NM_001110792.2(MECP2):c.842del (p.Gly281fs) AND Rett syndrome
- Germline classification:
- Pathogenic (14 submissions)
- Last evaluated:
- Mar 9, 2021
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- 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:
- RCV000168691.36
Allele description [Variation Report for NM_001110792.2(MECP2):c.842del (p.Gly281fs)]
NM_001110792.2(MECP2):c.842del (p.Gly281fs)
- Gene:
- MECP2:methyl-CpG binding protein 2 [Gene - OMIM - HGNC]
- Variant type:
- Deletion
- Cytogenetic location:
- Xq28
- Genomic location:
- Preferred name:
- NM_001110792.2(MECP2):c.842del (p.Gly281fs)
- Other names:
- NM_001110792.2(MECP2):c.842del; p.Gly281fs
- HGVS:
- NC_000023.11:g.154031025del
- NG_007107.3:g.111082del
- NM_001110792.2:c.842delMANE SELECT
- NM_001316337.2:c.527del
- NM_001369391.2:c.527del
- NM_001369392.2:c.527del
- NM_001369393.2:c.527del
- NM_001369394.2:c.527del
- NM_001386137.1:c.137del
- NM_001386138.1:c.137del
- NM_001386139.1:c.137del
- NM_004992.3(MECP2):c.806delG
- NM_004992.4:c.806del
- NP_001104262.1:p.Gly281fs
- NP_001303266.1:p.Gly176fs
- NP_001356320.1:p.Gly176fs
- NP_001356321.1:p.Gly176fs
- NP_001356322.1:p.Gly176fs
- NP_001356323.1:p.Gly176fs
- NP_001373066.1:p.Gly46fs
- NP_001373067.1:p.Gly46fs
- NP_001373068.1:p.Gly46fs
- NP_004983.1:p.Gly269fs
- LRG_764t1:c.842del
- LRG_764t2:c.806del
- AJ132917.1:c.806delG
- LRG_764:g.111082del
- LRG_764p1:p.Gly281fs
- LRG_764p2:p.Gly269fs
- NC_000023.10:g.153296473del
- NC_000023.10:g.153296473delC
- NC_000023.10:g.153296476del
- NC_000023.10:g.153296476delC
- NC_000023.10:g.153296476delC
- NC_000023.11:g.154031022delC
- NG_007107.2:g.111106del
- NM_001110792.2:c.842del
- NM_001110792.2:c.842delGMANE SELECT
- NM_004992.3(MECP2):c.806delG
- NM_004992.3:c.806delG
- p.G269AfsX20
- p.Gly269Alafs
- p.Gly269Alafs*20
- p.Gly269AlafsX20
- p.Gly269fs
This HGVS expression did not pass validation- Protein change:
- G176fs
- Links:
- OMIM: 300005.0003; dbSNP: rs61750241
- NCBI 1000 Genomes Browser:
- rs61750241
- Molecular consequence:
- NM_001110792.2:c.842del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001316337.2:c.527del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001369391.2:c.527del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001369392.2:c.527del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001369393.2:c.527del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001369394.2:c.527del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001386137.1:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001386138.1:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001386139.1:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_004992.4:c.806del - frameshift variant - [Sequence Ontology: SO:0001589]
- Observations:
- 49
Condition(s)
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000032817 | OMIM | no assertion criteria provided | Pathogenic (Jan 1, 2007) | germline | literature only | |
| SCV000222438 | RettBASE | no assertion criteria provided | Pathogenic (Jun 12, 2013) | germline, maternal, unknown, de novo | curation | |
| SCV000223843 | Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | unknown | clinical testing | |
| SCV000247997 | Genetic Services Laboratory, University of Chicago | criteria provided, single submitter (ACMG Guidelines, 2007) | Pathogenic (Nov 15, 2013) | germline | clinical testing | |
| SCV000680285 | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | criteria provided, single submitter (Classification criteria August 2017) | Pathogenic (Dec 9, 2017) | germline | clinical testing | |
| SCV000781707 | Center for Human Genetics, Inc, Center for Human Genetics, Inc | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Nov 1, 2016) | germline | clinical testing | |
| SCV000804883 | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | no assertion criteria provided | Pathogenic (May 3, 2016) | germline | clinical testing | |
| SCV000919617 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Mar 30, 2018) | germline | clinical testing | |
| SCV001711986 | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | reviewed by expert panel (ClinGen RettAS ACMG Specifications V1) | Pathogenic (Mar 9, 2021) | germline | curation | |
| SCV002525692 | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Aug 25, 2020) | germline | clinical testing | |
| SCV002581580 | MGZ Medical Genetics Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Apr 13, 2022) | germline | clinical testing | |
| SCV004042687 | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | de novo | clinical testing | |
| SCV004047986 | Neuberg Centre For Genomic Medicine, NCGM | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV004098850 | Centre for Population Genomics, CPG | criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022)) | Pathogenic (Aug 14, 2023) | germline | curation |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | unknown | yes | 35 | not provided | not provided | 34 | No | clinical testing, curation |
| not provided | germline | yes | 3 | not provided | not provided | 2 | Yes | clinical testing, curation |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
| not provided | maternal | yes | 1 | not provided | not provided | 1 | Yes | curation |
| not provided | de novo | yes | 11 | not provided | not provided | 10 | No | clinical testing, curation |
| not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
Citations
PubMed
Cortical reflex myoclonus in Rett syndrome.
Guerrini R, Bonanni P, Parmeggiani L, Santucci M, Parmeggiani A, Sartucci F.
Ann Neurol. 1998 Apr;43(4):472-9.
- PMID:
- 9546328
Preserved speech variant is allelic of classic Rett syndrome.
De Bona C, Zappella M, Hayek G, Meloni I, Vitelli F, Bruttini M, Cusano R, Loffredo P, Longo I, Renieri A.
Eur J Hum Genet. 2000 May;8(5):325-30.
- PMID:
- 10854091
Details of each submission
From OMIM, SCV000032817.5
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (4) |
Description
In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, Wan et al. (1999) identified a 1-bp deletion (806delG) in the MECP2 gene, resulting in a val288-to-ter (V288X) substitution in the transcription repression domain. The same mutation was found in her sister and daughter, who were affected with classic Rett syndrome (RTT; 312750), and in her hemizygous son, who died from congenital encephalopathy (300673).
Leuzzi et al. (2004) reported a 28-month-old boy with the 806delG mutation. The patient's mother did not carry the mutation, suggesting germline mosaicism or a de novo mutation. After a normal pregnancy and cesarean section, the patient was markedly hypotonic with weak suction and vomiting. He showed chaotic ocular movements, masticatory automatisms, and brief seizure-like episodes. Brain MRI was normal. Examination at age 10 months showed microcephaly, severe developmental delay, axial hypotonia, limb rigidity, hyperreflexia, lack of purposeful hand movements, and poor eye contact. In addition, he had paroxysmal myoclonic movements of the upper limbs that were unresponsive to conventional antiepileptic drugs. Neurophysiologic investigations showed arrhythmic multifocal myoclonus that was of cortical origin, although not associated with cortical hyperexcitability. The findings were similar to those observed in patients with Rett syndrome and believed to result from reduced dendritic branching and circuitry derangement (Guerrini et al., 1998).
Li et al. (2007) referred to this mutation as G269fs.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From RettBASE, SCV000222438.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 2 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 3 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 4 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 5 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 6 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 7 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 8 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 9 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 10 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 11 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 12 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 13 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 14 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 15 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 16 | not provided | 1 | not provided | Yes | curation | PubMed (13) |
| 17 | not provided | 1 | not provided | Yes | curation | PubMed (13) |
| 18 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 19 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 20 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 21 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 22 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 23 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 24 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 25 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 26 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 27 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 28 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 29 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 30 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 31 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 32 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 33 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 34 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 35 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 36 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 37 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 38 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 39 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 40 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 41 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 42 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 43 | not provided | 1 | not provided | not provided | curation | PubMed (13) |
| 44 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 45 | not provided | 1 | not provided | No | curation | PubMed (13) |
| 46 | not provided | 1 | not provided | No | curation | PubMed (13) |
Description
Rett syndrome - Classical
Rett syndrome - Classical
Rett syndrome - Classical
Rett syndrome - Classical
Rett syndrome - Classical
Rett syndrome - not certain
Rett syndrome - not certain
Rett syndrome - not certain
Rett syndrome - not certain
Rett syndrome - Not certain
Rett syndrome - Not certain
Rett syndrome - Not certain
Rett syndrome - Not certain
Rett syndrome - Not certain
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | 1 | Blood or skin | not provided | 1 | not provided | not provided | not provided | |
| 2 | unknown | yes | 1 | Blood or skin | not provided | 1 | not provided | not provided | not provided | |
| 3 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 4 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 5 | de novo | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 6 | unknown | yes | 1 | blood | 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 | unknown | yes | 1 | lymphoblastoid cell lines | not provided | 1 | not provided | not provided | not provided | |
| 10 | unknown | yes | 1 | Blood or skin | 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 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 13 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 14 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 15 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 16 | germline | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 17 | maternal | 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 | |
| 19 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 20 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 21 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 22 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 23 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 24 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 25 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 26 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 27 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 28 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 29 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 30 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 31 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 32 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 33 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 34 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 35 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 36 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 37 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 38 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 39 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 40 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 41 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 42 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 43 | unknown | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 44 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
| 45 | unknown | yes | 1 | Blood | not provided | 1 | not provided | not provided | not provided | |
| 46 | de novo | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
From Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics, SCV000223843.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | 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 | unknown | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Genetic Services Laboratory, University of Chicago, SCV000247997.1
| # | 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 Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680285.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | 1 | blood | not provided | 1 | not provided | not provided | not provided | |
From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781707.1
| # | 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 Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000804883.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919617.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (9) |
Description
Variant summary: MECP2 c.806delG (p.Gly269AlafsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.880C>T, p.Arg294X; c.1079C>A, p.Ser360X). The variant was absent in 177658 control chromosomes (gnomAD). c.806delG has been reported in the literature in numerous individuals affected with Rett Syndrome (Li_2007, Miltenberger-Miltenyi_2003), including one family in which the variant segregated with disease (Wan_1999). Additionally, one male mutation carrier was affected with encephalopathy (Leuzzi_2004). At least one publication reports experimental evidence evaluating an impact on protein function which shows this truncation variant disrupts MECP2 protein activity (Yusufzai_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as 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 ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV001711986.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | not provided |
Description
The p.Gly269Alafs*20 variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, 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 | |
From Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital, SCV002525692.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This is a recurrent variant, reported in multiple individuals with Rett Syndrome (NBK1497, PMID: 10577905, PMID: 10854091, PMID: 12111643, PMID: 17089071, PMID: 27354166 and others. Note: this variant has historically been described as V288X).
| # | 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 MGZ Medical Genetics Center, SCV002581580.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | 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 | 1 | not provided | not provided | not provided | |
From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004042687.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | 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 | 1 | not provided | not provided | not provided | |
From Neuberg Centre For Genomic Medicine, NCGM, SCV004047986.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
The frame shift (c.842del) variant has been reported as a de novo occurrence and in at least 2 individuals with Rett syndrome (Zahorakova et. al., 2016; De et. al., 2000). Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000). The p.Gly281AlafsTer20 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing.(Le et. al., 2018). The observed variant is found to be present in last exon. For these reasons, this variant has been classified as 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 | not provided | not provided | not provided | not provided | |
From Centre for Population Genomics, CPG, SCV004098850.1
| # | 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 to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0 , this variant is classified as Pathogenic . At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND in at least 2 individuals with unconfirmed parental relationships (PS2_Very strong). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). 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: Jun 2, 2024
PubMed [ID: 10577905]