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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PubMed: PMID:10508514 ,10991688‚Äö 11738864‚Äö 15057977‚Äö 15737703, ClinVar Variation ID: 143662 This variant is absent from gnomAD (PM2_Supporting).
ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.731del (p.Gly244fs)
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.
(4)
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
4
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.731del (p.Gly244fs)
Variation ID: 143662 Accession: VCV000143662.10
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: Xq28 X: 154031133 (GRCh38) [ NCBI UCSC ] X: 153296584 (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 Apr 6, 2024 Mar 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001110792.2:c.731del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Gly244fs frameshift NM_004992.4:c.695del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Gly232fs frameshift NM_001316337.2:c.416del NP_001303266.1:p.Gly139fs frameshift NM_001369391.2:c.416del NP_001356320.1:p.Gly139fs frameshift NM_001369392.2:c.416del NP_001356321.1:p.Gly139fs frameshift NM_001369393.2:c.416del NP_001356322.1:p.Gly139fs frameshift NM_001369394.2:c.416del NP_001356323.1:p.Gly139fs frameshift NM_001386137.1:c.26del NP_001373066.1:p.Gly9fs frameshift NM_001386138.1:c.26del NP_001373067.1:p.Gly9fs frameshift NM_001386139.1:c.26del NP_001373068.1:p.Gly9fs frameshift NM_004992.3:c.695del NM_004992.3:c.695delG NC_000023.11:g.154031137del NC_000023.10:g.153296588del NG_007107.3:g.110971del LRG_764:g.110971del LRG_764t1:c.731del LRG_764p1:p.Gly244fs LRG_764t2:c.695del LRG_764p2:p.Gly232fs AJ132917.1:c.695delG - Protein change
- G232fs, G139fs, G244fs, G9fs
- Other names
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NM_001110792.2(MECP2):c.731del
p.Gly244fs
- Canonical SPDI
- NC_000023.11:154031132:CCCCC:CCCC
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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.
- -
- 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 (2) |
criteria provided, single submitter
|
Mar 22, 2024 | RCV000133203.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 17, 2022 | RCV001385710.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 10, 2022 | RCV003137641.3 |
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
(Mar 22, 2024)
|
criteria provided, single submitter
Method: curation
|
Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
Centre for Population Genomics, CPG
Accession: SCV004808882.1
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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PubMed: PMID:10508514 ,10991688‚Äö 11738864‚Äö 15057977‚Äö 15737703, ClinVar Variation ID: 143662 This variant is absent from gnomAD (PM2_Supporting). (less)
|
|
|
Pathogenic
(Nov 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003821461.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Feb 17, 2022)
|
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: SCV001585671.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg255*) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg255*) have been determined to be pathogenic (PMID: 10508514, 11241840, 17089071, 23270700). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143662). This variant is also known as 770(G) and G231fsX247. This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 10991688, 15057977, 18562141). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly232Alafs*16) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 255 amino acid(s) of the MECP2 protein. (less)
|
|
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Pathogenic
(Feb 18, 2008)
|
no assertion criteria provided
Method: curation
|
Rett syndrome
Affected status: yes
Allele origin:
de novo,
unknown
|
RettBASE
Accession: SCV000188201.2
First in ClinVar: Aug 17, 2014 Last updated: Apr 24, 2015 |
Observation 1:
Number of individuals with the variant: 1
Family history: No
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 2:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
Observation 3:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
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 - classical
Observation 5:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg255*) have been determined to be pathogenic (PMID: 10508514, 11241840, 17089071, 23270700). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143662). This variant is also known as 770(G) and G231fsX247. This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 10991688, 15057977, 18562141). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly232Alafs*16) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 255 amino acid(s) of the MECP2 protein.
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:
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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PubMed: PMID:10508514 ,10991688‚Äö 11738864‚Äö 15057977‚Äö 15737703, ClinVar Variation ID: 143662 This variant is absent from gnomAD (PM2_Supporting).
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg255*) have been determined to be pathogenic (PMID: 10508514, 11241840, 17089071, 23270700). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143662). This variant is also known as 770(G) and G231fsX247. This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 10991688, 15057977, 18562141). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly232Alafs*16) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 255 amino acid(s) of the MECP2 protein.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pubertal trajectory in females with Rett syndrome: a population-based study. | Knight O | Brain & development | 2013 | PMID: 23270700 |
| Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant). | Renieri A | Brain & development | 2009 | PMID: 18562141 |
| MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. | Li MR | Journal of human genetics | 2007 | PMID: 17089071 |
| 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 |
| Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. | Schanen C | American journal of medical genetics. Part A | 2004 | PMID: 15057977 |
| Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in Rett patients with preserved speech. | Yamashita Y | Brain & development | 2001 | PMID: 11738864 |
| Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions. | Laccone F | Human mutation | 2001 | PMID: 11241840 |
| 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 |
| Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. | Amir RE | Nature genetics | 1999 | PMID: 10508514 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/492e4f15-d106-4051-aa55-3316c05b06f5 | - | - | - | - |
Text-mined citations for rs63260260 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.