NM_001110792.2(MECP2):c.1366G>A (p.Ala456Thr) AND Rett syndrome

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Aug 14, 2023
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:: RCV000659843.11

Allele description [Variation Report for NM_001110792.2(MECP2):c.1366G>A (p.Ala456Thr)]

NM_001110792.2(MECP2):c.1366G>A (p.Ala456Thr)

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.1366G>A (p.Ala456Thr)

Other names:

p.A444T:GCC>ACC; NM_001110792.2(MECP2):c.1366G>A; p.Ala456Thr

HGVS:

NC_000023.11:g.154030498C>T
NG_007107.3:g.111606G>A
NM_001110792.2:c.1366G>AMANE SELECT
NM_001316337.2:c.1051G>A
NM_001369391.2:c.1051G>A
NM_001369392.2:c.1051G>A
NM_001369393.2:c.1051G>A
NM_001369394.2:c.1051G>A
NM_001386137.1:c.661G>A
NM_001386138.1:c.661G>A
NM_001386139.1:c.661G>A
NM_004992.4:c.1330G>A
NP_001104262.1:p.Ala456Thr
NP_001303266.1:p.Ala351Thr
NP_001356320.1:p.Ala351Thr
NP_001356321.1:p.Ala351Thr
NP_001356322.1:p.Ala351Thr
NP_001356323.1:p.Ala351Thr
NP_001373066.1:p.Ala221Thr
NP_001373067.1:p.Ala221Thr
NP_001373068.1:p.Ala221Thr
NP_004983.1:p.Ala444Thr
NP_004983.1:p.Ala444Thr
LRG_764t1:c.1366G>A
LRG_764t2:c.1330G>A
AJ132917.1:c.1330G>A
LRG_764:g.111606G>A
LRG_764p1:p.Ala456Thr
LRG_764p2:p.Ala444Thr
NC_000023.10:g.153295949C>T
NG_007107.2:g.111630G>A
NM_004992.3:c.1330G>A
P51608:p.Ala444Thr
p.(Ala444Thr)

Protein change:

A221T

Links:

UniProtKB: P51608#VAR_018224; dbSNP: rs61753975

NCBI 1000 Genomes Browser:

rs61753975

Molecular consequence:

NM_001110792.2:c.1366G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001316337.2:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369391.2:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369392.2:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369393.2:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369394.2:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386137.1:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386138.1:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001386139.1:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004992.4:c.1330G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000781716	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001142077	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004098739	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Benign (Aug 14, 2023)	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

SCV000781716

Center for Human Genetics, Inc, Center for Human Genetics, Inc

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Nov 1, 2016)

germline

clinical testing

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

SCV001142077

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Benign
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV004098739

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Benign
(Aug 14, 2023)

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	yes	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	curation
not provided	unknown	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

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 Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781716.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001142077.1

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

From Centre for Population Genomics, CPG, SCV004098739.1

#	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 2.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID: 11738860, PMID: 11055898). This variant did not segregate in a similarly affected family member (BS4_Supporting, PMID: 11738860)

#	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: Jan 4, 2025

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