ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.941C>T (p.Pro314Leu)
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.941C>T (p.Pro314Leu)
Variation ID: 143738 Accession: VCV000143738.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154030923 (GRCh38) [ NCBI UCSC ] X: 153296374 (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 Jun 30, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001110792.2:c.941C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Pro314Leu missense NM_004992.4:c.905C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Pro302Leu missense NM_001316337.2:c.626C>T NP_001303266.1:p.Pro209Leu missense NM_001369391.2:c.626C>T NP_001356320.1:p.Pro209Leu missense NM_001369392.2:c.626C>T NP_001356321.1:p.Pro209Leu missense NM_001369393.2:c.626C>T NP_001356322.1:p.Pro209Leu missense NM_001369394.2:c.626C>T NP_001356323.1:p.Pro209Leu missense NM_001386137.1:c.236C>T NP_001373066.1:p.Pro79Leu missense NM_001386138.1:c.236C>T NP_001373067.1:p.Pro79Leu missense NM_001386139.1:c.236C>T NP_001373068.1:p.Pro79Leu missense NC_000023.11:g.154030923G>A NC_000023.10:g.153296374G>A NG_007107.3:g.111181C>T LRG_764:g.111181C>T LRG_764t1:c.941C>T LRG_764p1:p.Pro314Leu LRG_764t2:c.905C>T LRG_764p2:p.Pro302Leu P51608:p.Pro302Leu AJ132917.1:c.905C>T - Protein change
- P302L, P314L, P209L, P79L
- Other names
- NM_001110792.2(MECP2):c.941C>T
- p.Pro314Leu
- Canonical SPDI
- NC_000023.11:154030922:G:A
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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 |
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
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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Pathogenic (4) |
reviewed by expert panel
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Jun 30, 2022 | RCV000133281.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2018 | RCV000413239.2 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 4, 2023 | RCV000754784.3 |
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
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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
(Jun 30, 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: SCV002540711.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Comment:
The c.905C>T p.(Pro302Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro302Leu) variant has been observed in at least 5 individuals with Rett … (more)
The c.905C>T p.(Pro302Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro302Leu) variant has been observed in at least 5 individuals with Rett syndrome or severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756, 16473305, 32472557) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in at least 4 of these individuals (PMID: 10767337, 30377382, 23696494, 11313756) (PM6_very strong). The p.(Pro302Leu) variant occurs in the well-characterized transcriptional repression domain (TRD: aa 302-306) of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID: 10814718, 10814719, 10944854, 17387578, 15737703) (PM5). In summary, the c.905C>T p.(Pro302Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PP3, PP4, PM2_supporting). (less)
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Pathogenic
(Aug 04, 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: SCV003445287.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro302 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.Pro302 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10944854, 15737703, 16225173, 17387578). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 143738). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 302 of the MECP2 protein (p.Pro302Leu). (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: SCV000537170.1
First in ClinVar: Apr 24, 2015 Last updated: Apr 24, 2015 |
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
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Pathogenic
(Feb 14, 2018)
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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: SCV000490611.2
First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019 |
Comment:
The P302L missense variant in the MECP2 gene has been reported multiple times previously in association with Rett syndrome (Cheadle et al., 2000; RettBASE). It … (more)
The P302L missense variant in the MECP2 gene has been reported multiple times previously in association with Rett syndrome (Cheadle et al., 2000; RettBASE). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P302L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position predicted to be within the transcriptional repression domain (TRD). Multiple different missense variants at the same residue as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Rett syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. (less)
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Pathogenic
(Jan 09, 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: SCV004232210.1
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). This variant has been identified as a de novo occurrence in at least an individual with Rett syndrome without confirmation of paternity and maternity (PM6) PMID: 10767337, ClinVar Variation ID: 143738 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4, PP4). (PMID: 16473305 , ClinVar Variation ID: 143738) Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). (less)
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Uncertain significance
(Jan 21, 2008)
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no assertion criteria provided
Method: curation
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Rett syndrome
Affected status: unknown, yes
Allele origin:
unknown,
de novo
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RettBASE
Accession: SCV000188289.2
First in ClinVar: Aug 17, 2014 Last updated: Apr 24, 2015 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Not known
Observation 2:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood or fibroblasts
Comment on evidence:
Rett syndrome - classical
Observation 3:
Number of individuals with the variant: 1
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 - Not certain
Observation 5:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 6:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
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Pathogenic
(Sep 13, 2018)
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no assertion criteria provided
Method: clinical testing
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Severe neonatal-onset encephalopathy with microcephaly
Affected status: yes
Allele origin:
de novo
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The Raphael Recanati Genetics Institute, Rabin Medical Center
Accession: SCV000882666.1
First in ClinVar: Feb 06, 2019 Last updated: Feb 06, 2019
Comment:
X-linked de novo
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Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: Muslim Arabs
Geographic origin: Israel
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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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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 |
Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. | Zahorakova D | Journal of human genetics | 2007 | PMID: 17387578 |
Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. | Philippe C | European journal of medical genetics | 2006 | PMID: 16473305 |
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 |
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 |
Spectrum of MECP2 mutations in Rett syndrome. | Bienvenu T | Genetic testing | 2002 | PMID: 12180070 |
MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern. | Nielsen JB | European journal of human genetics : EJHG | 2001 | PMID: 11313756 |
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 |
Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome. | Amano K | Journal of human genetics | 2000 | PMID: 10944854 |
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/52ac3faa-63d1-44a4-b87d-a5d0ddf0702b | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5440749b-7ac5-4fba-8a4a-70847f234b72 | - | - | - | - |
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Text-mined citations for rs61749723 ...
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.