NM_001110792.2(MECP2):c.352C>T (p.Arg118Trp) AND Severe neonatal-onset encephalopathy with microcephaly

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 15, 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:: RCV000552837.18

Allele description [Variation Report for NM_001110792.2(MECP2):c.352C>T (p.Arg118Trp)]

NM_001110792.2(MECP2):c.352C>T (p.Arg118Trp)

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.352C>T (p.Arg118Trp)

Other names:

NM_001110792.2(MECP2):c.352C>T; p.Arg118Trp

HGVS:

NC_000023.11:g.154032268G>A
NG_007107.3:g.109836C>T
NM_001110792.2:c.352C>TMANE SELECT
NM_001316337.2:c.37C>T
NM_001369391.2:c.37C>T
NM_001369392.2:c.37C>T
NM_001369393.2:c.37C>T
NM_001369394.2:c.37C>T
NM_001386137.1:c.-245C>T
NM_001386138.1:c.-245C>T
NM_001386139.1:c.-245C>T
NM_004992.4:c.316C>T
NP_001104262.1:p.Arg118Trp
NP_001303266.1:p.Arg13Trp
NP_001356320.1:p.Arg13Trp
NP_001356321.1:p.Arg13Trp
NP_001356322.1:p.Arg13Trp
NP_001356323.1:p.Arg13Trp
NP_004983.1:p.Arg106Trp
NP_004983.1:p.Arg106Trp
LRG_764t1:c.352C>T
LRG_764t2:c.316C>T
AJ132917.1:c.316C>T
LRG_764:g.109836C>T
LRG_764p1:p.Arg118Trp
LRG_764p2:p.Arg106Trp
NC_000023.10:g.153297719G>A
NG_007107.2:g.109860C>T
NM_004992.3:c.316C>T
P51608:p.Arg106Trp
p.R106W

Protein change:

R106W; ARG106TRP

Links:

UniProtKB: P51608#VAR_010272; OMIM: 300005.0008; dbSNP: rs28934907

NCBI 1000 Genomes Browser:

rs28934907

Molecular consequence:

NM_001386137.1:c.-245C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-245C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-245C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.352C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.37C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.316C>T - 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
SCV000645663	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10508514, 18332345, 20098342, 23270700, 23421866, 12843318, 19442733, 21831886, 28492532
SCV001523354	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 20, 2019)	de novo	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16077729, 11058114, 10508514, 10852707, 20098342, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645663

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001523354

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 20, 2019)

de novo

clinical testing

PubMed (6)
[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	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Investigating genotype-phenotype relationships in Rett syndrome using an international data set.

Bebbington A, Anderson A, Ravine D, Fyfe S, Pineda M, de Klerk N, Ben-Zeev B, Yatawara N, Percy A, Kaufmann WE, Leonard H.

Neurology. 2008 Mar 11;70(11):868-75. doi: 10.1212/01.wnl.0000304752.50773.ec.

PubMed [citation]

PMID:: 18332345

Pubertal trajectory in females with Rett syndrome: a population-based study.

Knight O, Bebbington A, Siafarikas A, Woodhead H, Girdler S, Leonard H.

Brain Dev. 2013 Nov;35(10):912-20. doi: 10.1016/j.braindev.2012.11.007. Epub 2012 Dec 25.

PubMed [citation]

PMID:: 23270700

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645663.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 106 of the MECP2 protein (p.Arg106Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Rett syndrome (PMID: 10508514, 18332345, 20098342, 23270700, 23421866). ClinVar contains an entry for this variant (Variation ID: 11814). 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: 12843318, 19442733, 21831886). 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

From Baylor Genetics, SCV001523354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals with Rett syndrome [PMID: 16077729, 11058114, 10508514, 10852707, 20098342]

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

Last Updated: Nov 3, 2024

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