NM_001110792.2(MECP2):c.400G>A (p.Val134Met) 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:: RCV000133079.8

Allele description [Variation Report for NM_001110792.2(MECP2):c.400G>A (p.Val134Met)]

NM_001110792.2(MECP2):c.400G>A (p.Val134Met)

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.400G>A (p.Val134Met)

Other names:

NM_001110792.2(MECP2):c.400G>A; p.Val134Met

HGVS:

NC_000023.11:g.154032220C>T
NG_007107.3:g.109884G>A
NM_001110792.2:c.400G>AMANE SELECT
NM_001316337.2:c.85G>A
NM_001369391.2:c.85G>A
NM_001369392.2:c.85G>A
NM_001369393.2:c.85G>A
NM_001369394.2:c.85G>A
NM_001386137.1:c.-197G>A
NM_001386138.1:c.-197G>A
NM_001386139.1:c.-197G>A
NM_004992.4:c.364G>A
NP_001104262.1:p.Val134Met
NP_001303266.1:p.Val29Met
NP_001356320.1:p.Val29Met
NP_001356321.1:p.Val29Met
NP_001356322.1:p.Val29Met
NP_001356323.1:p.Val29Met
NP_004983.1:p.Val122Met
NP_004983.1:p.Val122Met
LRG_764t1:c.400G>A
LRG_764t2:c.364G>A
AJ132917.1:c.364G>A
LRG_764:g.109884G>A
LRG_764p1:p.Val134Met
LRG_764p2:p.Val122Met
NC_000023.10:g.153297671C>T
NG_007107.2:g.109908G>A
NM_004992.3:c.364G>A

Protein change:

V122M

Links:

dbSNP: rs267608455

NCBI 1000 Genomes Browser:

rs267608455

Molecular consequence:

NM_001386137.1:c.-197G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-197G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-197G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.400G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.85G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.85G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.85G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.85G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.85G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.364G>A - 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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Mus musculus small nuclear ribonucleoprotein N (Snrpn), transcript variant 4, mR...
Mus musculus small nuclear ribonucleoprotein N (Snrpn), transcript variant 4, mRNA
gi|1167503309|ref|NM_001349690.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188067	RettBASE	no assertion criteria provided	Uncertain significance (Feb 18, 2008)	de novo	curation	PubMed (1) [See all records that cite this PMID]
SCV002047365	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,
SCV004232214	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Jan 15, 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

SCV000188067

RettBASE

no assertion criteria provided

Uncertain significance
(Feb 18, 2008)

de novo

curation

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

SCV002047365

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,

SCV004232214

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Pathogenic
(Jan 15, 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	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

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.

Li MR, Pan H, Bao XH, Zhang YZ, Wu XR.

J Hum Genet. 2007;52(1):38-47. doi: 10.1007/s10038-006-0079-0. Epub 2006 Nov 7.

PubMed [citation]

PMID:: 17089071

Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.

McKnight D, Bean L, Karbassi I, Beattie K, Bienvenu T, Bonin H, Fang P, Chrisodoulou J, Friez M, Helgeson M, Krishnaraj R, Meng L, Mighion L, Neul J, Percy A, Ramsden S, Zoghbi H, Das S.

Hum Mutat. 2022 Aug;43(8):1097-1113. doi: 10.1002/humu.24302. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 34837432
PMCID:: PMC9135956

Details of each submission

From RettBASE, SCV000188067.2

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

Description

"Rett syndrome - not certain"

PubMed [ID: 17089071]

#	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

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002047365.1

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

Description

The p.Val122Met variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 17089071) (PP4). The p.Val122Met variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in this individual. It is also reported in the mosaic state in a male patient with clinical features of Rett syndrome (PMID 28837158, internal database - GeneDx) and therefore confirmed to be de novo (PS2, PS4_supporting). The p.Val122Met variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val122Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Val122Met variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PM1, PS4_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, SCV004232214.1

#	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 has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 17089071, PMID 28837158 Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate).ClinVar Variation ID: 143546 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 17089071

#	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: Aug 4, 2024

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