NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys) AND Severe neonatal-onset encephalopathy with microcephaly

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 8, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000698431.11

Allele description [Variation Report for NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)]

NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)

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.437C>G (p.Ser146Cys)

Other names:

NM_001110792.2(MECP2):c.437C>G; p.Ser146Cys

HGVS:

NC_000023.11:g.154031427G>C
NG_007107.3:g.110677C>G
NM_001110792.2:c.437C>GMANE SELECT
NM_001316337.2:c.122C>G
NM_001369391.2:c.122C>G
NM_001369392.2:c.122C>G
NM_001369393.2:c.122C>G
NM_001369394.2:c.122C>G
NM_001386137.1:c.-160C>G
NM_001386138.1:c.-160C>G
NM_001386139.1:c.-160C>G
NM_004992.4:c.401C>G
NP_001104262.1:p.Ser146Cys
NP_001303266.1:p.Ser41Cys
NP_001356320.1:p.Ser41Cys
NP_001356321.1:p.Ser41Cys
NP_001356322.1:p.Ser41Cys
NP_001356323.1:p.Ser41Cys
NP_004983.1:p.Ser134Cys
NP_004983.1:p.Ser134Cys
LRG_764t1:c.437C>G
LRG_764t2:c.401C>G
AJ132917.1:c.401C>G
LRG_764:g.110677C>G
LRG_764p1:p.Ser146Cys
LRG_764p2:p.Ser134Cys
NC_000023.10:g.153296878G>C
NG_007107.2:g.110701C>G
NM_004992.3:c.401C>G
NM_004992.4:c.401C>G
P51608:p.Ser134Cys

Protein change:

S134C

Links:

UniProtKB: P51608#VAR_010278; dbSNP: rs61748390

NCBI 1000 Genomes Browser:

rs61748390

Molecular consequence:

NM_001386137.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-160C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.437C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.122C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.401C>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
SCV000827093	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10767337, 10814718, 11738864, 11738883, 12655490, 17089071, 18337588, 21160487, 22182064, 23696494, 26418480, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000827093

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

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

Citations

PubMed

Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.

Cheadle JP, Gill H, Fleming N, Maynard J, Kerr A, Leonard H, Krawczak M, Cooper DN, Lynch S, Thomas N, Hughes H, Hulten M, Ravine D, Sampson JR, Clarke A.

Hum Mol Genet. 2000 Apr 12;9(7):1119-29. Erratum in: Hum Mol Genet 2000 Jul 1;9(11):1717.

PubMed [citation]

PMID:: 10767337

Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.

Huppke P, Laccone F, Krämer N, Engel W, Hanefeld F.

Hum Mol Genet. 2000 May 22;9(9):1369-75.

PubMed [citation]

PMID:: 10814718

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000827093.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the MECP2 protein (p.Ser134Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 10814718, 11738864, 11738883, 12655490, 17089071, 18337588, 21160487, 22182064, 23696494). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143562). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 26418480). For these reasons, this variant has been classified as Pathogenic.

#	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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