ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.1318G>A (p.Gly440Ser)
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.1318G>A (p.Gly440Ser)
Variation ID: 11831 Accession: VCV000011831.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154030546 (GRCh38) [ NCBI UCSC ] X: 153295997 (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 22, 2015 May 1, 2024 May 10, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001110792.2:c.1318G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Gly440Ser missense NM_004992.4:c.1282G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Gly428Ser missense NM_001316337.2:c.1003G>A NP_001303266.1:p.Gly335Ser missense NM_001369391.2:c.1003G>A NP_001356320.1:p.Gly335Ser missense NM_001369392.2:c.1003G>A NP_001356321.1:p.Gly335Ser missense NM_001369393.2:c.1003G>A NP_001356322.1:p.Gly335Ser missense NM_001369394.2:c.1003G>A NP_001356323.1:p.Gly335Ser missense NM_001386137.1:c.613G>A NP_001373066.1:p.Gly205Ser missense NM_001386138.1:c.613G>A NP_001373067.1:p.Gly205Ser missense NM_001386139.1:c.613G>A NP_001373068.1:p.Gly205Ser missense NC_000023.11:g.154030546C>T NC_000023.10:g.153295997C>T NG_007107.3:g.111558G>A LRG_764:g.111558G>A LRG_764t1:c.1318G>A LRG_764p1:p.Gly440Ser LRG_764t2:c.1282G>A LRG_764p2:p.Gly428Ser P51608:p.Gly428Ser AJ132917.1:c.1282G>A - Protein change
- G428S, G440S, G335S, G205S
- Other names
- NM_001110792.2(MECP2):c.1318G>A
- p.Gly440Ser
- Canonical SPDI
- NC_000023.11:154030545: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00011
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00013
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 | ||
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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 |
1827 | 2150 |
Conditions - Germline
Condition
Help
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
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
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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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Benign (2) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000012604.22 | |
Benign (1) |
no assertion criteria provided
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Oct 4, 2002 | RCV000132982.7 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 9, 2021 | RCV001719695.2 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 12, 2019 | RCV002371770.2 | |
Benign (2) |
reviewed by expert panel
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May 10, 2022 | RCV002260597.2 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 26, 2022 | RCV004540997.1 |
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
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
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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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Benign
(May 10, 2022)
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reviewed by expert panel
Method: curation
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Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
Accession: SCV002540679.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Comment:
The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds … (more)
The allele frequency of the p.Gly428Ser (NM_004992) variant in MECP2 is 0.014% in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Gly428Ser variant is observed in at least 2 unaffected individuals (PMID: 11238684, PMID: 12161600) (BS2). In summary the p.Gly428Ser variant in MECP2 is classified as Benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2). (less)
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Benign
(Aug 14, 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: SCV004098742.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 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 Panel … (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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID: 11238684). (less)
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Likely benign
(Oct 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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MECP2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004765532.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Jun 09, 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: SCV000513573.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 28454995, 11238684, 12161600, 11896461, 30560934)
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Benign
(Jan 29, 2024)
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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: SCV001008271.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Likely benign
(Sep 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002689596.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Oct 04, 2002)
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no assertion criteria provided
Method: curation
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Not specified
Affected status: not provided
Allele origin:
maternal,
unknown
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RettBASE
Accession: SCV000187966.2
First in ClinVar: Aug 15, 2014 Last updated: Apr 22, 2015 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Comment on evidence:
Not Rett synd. - Non-progressive encephalopathy of neonatal onset
Observation 2:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Not Rett synd. - Unaffected family member
Observation 3:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Not Rett synd. - Unaffected family member
Observation 4:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Not Rett synd. - Unaffected family member
Observation 5:
Number of individuals with the variant: 1
Sex: male
Tissue: Not known
Comment on evidence:
Not Rett synd. - Progressive encephalopathy of neonatal onset
Observation 6:
Number of individuals with the variant: 1
Sex: male
Tissue: Not known
Comment on evidence:
Not Rett synd. - Unaffected family member
Observation 7:
Number of individuals with the variant: 1
Sex: female
Tissue: Not known
Comment on evidence:
Not Rett synd. - Unaffected family member
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Pathogenic
(Aug 01, 2002)
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no assertion criteria provided
Method: literature only
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ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032839.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a male with nonprogressive encephalopathy of neonatal onset (300673), Imessaoudene et al. (2001) identified a 1282G-A transition in the MECP2 gene, resulting in a … (more)
In a male with nonprogressive encephalopathy of neonatal onset (300673), Imessaoudene et al. (2001) identified a 1282G-A transition in the MECP2 gene, resulting in a gly428-to-ser (G428S) substitution. They suggested that the patient's grandfather, whose DNA was unavailable, was mosaic for the G428S mutation. Laccone et al. (2002) questioned the validity of the G428S substitution as the disease-causing mutation. They identified the G428S substitution in a boy with severe encephalopathy and untreatable seizures who died at 18 months of age. They noted that the patient with the G428S mutation described by Imessaoudene et al. (2001) had a less severe phenotype and that the G428S change was more consistent with a rare genetic variant, as the grandpaternal mosaicism could not be proven. (less)
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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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MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution. | Laccone F | Journal of medical genetics | 2002 | PMID: 12161600 |
MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. | Imessaoudene B | Journal of medical genetics | 2001 | PMID: 11238684 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3b852f99-bb9c-46c9-a8db-011824c89688 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e4f79d84-f9c0-4e1b-84c1-fb00225eea4d | - | - | - | - |
Text-mined citations for rs61753971 ...
HelpRecord last updated May 12, 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.