NM_001110792.2(MECP2):c.1154C>G (p.Ser385Ter) AND Rett syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 15, 2024
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:: RCV000193072.10

Allele description [Variation Report for NM_001110792.2(MECP2):c.1154C>G (p.Ser385Ter)]

NM_001110792.2(MECP2):c.1154C>G (p.Ser385Ter)

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.1154C>G (p.Ser385Ter)

Other names:

NM_001110792.2(MECP2):c.1154C>G; p.Ser385Ter

HGVS:

NC_000023.11:g.154030710G>C
NG_007107.3:g.111394C>G
NM_001110792.2:c.1154C>GMANE SELECT
NM_001316337.2:c.839C>G
NM_001369391.2:c.839C>G
NM_001369392.2:c.839C>G
NM_001369393.2:c.839C>G
NM_001369394.2:c.839C>G
NM_001386137.1:c.449C>G
NM_001386138.1:c.449C>G
NM_001386139.1:c.449C>G
NM_004992.4:c.1118C>G
NP_001104262.1:p.Ser385Ter
NP_001303266.1:p.Ser280Ter
NP_001356320.1:p.Ser280Ter
NP_001356321.1:p.Ser280Ter
NP_001356322.1:p.Ser280Ter
NP_001356323.1:p.Ser280Ter
NP_001373066.1:p.Ser150Ter
NP_001373067.1:p.Ser150Ter
NP_001373068.1:p.Ser150Ter
NP_004983.1:p.Ser373Ter
NP_004983.1:p.Ser373Ter
LRG_764t1:c.1154C>G
LRG_764t2:c.1118C>G
AJ132917.1:c.1118C>G
LRG_764:g.111394C>G
LRG_764p1:p.Ser385Ter
LRG_764p2:p.Ser373Ter
NC_000023.10:g.153296161G>C
NG_007107.2:g.111418C>G
NM_001110792.1:c.1154C>G
NM_004992.3:c.1118C>G

Protein change:

S150*

Links:

dbSNP: rs267608569

NCBI 1000 Genomes Browser:

rs267608569

Molecular consequence:

NM_001110792.2:c.1154C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001316337.2:c.839C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001369391.2:c.839C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001369392.2:c.839C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001369393.2:c.839C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001369394.2:c.839C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001386137.1:c.449C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001386138.1:c.449C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001386139.1:c.449C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_004992.4:c.1118C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000247927	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001451529	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Aug 12, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004808762	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Pathogenic (Mar 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

SCV000247927

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2007)

Pathogenic
(Feb 8, 2013)

germline

clinical testing

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

SCV001451529

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Aug 12, 2019)

unknown

clinical testing

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

Citation Link,

SCV004808762

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Pathogenic
(Mar 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	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

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Rett syndrome and long-term disorder profile.

Smeets EE, Chenault M, Curfs LM, Schrander-Stumpel CT, Frijns JP.

Am J Med Genet A. 2009 Feb;149A(2):199-205. doi: 10.1002/ajmg.a.32491.

PubMed [citation]

PMID:: 19133691

See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000247927.1

#	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 Illumina Laboratory Services, Illumina, SCV001451529.1

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

Description

The MECP2 c.1154C>G (p.Ser385Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. This variant, which is also referred to as p.Ser373Ter, occurs in the C-terminal segment hot spot region and has been reported in a heterozygous state in a female with Rett syndrome (Smeets et al. 2009). The p.Ser385Ter variant is not found in the Genome Aggregation Database despite its location in a region of good sequencing coverage. Based on the collective evidence and application of the ACMG criteria, the p.Ser385Ter variant is classified as pathogenic for Rett syndrome.

#	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, SCV004808762.1

#	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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 19133691, 22190343 This variant is absent from gnomAD (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

Last Updated: Apr 15, 2024

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