NM_001110792.2(MECP2):c.325G>T (p.Asp109Tyr) AND Rett syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 10, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000133048.4

Allele description [Variation Report for NM_001110792.2(MECP2):c.325G>T (p.Asp109Tyr)]

NM_001110792.2(MECP2):c.325G>T (p.Asp109Tyr)

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.325G>T (p.Asp109Tyr)

Other names:

NM_001110792.2(MECP2):c.325G>T; p.Asp109Tyr

HGVS:

NC_000023.11:g.154032295C>A
NG_007107.3:g.109809G>T
NM_001110792.2:c.325G>TMANE SELECT
NM_001316337.2:c.10G>T
NM_001369391.2:c.10G>T
NM_001369392.2:c.10G>T
NM_001369393.2:c.10G>T
NM_001369394.2:c.10G>T
NM_001386137.1:c.-272G>T
NM_001386138.1:c.-272G>T
NM_001386139.1:c.-272G>T
NM_004992.4:c.289G>T
NP_001104262.1:p.Asp109Tyr
NP_001303266.1:p.Asp4Tyr
NP_001356320.1:p.Asp4Tyr
NP_001356321.1:p.Asp4Tyr
NP_001356322.1:p.Asp4Tyr
NP_001356323.1:p.Asp4Tyr
NP_004983.1:p.Asp97Tyr
NP_004983.1:p.Asp97Tyr
LRG_764t1:c.325G>T
LRG_764t2:c.289G>T
AJ132917.1:c.289G>T
LRG_764:g.109809G>T
LRG_764p1:p.Asp109Tyr
LRG_764p2:p.Asp97Tyr
NC_000023.10:g.153297746C>A
NG_007107.2:g.109833G>T
NM_004992.3:c.289G>T
P51608:p.Asp97Tyr

Protein change:

D109Y

Links:

UniProtKB: P51608#VAR_018182; dbSNP: rs61754448

NCBI 1000 Genomes Browser:

rs61754448

Molecular consequence:

NM_001386137.1:c.-272G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386138.1:c.-272G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001386139.1:c.-272G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.325G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.10G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.10G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.10G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.10G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.10G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.289G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188036	RettBASE	no assertion criteria provided	Uncertain significance (Dec 3, 2010)	unknown	curation	PubMed (4) [See all records that cite these PMIDs] 11402105, 11913567, 17420824, 20031356
SCV004232268	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Likely pathogenic (Jan 10, 2024)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 12843318, 34837432 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000188036

RettBASE

no assertion criteria provided

Uncertain significance
(Dec 3, 2010)

unknown

curation

PubMed (4)
[See all records that cite these PMIDs]

SCV004232268

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Likely pathogenic
(Jan 10, 2024)

germline

curation

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

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

Citations

PubMed

MeCP2 mutations in children with and without the phenotype of Rett syndrome.

Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, Schuette J, Innis J, Marino M, Philippart M, Narayanan V, Umansky R, Kronn D, Hoffman EP, Naidu S.

Neurology. 2001 Jun 12;56(11):1486-95.

PubMed [citation]

PMID:: 11402105

Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome.

Chae JH, Hwang YS, Kim KJ.

J Child Neurol. 2002 Jan;17(1):33-6.

PubMed [citation]

PMID:: 11913567

See all PubMed Citations (6)

Details of each submission

From RettBASE, SCV000188036.2

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

Description

"Rett syndrome - Classical"

PubMed [ID: 11402105]

"Rett syndrome - Not certain"

PubMed [ID: 11913567]

"Rett syndrome - not certain"

PubMed [ID: 17420824]

"Rett syndrome - Classical"

PubMed [ID: 20031356]

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

From Centre for Population Genomics, CPG, SCV004232268.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

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 likely pathogenic. At least the following criteria are met: Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). PMID: 11913567, 11402105, 17420824, 15526954, 20031356. At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4).PMID: 15526954 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). PMID: 12843318 This variant is absent from gnomAD (PM2_Supporting). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1).

#	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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