NM_001110792.2(MECP2):c.1477G>A (p.Val493Met) AND Rett syndrome

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Feb 18, 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:: RCV000030164.7

Allele description [Variation Report for NM_001110792.2(MECP2):c.1477G>A (p.Val493Met)]

NM_001110792.2(MECP2):c.1477G>A (p.Val493Met)

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.1477G>A (p.Val493Met)

Other names:

p.V481M:GTG>ATG; NM_001110792.2(MECP2):c.1477G>A; p.Val493Met

HGVS:

NC_000023.11:g.154030387C>T
NG_007107.3:g.111717G>A
NM_001110792.2:c.1477G>AMANE SELECT
NM_001316337.2:c.1162G>A
NM_001369391.2:c.1162G>A
NM_001369392.2:c.1162G>A
NM_001369393.2:c.1162G>A
NM_001369394.2:c.1162G>A
NM_001386137.1:c.772G>A
NM_001386138.1:c.772G>A
NM_001386139.1:c.772G>A
NM_004992.4:c.1441G>A
NP_001104262.1:p.Val493Met
NP_001303266.1:p.Val388Met
NP_001356320.1:p.Val388Met
NP_001356321.1:p.Val388Met
NP_001356322.1:p.Val388Met
NP_001356323.1:p.Val388Met
NP_001373066.1:p.Val258Met
NP_001373067.1:p.Val258Met
NP_001373068.1:p.Val258Met
NP_004983.1:p.Val481Met
NP_004983.1:p.Val481Met
LRG_764t1:c.1477G>A
LRG_764t2:c.1441G>A
AJ132917.1:c.1441G>A
LRG_764:g.111717G>A
LRG_764p1:p.Val493Met
LRG_764p2:p.Val481Met
NC_000023.10:g.153295838C>T
NG_007107.2:g.111741G>A
NM_001110792.1:c.1477G>A
NM_004992.3:c.1441G>A

Protein change:

V258M

Links:

dbSNP: rs193922678

NCBI 1000 Genomes Browser:

rs193922678

Molecular consequence:

NM_001110792.2:c.1477G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386137.1:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386138.1:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386139.1:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.1441G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Rattus norvegicus cDNA clone IMAGE:7442653, with apparent retained intron
Rattus norvegicus cDNA clone IMAGE:7442653, with apparent retained intron
gi|197246448|gb|BC168930.1|

Nucleotide
Homo sapiens
Homo sapiens

Genome
Genome Links for Protein (Select 387528013) (1)
Genome
PMC Links for Protein (Select 387528013) (0)
PMC

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052822	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	no assertion criteria provided	Uncertain significance (Mar 13, 2015)	germline	clinical testing
SCV000187995	RettBASE	no assertion criteria provided	Uncertain significance (Sep 27, 2012)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV002540691	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Likely benign (Feb 18, 2022)	germline	curation	Citation Link,
SCV004808735	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Likely benign (Mar 14, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

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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	clinical testing, curation
not provided	unknown	yes	2	not provided	not provided	2	No	curation

Citations

PubMed

Molecular diagnostic dilemmas in Rett syndrome.

Zvereff V, Carpenter L, Patton D, Cabral H, Rita D, Wilson A, Anyane-Yeboa K, White L, Friedman KJ.

Brain Dev. 2012 Oct;34(9):750-5. doi: 10.1016/j.braindev.2011.12.012. Epub 2012 Jan 25.

PubMed [citation]

PMID:: 22277191

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.

McKnight D, Bean L, Karbassi I, Beattie K, Bienvenu T, Bonin H, Fang P, Chrisodoulou J, Friez M, Helgeson M, Krishnaraj R, Meng L, Mighion L, Neul J, Percy A, Ramsden S, Zoghbi H, Das S.

Hum Mutat. 2022 Aug;43(8):1097-1113. doi: 10.1002/humu.24302. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 34837432
PMCID:: PMC9135956

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052822.2

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

Description

The Val493Met variant has not been identified in 87757 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). The Valine at position 493 is highly conserved in evolution, though computational tools do not provide strong support for or against an impact to the protein. The variant has been reported previously in two female patients with Rett syndrome (Fong et al 2009/MECP2 database and Zvereff et al 2012), however family history was not provided. This variant is more likely pathogenic but additional studies are needed to fully assess its clinical significance.

#	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 RettBASE, SCV000187995.2

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

Description

Rett syndrome - Not certain

"Rett syndrome - classical"

PubMed [ID: 22277191]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	Blood	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, SCV002540691.1

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

Description

The p.Val481Met variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Val481Met variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.007% in the Latino/Admixed American sub population including 2 hemizygous males (not sufficient for BS1). The p.Val481Met variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Val481Met variant has been observed in 1 individual with a Rett like disorder (PMID 22277191) and 1 individual with nonspecific neurological phenotypes (PMID 29655203) (Not sufficient for PS4_supporting). In summary, the p.Val481Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5).

#	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, SCV004808735.1

#	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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Variant is found in an individual with an alternate molecular basis of disease (BP5).

#	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

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