ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.710C>G (p.Pro237Arg)
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.710C>G (p.Pro237Arg)
Variation ID: 143653 Accession: VCV000143653.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154031154 (GRCh38) [ NCBI UCSC ] X: 153296605 (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 May 12, 2024 Mar 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001110792.2:c.710C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Pro237Arg missense NM_004992.4:c.674C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Pro225Arg missense NM_001316337.2:c.395C>G NP_001303266.1:p.Pro132Arg missense NM_001369391.2:c.395C>G NP_001356320.1:p.Pro132Arg missense NM_001369392.2:c.395C>G NP_001356321.1:p.Pro132Arg missense NM_001369393.2:c.395C>G NP_001356322.1:p.Pro132Arg missense NM_001369394.2:c.395C>G NP_001356323.1:p.Pro132Arg missense NM_001386137.1:c.5C>G NP_001373066.1:p.Pro2Arg missense NM_001386138.1:c.5C>G NP_001373067.1:p.Pro2Arg missense NM_001386139.1:c.5C>G NP_001373068.1:p.Pro2Arg missense NC_000023.11:g.154031154G>C NC_000023.10:g.153296605G>C NG_007107.3:g.110950C>G LRG_764:g.110950C>G LRG_764t1:c.710C>G LRG_764p1:p.Pro237Arg LRG_764t2:c.674C>G LRG_764p2:p.Pro225Arg P51608:p.Pro225Arg AJ132917.1:c.674C>G - Protein change
- P225R, P237R, P132R, P2R
- Other names
- NM_001110792.2(MECP2):c.710C>G
- p.Pro237Arg
- Canonical SPDI
- NC_000023.11:154031153:G:C
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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
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
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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
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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) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2024 | RCV000133193.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626873.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV000476280.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2020 | RCV001090502.20 | |
MECP2-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 27, 2024 | RCV004532609.1 |
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
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. |
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Pathogenic
(Jan 06, 2020)
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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: SCV001813722.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Published functional studies demonstrate a damaging effect (Guy et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated … (more)
Published functional studies demonstrate a damaging effect (Guy et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33084218, 10854091, 17089071, 10805343, 17387578, 21160487, 26984561, 11245712, 22190343, 26469135, 22139899, 15880509, 18056689, 19133691, 11524741, 29782864, 12180070, 18842453, 21954873, 12655490, 11214906, 12746405, 15675358, 29718204, 17142618, 16690727, 16473305, 12111643, 12075485, 10767337) (less)
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Pathogenic
(Jun 14, 2023)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004013295.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS2, PS3, PS4, PM2, PP3
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Pathogenic
(Feb 27, 2024)
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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: SCV004745606.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MECP2 c.674C>G variant is predicted to result in the amino acid substitution p.Pro225Arg. This variant was reported in multiple individuals with Rett syndrome, epilepsy … (more)
The MECP2 c.674C>G variant is predicted to result in the amino acid substitution p.Pro225Arg. This variant was reported in multiple individuals with Rett syndrome, epilepsy or intellectual disability and has been described as a recurrent causative variant documented as de novo in at least one patient (Cheadle et al. 2000. PubMed ID: 10767337; Table S2, Truty et al. 2019. PubMed ID: 31440721; Table S2, Dong et al. 2020. PubMed ID: 32005694; Table S1, Wen et al. 2020. PubMed ID: 32472557). In vitro functional studies found this variant interferes with protein function through decreased stability or conformational changes (Guy et al. 2018. PubMed ID: 29718204). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Absent speech
Developmental regression Irregular respiration Seizure Severe global developmental delay
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747576.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Jul 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449032.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jul 17, 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: SCV000544623.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 225 of the MECP2 protein (p.Pro225Arg). … (more)
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 225 of the MECP2 protein (p.Pro225Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with either classic or atypical Rett syndrome (PMID: 10767337, 10854091, 11524741, 12075485, 12111643, 16473305, 16690727, 17142618). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143653). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. This variant disrupts the p.Pro225 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12615169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 22, 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: SCV004808878.1
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: 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).(PMID: 17089071, 10767337). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 31427717, 17407838, 17387578, 17089071, 16473305, 19133691, 18842453, 10767337, 11245712). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD v4 (PM2_Supporting). (less)
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Pathogenic
(Mar 01, 2017)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246088.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 18, 2012)
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no assertion criteria provided
Method: curation
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Rett syndrome
Affected status: yes, unknown
Allele origin:
unknown,
de novo
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RettBASE
Accession: SCV000188191.2
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
Tissue: Blood
Comment on evidence:
Not known
Observation 2:
Number of individuals with the variant: 1
Tissue: blood
Comment on evidence:
Rett syndrome - atypical
Observation 3:
Number of individuals with the variant: 1
Sex: female
Comment on evidence:
Rett syndrome - Classical
Observation 4:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Classical
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
Family history: No
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
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 9:
Number of individuals with the variant: 1
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 - classical
Observation 11:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: Blood
Comment on evidence:
Rett syndrome - Not certain
Observation 12:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 13:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - not certain
Observation 14:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
Observation 15:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - Classical
Observation 16:
Number of individuals with the variant: 1
Family history: No
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
Observation 18:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood or skin
Comment on evidence:
Rett syndrome - Classical
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Likely pathogenic
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Rett syndrome
Affected status: yes
Allele origin:
unknown
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427577.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
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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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Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Molecular screening of MECP2 gene in a cohort of Lebanese patients suspected with Rett syndrome: report on a mild case with a novel indel mutation. | Corbani S | Journal of intellectual disability research : JIDR | 2012 | PMID: 21954873 |
Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations. | Hadzsiev K | Journal of human genetics | 2011 | PMID: 21160487 |
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 |
MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. | Li MR | Journal of human genetics | 2007 | PMID: 17089071 |
Comprehensive diagnosis of Rett's syndrome relying on genetic, epigenetic and expression evidence of deficiency of the methyl-CpG-binding protein 2 gene: study of a cohort of Israeli patients. | Petel-Galil Y | Journal of medical genetics | 2006 | PMID: 17142618 |
Very mild cases of Rett syndrome with skewed X inactivation. | Huppke P | Journal of medical genetics | 2006 | PMID: 16690727 |
Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. | Philippe C | European journal of medical genetics | 2006 | PMID: 16473305 |
Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). | Moog U | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2003 | PMID: 12615169 |
Spectrum of MECP2 mutations in Rett syndrome. | Bienvenu T | Genetic testing | 2002 | PMID: 12180070 |
MECP2 gene mutation analysis in Chinese patients with Rett syndrome. | Pan H | European journal of human genetics : EJHG | 2002 | PMID: 12111643 |
Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. | Huppke P | Neuropediatrics | 2002 | PMID: 12075485 |
Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation. | Yamada Y | Human mutation | 2001 | PMID: 11524741 |
MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features. | Auranen M | Neurology | 2001 | PMID: 11245712 |
Preserved speech variant is allelic of classic Rett syndrome. | De Bona C | European journal of human genetics : EJHG | 2000 | PMID: 10854091 |
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/09f78eee-d44a-40d6-815b-6db47f34dd91 | - | - | - | - |
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Text-mined citations for rs61749715 ...
HelpRecord last updated May 27, 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.