NM_001110792.2(MECP2):c.2T>C (p.Met1Thr) AND Rett syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 15, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001250739.4

Allele description [Variation Report for NM_001110792.2(MECP2):c.2T>C (p.Met1Thr)]

NM_001110792.2(MECP2):c.2T>C (p.Met1Thr)

Genes:

LOC130068854:ATAC-STARR-seq lymphoblastoid silent region 21085 [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.2T>C (p.Met1Thr)

Other names:

NM_001110792.2(MECP2):c.2T>C; p.Met1Thr

HGVS:

NC_000023.11:g.154097664A>G
NG_007107.2:g.44458T>C
NM_001110792.2:c.2T>CMANE SELECT
NM_001316337.2:c.-606T>C
NM_001369391.2:c.-901T>C
NM_001369392.2:c.-550T>C
NM_001369393.2:c.-426T>C
NM_004992.4:c.-159T>C
NP_001104262.1:p.Met1Thr
LRG_764t1:c.2T>C
LRG_764t2:c.-159T>C
LRG_764p1:p.Met1Thr
NC_000023.10:g.153363121A>G
NM_001110792.1:c.2T>C

Protein change:

M1T

Links:

dbSNP: rs2066907057

NCBI 1000 Genomes Browser:

rs2066907057

Molecular consequence:

NM_001316337.2:c.-606T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369391.2:c.-901T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369392.2:c.-550T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001369393.2:c.-426T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_004992.4:c.-159T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001110792.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001110792.2:c.2T>C - 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
SCV001426149	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Likely pathogenic (Jan 22, 2018)	germline	clinical testing	Citation Link,
SCV004232213	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Uncertain significance (Jan 15, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001426149

Blueprint Genetics

criteria provided, single submitter

(Blueprint Genetics Variant Classification Scheme)

Likely pathogenic
(Jan 22, 2018)

germline

clinical testing

Citation Link,

SCV004232213

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Uncertain significance
(Jan 15, 2024)

germline

curation

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

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

Citations

PubMed

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 Blueprint Genetics, SCV001426149.2

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

From Centre for Population Genomics, CPG, SCV004232213.2

#	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 a variant of uncertain significance. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). (RettBASE direct submission). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). Variation ID: 974567 , RettBASE direct submission) and >=2 different variants in the same Met 1 (NM_001110792.2) codon have been classified as pathogenic ClinVar ID Variation ID: 156661 , 1207096 PMID: 19365833

#	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: Oct 8, 2024

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