ClinVar Genomic variation as it relates to human health
NM_001110792.2(MECP2):c.490C>G (p.Pro164Ala)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001110792.2(MECP2):c.490C>G (p.Pro164Ala)
Variation ID: 11844 Accession: VCV000011844.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 154031374 (GRCh38) [ NCBI UCSC ] X: 153296825 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 8, 2024 Mar 26, 2021 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001110792.2:c.490C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001104262.1:p.Pro164Ala missense NM_004992.4:c.454C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004983.1:p.Pro152Ala missense NM_001316337.2:c.175C>G NP_001303266.1:p.Pro59Ala missense NM_001369391.2:c.175C>G NP_001356320.1:p.Pro59Ala missense NM_001369392.2:c.175C>G NP_001356321.1:p.Pro59Ala missense NM_001369393.2:c.175C>G NP_001356322.1:p.Pro59Ala missense NM_001369394.2:c.175C>G NP_001356323.1:p.Pro59Ala missense NM_001386137.1:c.-129+22C>G intron variant NM_001386138.1:c.-129+22C>G intron variant NM_001386139.1:c.-129+22C>G intron variant NC_000023.11:g.154031374G>C NC_000023.10:g.153296825G>C NG_007107.3:g.110730C>G LRG_764:g.110730C>G LRG_764t1:c.490C>G LRG_764p1:p.Pro164Ala LRG_764t2:c.454C>G LRG_764p2:p.Pro152Ala AJ132917.1:c.454C>G - Protein change
- P152A, P164A, P59A
- Other names
- NM_001110792.2(MECP2):c.490C>G
- p.Pro164Ala
- Canonical SPDI
- NC_000023.11:154031373:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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 |
1887 | 2214 |
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 (1) |
no assertion criteria provided
|
Jan 1, 2009 | RCV000012618.28 | |
Pathogenic (2) |
criteria provided, single submitter
|
Oct 14, 2020 | RCV000133115.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 29, 2024 | RCV000492792.9 | |
Likely pathogenic (3) |
reviewed by expert panel
|
Mar 26, 2021 | RCV000991003.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763200.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Nov 16, 2023 | RCV001246099.12 | |
Likely pathogenic (1) |
no assertion criteria provided
|
Apr 22, 2024 | RCV004734514.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Mar 26, 2021)
|
reviewed by expert panel
Method: curation
|
Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001711999.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701) (PS3_supporting). The variant has been reported to segregate in three … (more)
Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701) (PS3_supporting). The variant has been reported to segregate in three informative meioses (PMID 18989701, internal database) (PP1_Moderate). The p.Pro152Ala variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (10767337) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro152Ala variant in MECP2 is classified as likely pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS3_supporting, PP1_moderate, PM1, PM5, PP3). (less)
|
|
Uncertain significance
(May 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe neonatal-onset encephalopathy with microcephaly
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001523356.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Pathogenic
(Nov 16, 2023)
|
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: SCV001419437.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 152 of the MECP2 protein (p.Pro152Ala). … (more)
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 152 of the MECP2 protein (p.Pro152Ala). This variant is present in population databases (rs179363900, gnomAD no frequency). This missense change has been observed in individual(s) with mild forms of Rett syndrome (PMID: 18989701, 27929079, 29655203). ClinVar contains an entry for this variant (Variation ID: 11844). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 18989701, 26842955, 27929079). This variant disrupts the p.Pro152 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767337, 11241840, 27929079). 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)
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked intellectual disability-psychosis-macroorchidism syndrome
Syndromic X-linked intellectual disability Lubs type Autism, susceptibility to, X-linked 3 Severe neonatal-onset encephalopathy with microcephaly Rett syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893819.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Oct 14, 2020)
|
criteria provided, single submitter
Method: research
|
X-linked intellectual disability-psychosis-macroorchidism syndrome
Affected status: yes
Allele origin:
maternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV001442525.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Comment:
ACMG codes:PS3; PS4M; PM1; PM2; PM5; PP4
Clinical Features:
Congenital ocular coloboma (present) , Micrognathia (present) , Corpus callosum, agenesis of (present) , Muscular hypotonia (present) , Epispadias (present) , Low-set ears (present) , … (more)
Congenital ocular coloboma (present) , Micrognathia (present) , Corpus callosum, agenesis of (present) , Muscular hypotonia (present) , Epispadias (present) , Low-set ears (present) , Flexion contracture (present) , Depressed nasal bridge (present) (less)
|
|
Likely pathogenic
(Aug 14, 2023)
|
criteria provided, single submitter
Method: curation
|
Rett syndrome
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
Centre for Population Genomics, CPG
Accession: SCV004098714.1
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 likely pathogenic. At least the following criteria are met: Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3, PMID: 18989701). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Another missense variant (c.491C>G, p.Pro164Arg, ClinVar Variation ID: 143579) in the same codon has been classified as pathogenic for Rett syndrome by the ClinGen Rett and Angelman-like Disorders Expert Panel (PM5). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). (less)
|
|
Likely pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001142091.4
First in ClinVar: Jan 09, 2020 Last updated: Dec 24, 2023 |
Comment:
Other patients with the same variant not presenting phenotype.
|
|
Pathogenic
(Nov 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017251.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582724.4
First in ClinVar: Jul 02, 2017 Last updated: Sep 16, 2024 |
Comment:
Reported in a female with pervasive developmental disorder, obesity, abnormal EEG, and inherited from her father with learning disabilities and obesity (PMID: 18989701); In silico … (more)
Reported in a female with pervasive developmental disorder, obesity, abnormal EEG, and inherited from her father with learning disabilities and obesity (PMID: 18989701); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27929079, 29655203, 26842955, 11402105, 23262346, 28785396, 33258288, 34002468, 31974426, 15526954, 35318820, 34205017, 20425298, 30573328, 31291284, 18989701, 12843318, 21831886, 34926809, 10767337) (less)
|
|
Pathogenic
(Jan 01, 2009)
|
no assertion criteria provided
Method: literature only
|
RETT SYNDROME, ZAPPELLA VARIANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032853.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
In a father and his 10-year-old daughter with neuropsychiatric features reminiscent of the mild phenotype of Zappella variant Rett syndrome (see 312750), Adegbola et al. … (more)
In a father and his 10-year-old daughter with neuropsychiatric features reminiscent of the mild phenotype of Zappella variant Rett syndrome (see 312750), Adegbola et al. (2009) identified a heterozygous 454C-G transversion in exon 4 of the MECP2 gene, resulting in a pro152-to-ala (P152A) substitution in the methyl-binding domain of the protein. The girl had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, had mild autistic features, and IQ of 58. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. In vitro functional expression studies in mouse fibroblasts demonstrated that the mutant protein showed varying levels of diffuse nuclear staining outside of the heterochromatic foci compared to wildtype, which localizes exclusively to heterochromatic foci. Biochemical studies showed that mutant P152A had a 40% reduction in association with insoluble heterochromatin compared to wildtype. Classic Rett mutations showed an 70 to 80% decrease. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family. (less)
|
|
Likely pathogenic
(Apr 22, 2024)
|
no assertion criteria provided
Method: clinical testing
|
MECP2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005356795.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The MECP2 c.454C>G variant is predicted to result in the amino acid substitution p.Pro152Ala. This variant has been reported in the heterozygous and hemizygous states … (more)
The MECP2 c.454C>G variant is predicted to result in the amino acid substitution p.Pro152Ala. This variant has been reported in the heterozygous and hemizygous states in multiple individuals with X-linked intellectual developmental disorder (Adegbola et al. 2009. PubMed ID: 18989701; Table S1, Lindy et al. 2018. PubMed ID: 29655203; Table S2, Quaio et al. 2020. PubMed ID: 33258288). This variant is reported in one of ~182,000 alleles in gnomAD. An in vitro experimental study suggests this variant leads to a partial reduction in heterochromatin binding (Figure 1, Adegbola et al. 2009. PubMed ID: 18989701). Alternate nucleotide substitutions affecting the same amino acid (p.Pro152Arg and p.Pro152Leu) have been reported in multiple individuals with Rett syndrome or autism spectrum disorder (Table 1, Cheadle et al. 2000. PubMed ID: 10767337; Table 1, Wen et al. 2017. PubMed ID: 28785396). In summary, the c.454C>G (p.Pro152Ala) variant is interpreted as likely pathogenic. (less)
|
|
Pathogenic
(Mar 04, 2009)
|
no assertion criteria provided
Method: curation
|
Mental retardation, X-linked, syndromic 13
Affected status: unknown, yes
Allele origin:
paternal,
unknown
|
RettBASE
Accession: SCV000188106.2
First in ClinVar: Aug 15, 2014 Last updated: Apr 22, 2015 |
Observation 1:
Number of individuals with the variant: 1
Family history: Yes
Sex: female
Tissue: blood
Comment on evidence:
Not Rett synd. - Pervasive developmental disorder-not otherwise specified
Observation 2:
Number of individuals with the variant: 1
Family history: Yes
Sex: male
Tissue: blood
Comment on evidence:
Not Rett synd. - Not specified
Observation 3:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Not known
Observation 4:
Number of individuals with the variant: 1
Sex: female
Tissue: blood
Comment on evidence:
Not known
Observation 5:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Not known
Observation 6:
Number of individuals with the variant: 1
Sex: female
Tissue: Blood
Comment on evidence:
Not known
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. | Lindy AS | Epilepsia | 2018 | PMID: 29655203 |
From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2. | Sheikh TI | Scientific reports | 2016 | PMID: 27929079 |
MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome. | Tai DJ | Nature communications | 2016 | PMID: 26842955 |
Spectrum of MECP2 gene mutations in a cohort of Indian patients with Rett syndrome: report of two novel mutations. | Das DK | Gene | 2013 | PMID: 23262346 |
A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype. | Adegbola AA | Human genetics | 2009 | PMID: 18989701 |
Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype. | Chae JH | Journal of child neurology | 2004 | PMID: 15526954 |
MeCP2 mutations in children with and without the phenotype of Rett syndrome. | Hoffbuhr K | Neurology | 2001 | PMID: 11402105 |
Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions. | Laccone F | Human mutation | 2001 | PMID: 11241840 |
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/5ac42611-e04e-4788-93b8-7c929a6dc343 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/692d4de8-21e1-4102-8ec2-4da4b8d9c892 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs179363900 ...
HelpRecord last updated Oct 13, 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.