NM_001110792.2(MECP2):c.1225G>A (p.Glu409Lys) AND Rett syndrome

Germline classification:: Benign (4 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:: RCV000202529.12

Allele description [Variation Report for NM_001110792.2(MECP2):c.1225G>A (p.Glu409Lys)]

NM_001110792.2(MECP2):c.1225G>A (p.Glu409Lys)

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.1225G>A (p.Glu409Lys)

Other names:

p.E397K:GAG>AAG; NM_001110792.2(MECP2):c.1225G>A; p.Glu409Lys

HGVS:

NC_000023.11:g.154030639C>T
NG_007107.3:g.111465G>A
NM_001110792.1:c.1225G>A
NM_001110792.2:c.1225G>AMANE SELECT
NM_001316337.2:c.910G>A
NM_001369391.2:c.910G>A
NM_001369392.2:c.910G>A
NM_001369393.2:c.910G>A
NM_001369394.2:c.910G>A
NM_001386137.1:c.520G>A
NM_001386138.1:c.520G>A
NM_001386139.1:c.520G>A
NM_004992.4:c.1189G>A
NP_001104262.1:p.Glu409Lys
NP_001303266.1:p.Glu304Lys
NP_001356320.1:p.Glu304Lys
NP_001356321.1:p.Glu304Lys
NP_001356322.1:p.Glu304Lys
NP_001356323.1:p.Glu304Lys
NP_001373066.1:p.Glu174Lys
NP_001373067.1:p.Glu174Lys
NP_001373068.1:p.Glu174Lys
NP_004983.1:p.Glu397Lys
NP_004983.1:p.Glu397Lys
LRG_764t1:c.1225G>A
LRG_764t2:c.1189G>A
AJ132917.1:c.1189G>A
LRG_764:g.111465G>A
LRG_764p1:p.Glu409Lys
LRG_764p2:p.Glu397Lys
NC_000023.10:g.153296090C>T
NG_007107.2:g.111489G>A
NM_001110792.2:c.1225G>A
NM_004992.3:c.1189G>A
P51608:p.Glu397Lys
p.(Glu397Lys)

Protein change:

E174K

Links:

UniProtKB: P51608#VAR_010283; dbSNP: rs56268439

NCBI 1000 Genomes Browser:

rs56268439

Molecular consequence:

NM_001110792.2:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386137.1:c.520G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386138.1:c.520G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386139.1:c.520G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.1189G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000257517	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Uncertain significance (Sep 4, 2013)	germline	clinical testing
SCV001142081	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002540719	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Benign (May 10, 2022)	germline	curation	Citation Link,
SCV004098724	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	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	1	not provided	not provided	1	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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 Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000257517.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Mendelics, SCV001142081.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002540719.1

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

Description

The allele frequency of the p.Glu397Lys variant in MECP2 (NM_004992) is 0.393% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as Benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Glu397Lys variant is observed in at least 2 unaffected individuals (PMID 10577905,12384770, RettBASE) (BS2). In summary, the p.Glu397Lys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2).

#	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, SCV004098724.1

#	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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1).

#	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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