NM_001110792.2(MECP2):c.1193_1224del (p.Leu398fs) AND Rett syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000168702.6

Allele description [Variation Report for NM_001110792.2(MECP2):c.1193_1224del (p.Leu398fs)]

NM_001110792.2(MECP2):c.1193_1224del (p.Leu398fs)

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.1193_1224del (p.Leu398fs)

Other names:

NM_001110792.2(MECP2):c.1193_1224del; p.Leu398fs

HGVS:

NC_000023.11:g.154030642_154030673del
NG_007107.3:g.111433_111464del
NM_001110792.2:c.1193_1224delMANE SELECT
NM_001316337.2:c.878_909del
NM_001369391.2:c.878_909del
NM_001369392.2:c.878_909del
NM_001369393.2:c.878_909del
NM_001369394.2:c.878_909del
NM_001386137.1:c.488_519del
NM_001386138.1:c.488_519del
NM_001386139.1:c.488_519del
NM_004992.4:c.1157_1188del
NP_001104262.1:p.Leu398fs
NP_001303266.1:p.Leu293fs
NP_001356320.1:p.Leu293fs
NP_001356321.1:p.Leu293fs
NP_001356322.1:p.Leu293fs
NP_001356323.1:p.Leu293fs
NP_001373066.1:p.Leu163fs
NP_001373067.1:p.Leu163fs
NP_001373068.1:p.Leu163fs
NP_004983.1:p.Leu386fs
LRG_764t1:c.1193_1224del
LRG_764t2:c.1157_1188del
AJ132917.1:c.1157_1188del32
LRG_764:g.111433_111464del
LRG_764p1:p.Leu398fs
LRG_764p2:p.Leu386fs
NC_000023.10:g.153296093_153296124del
NC_000023.11:g.154030642_154030673del
NG_007107.2:g.111457_111488del
NM_004992.3:c.1157_1188del32
p.Leu386ArgfsX8

Protein change:

L163fs

Links:

dbSNP: rs267608585

NCBI 1000 Genomes Browser:

rs267608585

Molecular consequence:

NM_001110792.2:c.1193_1224del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001316337.2:c.878_909del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369391.2:c.878_909del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369392.2:c.878_909del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369393.2:c.878_909del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369394.2:c.878_909del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386137.1:c.488_519del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386138.1:c.488_519del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386139.1:c.488_519del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004992.4:c.1157_1188del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Rett syndrome (RTT)
Synonyms:: Autism, dementia, ataxia, and loss of purposeful hand use; Rett's disorder
Identifiers:: MONDO: MONDO:0010726; MedGen: C0035372; Orphanet: 3095; Orphanet: 778; OMIM: 312750

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187872	RettBASE	no assertion criteria provided	Pathogenic (Nov 1, 2011)	maternal, unknown	curation	PubMed (7) [See all records that cite these PMIDs] 21160487, 11738860, 11746022, 12075485, 12180070, 15173251, 16473305
SCV001430670	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 16, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11746022, 16473305, 18562141, 19914908, 28544139, 25741868
SCV001554524	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 16, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15173251, 16473305, 21160487, 11746022 Citation Link,
SCV004808974	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Mar 8, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	9	not provided	not provided	9	No	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	no	1	not provided	not provided	1	not provided	curation
not provided	maternal	yes	2	not provided	not provided	2	not provided	curation

Citations

PubMed

Spectrum of MECP2 mutations in Rett syndrome.

Lee SS, Wan M, Francke U.

Brain Dev. 2001 Dec;23 Suppl 1:S138-43.

PubMed [citation]

PMID:: 11738860

Influence of mutation type and location on phenotype in 123 patients with Rett syndrome.

Huppke P, Held M, Hanefeld F, Engel W, Laccone F.

Neuropediatrics. 2002 Apr;33(2):63-8.

PubMed [citation]

PMID:: 12075485

See all PubMed Citations (12)

Details of each submission

From RettBASE, SCV000187872.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (7)
2	not provided	1	not provided	No	curation	PubMed (7)
3	not provided	1	not provided	not provided	curation	PubMed (7)
4	not provided	1	not provided	not provided	curation	PubMed (7)
5	not provided	1	not provided	not provided	curation	PubMed (7)
6	not provided	1	not provided	not provided	curation	PubMed (7)
7	not provided	1	not provided	not provided	curation	PubMed (7)
8	not provided	1	not provided	not provided	curation	PubMed (7)
9	not provided	1	not provided	not provided	curation	PubMed (7)
10	not provided	1	not provided	not provided	curation	PubMed (7)
11	not provided	1	not provided	No	curation	PubMed (7)
12	not provided	1	not provided	not provided	curation	PubMed (7)

Description

"Not Rett synd. - Unaffected family member"

PubMed [ID: 21160487]

Rett syndrome - not certain

Rett syndrome - Preserved speech

"Rett syndrome - Classical"

PubMed [ID: 11738860]

"Rett syndrome - not certain"

PubMed [ID: 11746022]

"Rett syndrome - not certain"

PubMed [ID: 11746022]

"Rett syndrome - not certain"

PubMed [ID: 11746022]

"Rett syndrome - not certain"

PubMed [ID: 12075485]

"Rett syndrome - Classical"

PubMed [ID: 12180070]

"Rett syndrome - Atypical"

PubMed [ID: 15173251]

"Rett syndrome - atypical"

PubMed [ID: 16473305]

"Rett syndrome - Not certain"

PubMed [ID: 16473305]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	no	1	not provided	not provided		1	not provided	not provided	not provided
2	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
3	maternal	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	Blood or skin	not provided		1	not provided	not provided	not provided
5	unknown	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	lymphoblastoid cell lines	not provided		1	not provided	not provided	not provided
9	maternal	yes	1	not provided	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	Blood	not provided		1	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001430670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This MECP2 variant (rs267608585) is absent in a large population dataset and has an entry in ClinVar. This variant has been reported in patients with classic and variant forms of Rett syndrome. This 32-bp deletion results in a frameshift that is predicted to lead to a premature stop codon (PTC) in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. This variant is located within a hotspot of deletions in the C-terminus of the MeCP2 protein, which represent ~12% of disease-associated variants in MECP2. We consider it to be 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001554524.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: MECP2 c.1157_1188del32 (p.Leu386ArgfsX8) 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. The variant was absent in 173875 control chromosomes (gnomAD). c.1157_1188del32 has been reported in the literature in individuals affected with Rett Syndrome (e.g. Zappella_2001, Kammoun_2004, Philippe_2006, Hadzsiev_2011). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite 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 Centre for Population Genomics, CPG, SCV004808974.1

#	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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PubMed: 21160487‚Äö 11738860‚Äö 11746022‚Äö 12075485‚Äö 12180070‚Äö 15173251‚Äö 16473305, ClinVar Variation ID: 143366) 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: May 12, 2024

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