NM_001110792.2(MECP2):c.941C>T (p.Pro314Leu) AND Rett syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jun 30, 2022
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:: RCV000133281.7

Allele description

NM_001110792.2(MECP2):c.941C>T (p.Pro314Leu)

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.941C>T (p.Pro314Leu)

Other names:

NM_001110792.2(MECP2):c.941C>T; p.Pro314Leu

HGVS:

NC_000023.11:g.154030923G>A
NG_007107.3:g.111181C>T
NM_001110792.2:c.941C>TMANE SELECT
NM_001316337.2:c.626C>T
NM_001369391.2:c.626C>T
NM_001369392.2:c.626C>T
NM_001369393.2:c.626C>T
NM_001369394.2:c.626C>T
NM_001386137.1:c.236C>T
NM_001386138.1:c.236C>T
NM_001386139.1:c.236C>T
NM_004992.4:c.905C>T
NP_001104262.1:p.Pro314Leu
NP_001303266.1:p.Pro209Leu
NP_001356320.1:p.Pro209Leu
NP_001356321.1:p.Pro209Leu
NP_001356322.1:p.Pro209Leu
NP_001356323.1:p.Pro209Leu
NP_001373066.1:p.Pro79Leu
NP_001373067.1:p.Pro79Leu
NP_001373068.1:p.Pro79Leu
NP_004983.1:p.Pro302Leu
NP_004983.1:p.Pro302Leu
LRG_764t1:c.941C>T
LRG_764t2:c.905C>T
AJ132917.1:c.905C>T
LRG_764:g.111181C>T
LRG_764p1:p.Pro314Leu
LRG_764p2:p.Pro302Leu
NC_000023.10:g.153296374G>A
NC_000023.10:g.153296374G>A
NG_007107.2:g.111205C>T
NM_001110792.1:c.941C>T
NM_004992.3:c.905C>T
P51608:p.Pro302Leu

Protein change:

P209L

Links:

UniProtKB: P51608#VAR_018208; dbSNP: rs61749723

NCBI 1000 Genomes Browser:

rs61749723

Molecular consequence:

NM_001110792.2:c.941C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386137.1:c.236C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386138.1:c.236C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386139.1:c.236C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.905C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188289	RettBASE	no assertion criteria provided	Uncertain significance (Jan 21, 2008)	de novo, unknown	curation	PubMed (2) [See all records that cite these PMIDs] 11313756, 12180070
SCV000537170	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 30, 2015)	de novo	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11055848, 16473305, 23696494, 10767337, 15057977, 25741868
SCV002540711	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Pathogenic (Jun 30, 2022)	germline	curation	Citation Link,
SCV004232210	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Jan 9, 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	curation
not provided	unknown	yes	4	not provided	not provided	4	No	curation
not provided	unknown	unknown	1	not provided	not provided	1	not provided	curation
not provided	de novo	yes	2	not provided	not provided	1	No	clinical testing, curation

Citations

PubMed

MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern.

Nielsen JB, Henriksen KF, Hansen C, Silahtaroglu A, Schwartz M, Tommerup N.

Eur J Hum Genet. 2001 Mar;9(3):178-84.

PubMed [citation]

PMID:: 11313756

Spectrum of MECP2 mutations in Rett syndrome.

Bienvenu T, Villard L, De Roux N, Bourdon V, Fontes M, Beldjord C, Tardieu M, Jonveaux P, Chelly J; French Consortium for MECP2 Gene Analysis..

Genet Test. 2002 Spring;6(1):1-6.

PubMed [citation]

PMID:: 12180070

See all PubMed Citations (9)

Details of each submission

From RettBASE, SCV000188289.2

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

Description

Not known

Rett syndrome - classical

Rett syndrome - Classical

Rett syndrome - Not certain

"Rett syndrome - not certain"

PubMed [ID: 11313756]

"Rett syndrome - Classical"

PubMed [ID: 12180070]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	1	blood	not provided		1	not provided	not provided	not provided
2	de novo	yes	1	blood or fibroblasts	not provided		1	not provided	not provided	not provided
3	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	Blood	not provided		1	not provided	not provided	not provided
5	unknown	yes	1	blood	not provided		1	not provided	not provided	not provided
6	unknown	yes	1	Blood or skin	not provided		1	not provided	not provided	not provided

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000537170.1

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

#	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		1	not provided	not provided	not provided

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002540711.1

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

Description

The c.905C>T p.(Pro302Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro302Leu) variant has been observed in at least 5 individuals with Rett syndrome or severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756, 16473305, 32472557) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in at least 4 of these individuals (PMID: 10767337, 30377382, 23696494, 11313756) (PM6_very strong). The p.(Pro302Leu) variant occurs in the well-characterized transcriptional repression domain (TRD: aa 302-306) of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). 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: 10814718, 10814719, 10944854, 17387578, 15737703) (PM5). In summary, the c.905C>T p.(Pro302Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PP3, PP4, 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

From Centre for Population Genomics, CPG, SCV004232210.1

#	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: This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in at least an individual with Rett syndrome without confirmation of paternity and maternity (PM6) PMID: 10767337, ClinVar Variation ID: 143738 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4, PP4). (PMID: 16473305 , ClinVar Variation ID: 143738) Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3).

#	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: Feb 28, 2024

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