NM_001110792.2(MECP2):c.477C>G (p.Asp159Glu) AND Severe neonatal-onset encephalopathy with microcephaly

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 18, 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:: RCV001957206.5

Allele description [Variation Report for NM_001110792.2(MECP2):c.477C>G (p.Asp159Glu)]

NM_001110792.2(MECP2):c.477C>G (p.Asp159Glu)

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.477C>G (p.Asp159Glu)

Other names:

NM_001110792.2(MECP2):c.477C>G; p.Asp159Glu

HGVS:

NC_000023.11:g.154031387G>C
NG_007107.3:g.110717C>G
NM_001110792.2:c.477C>GMANE SELECT
NM_001316337.2:c.162C>G
NM_001369391.2:c.162C>G
NM_001369392.2:c.162C>G
NM_001369393.2:c.162C>G
NM_001369394.2:c.162C>G
NM_001386137.1:c.-129+9C>G
NM_001386138.1:c.-129+9C>G
NM_001386139.1:c.-129+9C>G
NM_004992.4:c.441C>G
NP_001104262.1:p.Asp159Glu
NP_001303266.1:p.Asp54Glu
NP_001356320.1:p.Asp54Glu
NP_001356321.1:p.Asp54Glu
NP_001356322.1:p.Asp54Glu
NP_001356323.1:p.Asp54Glu
NP_004983.1:p.Asp147Glu
LRG_764t1:c.477C>G
LRG_764t2:c.441C>G
LRG_764:g.110717C>G
LRG_764p1:p.Asp159Glu
LRG_764p2:p.Asp147Glu
NC_000023.10:g.153296838G>C
NG_007107.2:g.110741C>G

Protein change:

D147E

Links:

dbSNP: rs782468872

NCBI 1000 Genomes Browser:

rs782468872

Molecular consequence:

NM_001386137.1:c.-129+9C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001386138.1:c.-129+9C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001386139.1:c.-129+9C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001110792.2:c.477C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.162C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.162C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.162C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.162C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.162C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.441C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Severe neonatal-onset encephalopathy with microcephaly
Synonyms:: Encephalopathy, neonatal severe; Encephalopathy, neonatal severe, due to MECP2 mutations
Identifiers:: MONDO: MONDO:0010397; MedGen: C1968556; Orphanet: 209370; OMIM: 300673

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002205415	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28394482, 32472557, 28492532
SCV004808824	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Uncertain significance (Feb 18, 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

SCV002205415

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004808824

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Uncertain significance
(Feb 18, 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	clinical testing, curation

Citations

PubMed

Familial cases and male cases with MECP2 mutations.

Zhang Q, Zhao Y, Bao X, Luo J, Zhang X, Li J, Wei L, Wu X.

Am J Med Genet B Neuropsychiatr Genet. 2017 Jun;174(4):451-457. doi: 10.1002/ajmg.b.32534. Epub 2017 Apr 10.

PubMed [citation]

PMID:: 28394482
PMCID:: PMC5485058

MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort.

Wen Y, Wang J, Zhang Q, Chen Y, Wu X, Bao X.

Clin Genet. 2020 Sep;98(3):240-250. doi: 10.1111/cge.13790. Epub 2020 Jun 21.

PubMed [citation]

PMID:: 32472557

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002205415.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1424572). This missense change has been observed in individual(s) with MECP2-related conditions (PMID: 28394482, 32472557). This variant is present in population databases (rs782468872, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 147 of the MECP2 protein (p.Asp147Glu).

#	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, SCV004808824.1

#	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 a variant of uncertain significance. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Co-segregation with disease in multiple affected family members in at least 2 informative meiosis (PP1). PMID: 28394482

#	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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