NM_001110792.2(MECP2):c.508A>G (p.Thr170Ala) AND Rett syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 26, 2021
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:: RCV000133128.7

Allele description [Variation Report for NM_001110792.2(MECP2):c.508A>G (p.Thr170Ala)]

NM_001110792.2(MECP2):c.508A>G (p.Thr170Ala)

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.508A>G (p.Thr170Ala)

Other names:

NM_001110792.2(MECP2):c.508A>G; p.Thr170Ala

HGVS:

NC_000023.11:g.154031356T>C
NG_007107.3:g.110748A>G
NM_001110792.2:c.508A>GMANE SELECT
NM_001316337.2:c.193A>G
NM_001369391.2:c.193A>G
NM_001369392.2:c.193A>G
NM_001369393.2:c.193A>G
NM_001369394.2:c.193A>G
NM_001386137.1:c.-129+40A>G
NM_001386138.1:c.-129+40A>G
NM_001386139.1:c.-129+40A>G
NM_004992.4:c.472A>G
NP_001104262.1:p.Thr170Ala
NP_001303266.1:p.Thr65Ala
NP_001356320.1:p.Thr65Ala
NP_001356321.1:p.Thr65Ala
NP_001356322.1:p.Thr65Ala
NP_001356323.1:p.Thr65Ala
NP_004983.1:p.Thr158Ala
NP_004983.1:p.Thr158Ala
LRG_764t1:c.508A>G
LRG_764t2:c.472A>G
AJ132917.1:c.472A>G
LRG_764:g.110748A>G
LRG_764p1:p.Thr170Ala
LRG_764p2:p.Thr158Ala
NC_000023.10:g.153296807T>C
NC_000023.10:g.153296807T>C
NG_007107.2:g.110772A>G
NM_004992.3:c.472A>G
P51608:p.Thr158Ala

Protein change:

T158A

Links:

UniProtKB: P51608#VAR_023557; dbSNP: rs61748411

NCBI 1000 Genomes Browser:

rs61748411

Molecular consequence:

NM_001386137.1:c.-129+40A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001386138.1:c.-129+40A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001386139.1:c.-129+40A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001110792.2:c.508A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.193A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.472A>G - missense variant - [Sequence Ontology: SO:0001583]

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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Gene ID:102366347

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CFAP74 cilia and flagella associated protein 74 [Homo sapiens]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188120	RettBASE	no assertion criteria provided	Uncertain significance (Aug 6, 2004)	de novo, unknown	curation	PubMed (2) [See all records that cite these PMIDs] 11269512, 15057977
SCV002047358	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Pathogenic (Oct 26, 2021)	germline	curation	Citation Link,
SCV004808749	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Mar 14, 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

SCV000188120

RettBASE

no assertion criteria provided

Uncertain significance
(Aug 6, 2004)

de novo, unknown

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV002047358

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)

Pathogenic
(Oct 26, 2021)

germline

curation

Citation Link,

SCV004808749

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Pathogenic
(Mar 14, 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	unknown	yes	1	not provided	not provided	1	No	curation
not provided	de novo	yes	1	not provided	not provided	1	No	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.

Vacca M, Filippini F, Budillon A, Rossi V, Mercadante G, Manzati E, Gualandi F, Bigoni S, Trabanelli C, Pini G, Calzolari E, Ferlini A, Meloni I, Hayek G, Zappella M, Renieri A, D'Urso M, D'Esposito M, MacDonald F, Kerr A, Dhanjal S, Hultén M.

J Mol Med (Berl). 2001;78(11):648-55.

PubMed [citation]

PMID:: 11269512

Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.

Schanen C, Houwink EJ, Dorrani N, Lane J, Everett R, Feng A, Cantor RM, Percy A.

Am J Med Genet A. 2004 Apr 15;126A(2):129-40.

PubMed [citation]

PMID:: 15057977

See all PubMed Citations (3)

Details of each submission

From RettBASE, SCV000188120.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	No	curation	PubMed (2)
2	not provided	1	not provided	No	curation	PubMed (2)

Description

"Rett syndrome - classical"

PubMed [ID: 11269512]

"Rett syndrome - Preserved speech"

PubMed [ID: 15057977]

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

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002047358.1

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

Description

The p.Thr158Ala variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with preserved speech variant Rett syndrome (PMID 11269512) (PM6). The p.Thr158Ala variant has been observed in 2 other individuals with Rett syndrome (PMID 18842453, 15057977) (PS4_moderate, PP4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18337588, 23270700, 23421866, 10508514, internal database - Invitae) (PM5_strong). The p.Thr158Ala variant in MECP2 is absent from gnomAD (PM2_supporting). Heterochromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr158Ala variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3, PP4).

#	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, SCV004808749.1

#	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 pathogenic. At least the following criteria are met: >=2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6).(PMID 11269512) Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). PMID 18842453, 15057977, ClinVar Variation ID: 143590 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).

#	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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