ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.507C>A (p.Phe169Leu)
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.507C>A (p.Phe169Leu)
Variation ID: 1027605 Accession: VCV001027605.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154031357 (GRCh38) [ NCBI UCSC ] X: 153296808 (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 Mar 22, 2021 Feb 14, 2024 Oct 22, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001110792.2:c.507C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Phe169Leu missense NM_004992.4:c.471C>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Phe157Leu missense NM_001316337.2:c.192C>A NP_001303266.1:p.Phe64Leu missense NM_001369391.2:c.192C>A NP_001356320.1:p.Phe64Leu missense NM_001369392.2:c.192C>A NP_001356321.1:p.Phe64Leu missense NM_001369393.2:c.192C>A NP_001356322.1:p.Phe64Leu missense NM_001369394.2:c.192C>A NP_001356323.1:p.Phe64Leu missense NM_001386137.1:c.-129+39C>A intron variant NM_001386138.1:c.-129+39C>A intron variant NM_001386139.1:c.-129+39C>A intron variant NC_000023.11:g.154031357G>T NC_000023.10:g.153296808G>T NG_007107.3:g.110747C>A LRG_764:g.110747C>A LRG_764t1:c.507C>A LRG_764p1:p.Phe169Leu LRG_764t2:c.471C>A LRG_764p2:p.Phe157Leu - Protein change
- F157L, F169L, F64L
- Other names
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- Canonical SPDI
- NC_000023.11:154031356:G: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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- Links
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 |
1825 | 2148 |
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
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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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2021 | RCV001328391.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2021 | RCV001863184.3 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Mar 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001519515.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
Variant summary: MECP2 c.471C>A (p.Phe157Leu) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. … (more)
Variant summary: MECP2 c.471C>A (p.Phe157Leu) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182743 control chromosomes (gnomAD). p.F157L has been reported in the literature in individuals affected with Rett Syndrome (Lima_2009, Kim_2012, Gauthier_2005, Wen_2020). Additionally, Khajuria_2020 reported the F157L variant as a de novo variant in an individual with RTT. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, missense variants nearby residues (F157I, D156H/G/E/A, T158A/M) have been reported in the Human Gene Mutation Database in association with Rett syndrome, supporting the functional importance of this region of the protein. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Oct 22, 2021)
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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: SCV002222897.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with Rett syndrome (PMID: 15675358, 16225173, 18021529, 19722030, 22476991, 30536762). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 157 of the MECP2 protein (p.Phe157Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. (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 mutation spectrum and its clinical characteristics in a Chinese cohort. | Wen Y | Clinical genetics | 2020 | PMID: 32472557 |
The Molecular Basis of MeCP2 Function in the Brain. | Tillotson R | Journal of molecular biology | 2020 | PMID: 31629770 |
The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. | Neul JL | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2019 | PMID: 30536762 |
Genotype-phenotype relationship among Egyptian children with Rett syndrome. | Mansour L | The Journal of the Egyptian Public Health Association | 2015 | PMID: 26544843 |
Apneic crises: a clue for MECP2 testing in severe neonatal hypotonia-respiratory failure. | Falsaperla R | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2012 | PMID: 22497713 |
Genetic and epileptic features in Rett syndrome. | Kim HJ | Yonsei medical journal | 2012 | PMID: 22476991 |
Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice. | Halbach NS | American journal of medical genetics. Part A | 2012 | PMID: 22190343 |
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 |
Clinical stringency greatly improves mutation detection in Rett syndrome. | Gauthier J | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2005 | PMID: 16225173 |
[Clinical symptoms of the Rett syndrome patients with MECP2 gene abnormalities]. | Miura K | No to hattatsu = Brain and development | 2005 | PMID: 15675358 |
Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome. | Van den Veyver IB | Brain & development | 2001 | PMID: 11738862 |
Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations. | Amir RE | American journal of medical genetics | 2000 | PMID: 11180222 |
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Text-mined citations for rs267608484 ...
HelpRecord last updated Feb 14, 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.