NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys) AND Rett syndrome
- Germline classification:
- Pathogenic/Likely pathogenic (10 submissions)
- Last evaluated:
- Mar 8, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000133095.24
Allele description [Variation Report for NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)]
NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)
- Gene:
- MECP2:methyl-CpG binding protein 2 [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- Xq28
- Genomic location:
- Preferred name:
- NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)
- Other names:
- NM_001110792.2(MECP2):c.437C>G; p.Ser146Cys
- HGVS:
- NC_000023.11:g.154031427G>C
- NG_007107.3:g.110677C>G
- NM_001110792.2:c.437C>GMANE SELECT
- NM_001316337.2:c.122C>G
- NM_001369391.2:c.122C>G
- NM_001369392.2:c.122C>G
- NM_001369393.2:c.122C>G
- NM_001369394.2:c.122C>G
- NM_001386137.1:c.-160C>G
- NM_001386138.1:c.-160C>G
- NM_001386139.1:c.-160C>G
- NM_004992.4:c.401C>G
- NP_001104262.1:p.Ser146Cys
- NP_001303266.1:p.Ser41Cys
- NP_001356320.1:p.Ser41Cys
- NP_001356321.1:p.Ser41Cys
- NP_001356322.1:p.Ser41Cys
- NP_001356323.1:p.Ser41Cys
- NP_004983.1:p.Ser134Cys
- NP_004983.1:p.Ser134Cys
- LRG_764t1:c.437C>G
- LRG_764t2:c.401C>G
- AJ132917.1:c.401C>G
- LRG_764:g.110677C>G
- LRG_764p1:p.Ser146Cys
- LRG_764p2:p.Ser134Cys
- NC_000023.10:g.153296878G>C
- NG_007107.2:g.110701C>G
- NM_004992.3:c.401C>G
- NM_004992.4:c.401C>G
- P51608:p.Ser134Cys
This HGVS expression did not pass validation- Protein change:
- S134C
- Links:
- UniProtKB: P51608#VAR_010278; dbSNP: rs61748390
- NCBI 1000 Genomes Browser:
- rs61748390
- Molecular consequence:
- NM_001386137.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
- NM_001386138.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
- NM_001386139.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
- NM_001110792.2:c.437C>G - missense variant - [Sequence Ontology: SO:0001583]
- NM_001316337.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369391.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369392.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369393.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369394.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
- NM_004992.4:c.401C>G - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 17
Condition(s)
-
Profile neighbors for GEO Profiles (Select 98762514) (199)
GEO Profiles
-
BioProject Links for Protein (Select 2248517099) (1)
BioProject
-
Taxonomy Links for Protein (Select 2502704806) (1)
Taxonomy
-
Perrottetia racemosa chloroplast, complete genome
Perrottetia racemosa chloroplast, complete genomegi|2248517016|ref|NC_063900.1|Nucleotide
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See more...Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000188085 | RettBASE | no assertion criteria provided | Pathogenic (Nov 1, 2011) | maternal, de novo, unknown | curation | |
| SCV000247967 | Genetic Services Laboratory, University of Chicago | criteria provided, single submitter (ACMG Guidelines, 2007) | Pathogenic (Feb 8, 2013) | germline | clinical testing | |
| SCV000537175 | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Jul 7, 2015) | de novo | clinical testing | |
| SCV001362253 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Mar 11, 2021) | germline | clinical testing | |
| SCV001427579 | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | no assertion criteria provided | Pathogenic (Jan 1, 2019) | de novo | clinical testing | |
| SCV002053932 | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic | de novo | research | |
| SCV002107099 | DASA | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 5, 2022) | germline | clinical testing | |
| SCV002506805 | New York Genome Center - CSER-NYCKidSeq | criteria provided, single submitter (NYGC Assertion Criteria 2020) | Pathogenic (Jun 11, 2021) | germline | clinical testing | |
| SCV004100763 | Institute of Human Genetics, University of Leipzig Medical Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 9, 2023) | unknown | clinical testing | |
| SCV004808969 | Centre for Population Genomics, CPG | criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022)) | Pathogenic (Mar 8, 2024) | germline | curation |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | yes | 2 | not provided | not provided | 1 | not provided | clinical testing |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
| not provided | unknown | yes | 9 | not provided | not provided | 9 | No | clinical testing, curation |
| not provided | unknown | unknown | 1 | not provided | not provided | 1 | not provided | curation |
| not provided | de novo | yes | 6 | not provided | not provided | 5 | No | clinical testing, research, curation |
| not provided | maternal | yes | 2 | not provided | not provided | 2 | Yes | curation |
| not provided | unknown | no | 1 | not provided | not provided | 1 | Yes | curation |
Citations
PubMed
Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..
Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.
- PMID:
- 18414213
Fukuda T, Yamashita Y, Nagamitsu S, Miyamoto K, Jin JJ, Ohmori I, Ohtsuka Y, Kuwajima K, Endo S, Iwai T, Yamagata H, Tabara Y, Miki T, Matsuishi T, Kondo I.
Brain Dev. 2005 Apr;27(3):211-7.
- PMID:
- 15737703
Details of each submission
From RettBASE, SCV000188085.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | curation | PubMed (10) |
| 2 | not provided | 1 | not provided | Yes | curation | PubMed (10) |
| 3 | not provided | 1 | not provided | Yes | curation | PubMed (10) |
| 4 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 5 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 6 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 7 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 8 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 9 | not provided | 1 | not provided | not provided | curation | PubMed (10) |
| 10 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 11 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 12 | not provided | 1 | not provided | not provided | curation | PubMed (10) |
| 13 | not provided | 1 | not provided | not provided | curation | PubMed (10) |
| 14 | not provided | 1 | not provided | not provided | curation | PubMed (10) |
| 15 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 16 | not provided | 1 | not provided | Yes | curation | PubMed (10) |
| 17 | not provided | 1 | not provided | No | curation | PubMed (10) |
| 18 | not provided | 1 | not provided | No | curation | PubMed (10) |
Description
Rett syndrome - Atypical
Rett syndrome - Atypical
Rett syndrome - classical
Rett syndrome - Classical
Rett syndrome - not certain
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 2 | unknown | no | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 3 | maternal | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 4 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 5 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 6 | de novo | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 7 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 8 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 9 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 10 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 11 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 12 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 13 | unknown | yes | 1 | Blood or skin | not provided | 1 | not provided | not provided | not provided | |
| 14 | unknown | yes | 1 | Blood or skin | not provided | 1 | not provided | not provided | not provided | |
| 15 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 16 | maternal | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 17 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 18 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
From Genetic Services Laboratory, University of Chicago, SCV000247967.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000537175.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (10) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | de novo | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362253.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
Description
Variant summary: MECP2 c.401C>G (p.Ser134Cys) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181626 control chromosomes (gnomAD). c.401C>G has been reported in the literature in multiple individuals affected with Rett Syndrome, in some cases as a de novo mutation (example: Chapleau_2013, Li_2007, Neul_2008, Petel-Galil_2006, Roende_2011, Zahorakova_2007). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant has been reported to reduce the ability of the MECP2 protein to bind and cluster heterochromatin and was shown to cause destabilization of the methyl-CpG-binding domain of the protein (example: Agarwal_2011, Kucukkal_2015). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV001427579.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | de novo | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002053932.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | research | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | de novo | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From DASA, SCV002107099.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (11) |
Description
The c.401C>G;p.(Ser134Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 143562; PMID: 10814718; PMID: 11738864; PMID: 17089071; PMID: 12655490; PMID: 21160487; PMID: 11738883; PMID: 18337588) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (MBD) - PM1. This variant is not present in population databases (rs61748390- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 143563) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 10767337; 23696494; 22182064) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From New York Genome Center - CSER-NYCKidSeq, SCV002506805.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (6) |
Description
The heterozygous c.401C>G (p.Ser134Cys) missense variant identified in the MECP2 gene is a known pathogenic variant and has been reported in multiple unrelated individuals affected with Rett syndrome [PMID:10767337; PMID:12661945; PMID:21228398; PMID:26418480; PMID: 31164858]. The variant has been reported as Pathogenic/Likely Pathogenic in ClinVar by multiple independent laboratories [Variation ID: 143562]. The variant is absent from gnomAD(v3) suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools [CADD score = 27.7, REVEL score = 0.988). Functional studies have suggested that the c.401C>G (p.Ser134Cys) variant destabilizes the MBD domain of the MECP2 protein and reduces its ability to bind and cluster heterochromatin [PMID: 26418480; PMID: 21831886]. Based on the available evidence, the heterozygous c.401C>G (p.Ser134Cys) missense variant identified in the MECP2 gene is reported as Pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
From Institute of Human Genetics, University of Leipzig Medical Center, SCV004100763.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
Criteria applied: PS2_VSTR,PS4,PM5_STR,PM1,PM2_SUP,PP3
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Centre for Population Genomics, CPG, SCV004808969.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
Description
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, 10991688, 11269512) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 17407838, 17387578, 11269512, 17089071, 11738864, 10991688, 10814718, ClinVar Variation ID: 143562) Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: Oct 13, 2024
PubMed [ID: 16182490]