NM_001110792.2(MECP2):c.1469G>A (p.Arg490Gln) AND Rett syndrome

Germline classification:: Likely benign (2 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:: RCV002260620.3

Allele description [Variation Report for NM_001110792.2(MECP2):c.1469G>A (p.Arg490Gln)]

NM_001110792.2(MECP2):c.1469G>A (p.Arg490Gln)

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.1469G>A (p.Arg490Gln)

Other names:

p.R478Q:CGG>CAG; NM_001110792.2(MECP2):c.1469G>A; p.Arg490Gln

HGVS:

NC_000023.11:g.154030395C>T
NG_007107.3:g.111709G>A
NM_001110792.2:c.1469G>AMANE SELECT
NM_001316337.2:c.1154G>A
NM_001369391.2:c.1154G>A
NM_001369392.2:c.1154G>A
NM_001369393.2:c.1154G>A
NM_001369394.2:c.1154G>A
NM_001386137.1:c.764G>A
NM_001386138.1:c.764G>A
NM_001386139.1:c.764G>A
NM_004992.4:c.1433G>A
NP_001104262.1:p.Arg490Gln
NP_001303266.1:p.Arg385Gln
NP_001356320.1:p.Arg385Gln
NP_001356321.1:p.Arg385Gln
NP_001356322.1:p.Arg385Gln
NP_001356323.1:p.Arg385Gln
NP_001373066.1:p.Arg255Gln
NP_001373067.1:p.Arg255Gln
NP_001373068.1:p.Arg255Gln
NP_004983.1:p.Arg478Gln
NP_004983.1:p.Arg478Gln
LRG_764t1:c.1469G>A
LRG_764t2:c.1433G>A
LRG_764:g.111709G>A
LRG_764p1:p.Arg490Gln
LRG_764p2:p.Arg478Gln
NC_000023.10:g.153295846C>T
NG_007107.2:g.111733G>A
NM_004992.3:c.1433G>A

Protein change:

R255Q

Links:

dbSNP: rs145790362

NCBI 1000 Genomes Browser:

rs145790362

Molecular consequence:

NM_001110792.2:c.1469G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386137.1:c.764G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386138.1:c.764G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386139.1:c.764G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.1433G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002540688	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,
SCV004098754	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Likely benign (Aug 14, 2023)	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

SCV002540688

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,

SCV004098754

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Likely benign
(Aug 14, 2023)

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

Citations

PubMed

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 ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002540688.1

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

Description

The p.Arg478Gln variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Arg478Gln variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). In summary, the p.Arg478Gln 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, SCV004098754.1

#	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 2.0, this variant is classified as Likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD V3 is between 0.008% and 0.03% (BS1). The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_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: Sep 29, 2024

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