NM_001110792.2(MECP2):c.746dup (p.Gly250fs) AND Rett syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 13, 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:: RCV000133208.7

Allele description [Variation Report for NM_001110792.2(MECP2):c.746dup (p.Gly250fs)]

NM_001110792.2(MECP2):c.746dup (p.Gly250fs)

Gene:

MECP2:methyl-CpG binding protein 2 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001110792.2(MECP2):c.746dup (p.Gly250fs)

Other names:

NM_001110792.2(MECP2):c.746dup; p.Gly250fs

HGVS:

NC_000023.11:g.154031123dup
NG_007107.3:g.110986dup
NM_001110792.2:c.746dupMANE SELECT
NM_001316337.2:c.431dup
NM_001369391.2:c.431dup
NM_001369392.2:c.431dup
NM_001369393.2:c.431dup
NM_001369394.2:c.431dup
NM_001386137.1:c.41dup
NM_001386138.1:c.41dup
NM_001386139.1:c.41dup
NM_004992.4:c.710dup
NP_001104262.1:p.Gly250fs
NP_001303266.1:p.Gly145fs
NP_001356320.1:p.Gly145fs
NP_001356321.1:p.Gly145fs
NP_001356322.1:p.Gly145fs
NP_001356323.1:p.Gly145fs
NP_001373066.1:p.Gly15fs
NP_001373067.1:p.Gly15fs
NP_001373068.1:p.Gly15fs
NP_004983.1:p.Gly238fs
LRG_764t1:c.746dup
LRG_764t2:c.710dup
AJ132917.1:c.710dupG
LRG_764:g.110986dup
LRG_764p1:p.Gly250fs
LRG_764p2:p.Gly238fs
NC_000023.10:g.153296568_153296569insC
NC_000023.10:g.153296574dup
NG_007107.2:g.111010dup
NM_004992.3:c.710dupG
NM_004992.4:c.710dupG
p.Pro238Trpfs*21

Protein change:

G145fs

Links:

dbSNP: rs61749743

NCBI 1000 Genomes Browser:

rs61749743

Molecular consequence:

NM_001110792.2:c.746dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001316337.2:c.431dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369391.2:c.431dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369392.2:c.431dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369393.2:c.431dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369394.2:c.431dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386137.1:c.41dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386138.1:c.41dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386139.1:c.41dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004992.4:c.710dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000188206	RettBASE	no assertion criteria provided	Pathogenic (Jun 12, 2013)	de novo, unknown	curation	PubMed (4) [See all records that cite these PMIDs] 11402105, 11462237, 17986102, 23262346
SCV000223846	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000537187	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 14, 2015)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23262346, 17986102, 1402105, 11462237, 25741868
SCV004808978	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Mar 13, 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	de novo	yes	2	not provided	not provided	2	No	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	yes	5	not provided	not provided	3	No	clinical testing, curation

Citations

PubMed

MeCP2 mutations in children with and without the phenotype of Rett syndrome.

Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, Schuette J, Innis J, Marino M, Philippart M, Narayanan V, Umansky R, Kronn D, Hoffman EP, Naidu S.

Neurology. 2001 Jun 12;56(11):1486-95.

PubMed [citation]

PMID:: 11402105

Spectrum of MECP2 gene mutations in a cohort of Indian patients with Rett syndrome: report of two novel mutations.

Das DK, Raha S, Sanghavi D, Maitra A, Udani V.

Gene. 2013 Feb 15;515(1):78-83. doi: 10.1016/j.gene.2012.11.024. Epub 2012 Dec 20.

PubMed [citation]

PMID:: 23262346

See all PubMed Citations (7)

Details of each submission

From RettBASE, SCV000188206.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (4)
2	not provided	1	not provided	No	curation	PubMed (4)
3	not provided	1	not provided	not provided	curation	PubMed (4)
4	not provided	1	not provided	No	curation	PubMed (4)
5	not provided	1	not provided	No	curation	PubMed (4)

Description

Rett syndrome - Not certain

"Rett syndrome - classical"

PubMed [ID: 11402105]

"Rett syndrome - Classical"

PubMed [ID: 11462237]

"Rett syndrome - Classical"

PubMed [ID: 17986102]

"Rett syndrome - not certain"

PubMed [ID: 23262346]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	de novo	yes	1	not known	not provided		1	not provided	not provided	not provided
3	de novo	yes	1	Blood	not provided		1	not provided	not provided	not provided
4	unknown	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

From Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics, SCV000223846.1

#	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 Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000537187.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

Psychomotor arrest; Microcephaly; Partial epilepsy; Spasticity; Scoliosis; Hypercholesterolemia; Characteristic hand movements

#	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 Centre for Population Genomics, CPG, SCV004808978.1

#	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). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). (PMID 11462237‚Äö 17986102‚ÄöClinVar Variation ID: 143666)

#	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 7, 2024

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