This variant is associated with the following publications: (PMID: 31780880, 11055898, 12655490, 11214906, 15057977, 16473305, 24970834, 10767337, 23921973) (less)
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Pathogenic
(Dec 06, 2023)
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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: SCV004232314.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 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: This variant is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong).(PubMed: 11055898‚ 15057977‚ 16473305, 10767337, 23921973 ClinVar database Variation ID: 143746) (less)
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Pathogenic
(Feb 15, 2011)
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no assertion criteria provided
Method: curation
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Rett syndrome
Affected status: yes
Allele origin:
unknown,
de novo
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RettBASE
Accession: SCV000188299.2
First in ClinVar: Aug 17, 2014 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 - Classical
Observation 4:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 5:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 6:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 7:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 8:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 9:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 10:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 11:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Not certain
Observation 12:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 13:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - classical
Observation 14:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 15:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 16:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 17:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
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Pathogenic
(Oct 09, 2022)
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no assertion criteria provided
Method: research
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Rett syndrome
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, University of Torino
Accession: SCV002583294.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Sex: female
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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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Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. | Heckman LD | eLife | 2014 | PMID: 24970834 |
Subclinical inflammatory status in Rett syndrome. | Cortelazzo A | Mediators of inflammation | 2014 | PMID: 24511209 |
Brief report: MECP2 mutations in people without Rett syndrome. | Suter B | Journal of autism and developmental disorders | 2014 | PMID: 23921973 |
Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. | Lyst MJ | Nature neuroscience | 2013 | PMID: 23770565 |
Detection of rarely identified multiple mutations in MECP2 gene do not contribute to enhanced severity in Rett syndrome. | Chapleau CA | American journal of medical genetics. Part A | 2013 | PMID: 23696494 |
Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. | Philippe C | European journal of medical genetics | 2006 | PMID: 16473305 |
Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. | Schanen C | American journal of medical genetics. Part A | 2004 | PMID: 15057977 |
InterRett and RettBASE: International Rett Syndrome Association databases for Rett syndrome. | Fyfe S | Journal of child neurology | 2003 | PMID: 14649554 |
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 |
Reduction of mortality in specific-pathogen-free layer chickens by a caprine serum fraction after infection with Pasteurella multocida. | Willeford KO | Poultry science | 2000 | PMID: 11055848 |
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 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e72e272f-0472-4909-bfbd-113b7f3fcb0e | - | - | - | - |
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Text-mined citations for rs61751443 ...
HelpRecord last updated Feb 28, 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.