NM_001110792.2(MECP2):c.509C>T (p.Thr170Met) AND multiple conditions

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 30, 2021
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:: RCV000763199.13

Allele description [Variation Report for NM_001110792.2(MECP2):c.509C>T (p.Thr170Met)]

NM_001110792.2(MECP2):c.509C>T (p.Thr170Met)

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.509C>T (p.Thr170Met)

Other names:

p.T158M:ACG>ATG; NM_001110792.2(MECP2):c.509C>T; p.Thr170Met

HGVS:

NC_000023.11:g.154031355G>A
NG_007107.3:g.110749C>T
NM_001110792.2:c.509C>TMANE SELECT
NM_001316337.2:c.194C>T
NM_001369391.2:c.194C>T
NM_001369392.2:c.194C>T
NM_001369393.2:c.194C>T
NM_001369394.2:c.194C>T
NM_001386137.1:c.-129+41C>T
NM_001386138.1:c.-129+41C>T
NM_001386139.1:c.-129+41C>T
NM_004992.4:c.473C>T
NP_001104262.1:p.Thr170Met
NP_001303266.1:p.Thr65Met
NP_001356320.1:p.Thr65Met
NP_001356321.1:p.Thr65Met
NP_001356322.1:p.Thr65Met
NP_001356323.1:p.Thr65Met
NP_004983.1:p.Thr158Met
NP_004983.1:p.Thr158Met
LRG_764t1:c.509C>T
LRG_764t2:c.473C>T
AJ132917.1:c.473C>T
LRG_764:g.110749C>T
LRG_764p1:p.Thr170Met
LRG_764p2:p.Thr158Met
NC_000023.10:g.153296806G>A
NG_007107.2:g.110773C>T
NM_001110792.1:c.509C>T
NM_001316337.2:c.194C>T
NM_001369391.2:c.194C>T
NM_004992.3:c.473C>T
NM_004992.3:c.[473C>T]
NM_004992.4:c.473C>T
P51608:p.Thr158Met
p.(Thr158Met)

Protein change:

T158M; THR158MET

Links:

UniProtKB: P51608#VAR_010275; OMIM: 300005.0007; dbSNP: rs28934906

NCBI 1000 Genomes Browser:

rs28934906

Molecular consequence:

NM_001386137.1:c.-129+41C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001386138.1:c.-129+41C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001386139.1:c.-129+41C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001110792.2:c.509C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.473C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Name:: Syndromic X-linked intellectual disability Lubs type (MRXSL)
Synonyms:: MENTAL RETARDATION, X-LINKED, WITH RECURRENT RESPIRATORY INFECTIONS; Lubs X-linked mental retardation syndrome; XLMR syndrome, Lubs type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010283; MedGen: C1846058; OMIM: 300260

Name:: X-linked intellectual disability-psychosis-macroorchidism syndrome (MRXS13)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13; PPM-X syndrome
Identifiers:: MONDO: MONDO:0010235; MedGen: C0796222; Orphanet: 3077; OMIM: 300055

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

Name:: Autism, susceptibility to, X-linked 3 (AUTSX3)
Synonyms:: Austism susceptibility, X-linked; Autism susceptibility, X-linked 3
Identifiers:: MONDO: MONDO:0010342; MedGen: C1845336; OMIM: 300496

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Gene ID:104294911

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000893818	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001450670	Service de Génétique Moléculaire, Hôpital Robert Debré	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV003920187	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000893818

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001450670

Service de Génétique Moléculaire, Hôpital Robert Debré

no assertion criteria provided

Pathogenic

unknown

clinical testing

SCV003920187

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 30, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000893818.1

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

#	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 Service de Génétique Moléculaire, Hôpital Robert Debré, SCV001450670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920187.1

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

Description

MECP2 NM_004992.3 exon 4 p.Thr158Met (c.473C>T): This variant is one of the most common mutations associated with Rett syndrome, identified in several individuals (n>100) including males, with Rett syndrome. This variant has been identified to segregate with disease and has also been reported to occur as de novo (Selected publications: Amir 1999 PMID: 10508514, Villard 2000 PMID:11071498, Neul 2008 PMID:18337588, Bao 2013 PMID:23421866, RettBASE http://mecp2.chw.edu.au/). This variant is not present in large control databases. This variant is present in ClinVar, with multiple labs classifying this variant as pathogenic (Variation ID:11811). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, in vivo functional studies support a deleterious effect of this variant, suggesting impaired binding stability and selectivity for methylated DNA (Yusufzai 2000 PMID:11058114, Bao 2013 PMID:23421866). Furthermore, this variant occurs in exon 4; the vast majority of pathogenic variants are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. Loss of function has been established for this gene, but missense variants have been described as pathogenic as well. (Philippe 2006 16473305). In summary, this variant is 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: Nov 3, 2024

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