NM_001110792.2(MECP2):c.1490_1493del (p.Val497fs) AND Rett syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 10, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000168709.7

Allele description [Variation Report for NM_001110792.2(MECP2):c.1490_1493del (p.Val497fs)]

NM_001110792.2(MECP2):c.1490_1493del (p.Val497fs)

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.1490_1493del (p.Val497fs)

Other names:

NM_001110792.2(MECP2):c.1490_1493del; p.Val497fs

HGVS:

NC_000023.10:g.153295822_153295825del
NC_000023.11:g.154030373_154030376del
NG_007107.3:g.111730_111733del
NM_001110792.2:c.1490_1493delMANE SELECT
NM_001316337.2:c.1175_1178del
NM_001369391.2:c.1175_1178del
NM_001369392.2:c.1175_1178del
NM_001369393.2:c.1175_1178del
NM_001369394.2:c.1175_1178del
NM_001386137.1:c.785_788del
NM_001386138.1:c.785_788del
NM_001386139.1:c.785_788del
NM_004992.4:c.1454_1457del
NP_001104262.1:p.Val497fs
NP_001303266.1:p.Val392fs
NP_001356320.1:p.Val392fs
NP_001356321.1:p.Val392fs
NP_001356322.1:p.Val392fs
NP_001356323.1:p.Val392fs
NP_001373066.1:p.Val262fs
NP_001373067.1:p.Val262fs
NP_001373068.1:p.Val262fs
NP_004983.1:p.Val485fs
NP_004983.1:p.Val485fs
LRG_764t1:c.1490_1493del
LRG_764t2:c.1454_1457del
AJ132917.1:c.1454_1457del4
LRG_764:g.111730_111733del
LRG_764p1:p.Val497fs
LRG_764p2:p.Val485fs
NC_000023.10:g.153295822_153295825del
NC_000023.10:g.153295822_153295825delCTAA
NC_000023.10:g.153295824_153295827del
NC_000023.11:g.154030373_154030376del
NG_007107.2:g.111754_111757del
NM_004992.3:c.1454_1457del
NM_004992.3:c.1454_1457delTTAG
p.Val485AlafsX26

Protein change:

V262fs

Links:

dbSNP: rs267608640

NCBI 1000 Genomes Browser:

rs267608640

Molecular consequence:

NM_001110792.2:c.1490_1493del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001316337.2:c.1175_1178del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369391.2:c.1175_1178del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369392.2:c.1175_1178del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369393.2:c.1175_1178del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369394.2:c.1175_1178del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386137.1:c.785_788del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386138.1:c.785_788del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001386139.1:c.785_788del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004992.4:c.1454_1457del - 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
SCV000188003	RettBASE	no assertion criteria provided	Uncertain significance (Jan 21, 2008)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 11402105, 16473305
SCV002540721	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Pathogenic (May 10, 2022)	germline	curation	Citation Link,
SCV004232288	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Jan 10, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000188003

RettBASE

no assertion criteria provided

Uncertain significance
(Jan 21, 2008)

unknown

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV002540721

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)

Pathogenic
(May 10, 2022)

germline

curation

Citation Link,

SCV004232288

Centre for Population Genomics, CPG

criteria provided, single submitter

(McKnight et al. (Hum Mutat. 2022))

Pathogenic
(Jan 10, 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	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	yes	2	not provided	not provided	2	not provided	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 and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update.

Philippe C, Villard L, De Roux N, Raynaud M, Bonnefond JP, Pasquier L, Lesca G, Mancini J, Jonveaux P, Moncla A, Chelly J, Bienvenu T.

Eur J Med Genet. 2006 Jan-Feb;49(1):9-18.

PubMed [citation]

PMID:: 16473305

See all PubMed Citations (3)

Details of each submission

From RettBASE, SCV000188003.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (2)
2	not provided	1	not provided	not provided	curation	PubMed (2)

Description

"Rett syndrome - Not certain"

PubMed [ID: 11402105]

"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	yes	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

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002540721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The p.Val485fs (NM_004992) variant in MECP2 is predicted to cause a frameshift that results in a read-through of the stop codon (PVS1). The p.Val485fs variant in MECP2 has been reported as de novo occurrence in at least two individuals (biological parentage unconfirmed) with Rett Syndrome (PMID 11402105, Clinvar Variation ID: 143485) (PM6_strong). The p.Val485fs variant has been observed in at least 3 other individuals with Rett Syndrome (PMID 11402105, PMID 16473305, ClinVar) (PS4_moderate). The p.Val485fs variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Val485fs variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett Syndrome (PMID 11402105) (PP4). In summary the p.Val485fs variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4).

#	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, SCV004232288.1

#	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 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 11402105, Clinvar Variation ID: 143485) Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). (PubMed: 11402105‚ 16473305 , ClinVar 143485) 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: Feb 28, 2024

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