NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter) AND not provided

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: Oct 18, 2022
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:: RCV000081212.60

Allele description [Variation Report for NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter)]

NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter)

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.844C>T (p.Arg282Ter)

Other names:

NP_004983.1:p.Arg270*; p.R270*:CGA>TGA; NM_001110792.2(MECP2):c.844C>T; p.Arg282Ter

HGVS:

NC_000023.11:g.154031020G>A
NG_007107.3:g.111084C>T
NM_001110792.2:c.844C>TMANE SELECT
NM_001316337.2:c.529C>T
NM_001369391.2:c.529C>T
NM_001369392.2:c.529C>T
NM_001369393.2:c.529C>T
NM_001369394.2:c.529C>T
NM_001386137.1:c.139C>T
NM_001386138.1:c.139C>T
NM_001386139.1:c.139C>T
NM_004992.4:c.808C>T
NP_001104262.1:p.Arg282Ter
NP_001303266.1:p.Arg177Ter
NP_001356320.1:p.Arg177Ter
NP_001356321.1:p.Arg177Ter
NP_001356322.1:p.Arg177Ter
NP_001356323.1:p.Arg177Ter
NP_001373066.1:p.Arg47Ter
NP_001373067.1:p.Arg47Ter
NP_001373068.1:p.Arg47Ter
NP_004983.1:p.Arg270Ter
NP_004983.1:p.Arg270Ter
LRG_764t1:c.844C>T
LRG_764t2:c.808C>T
AJ132917.1:c.808C>T
LRG_764:g.111084C>T
LRG_764p1:p.Arg282Ter
LRG_764p2:p.Arg270Ter
NC_000023.10:g.153296471G>A
NG_007107.2:g.111108C>T
NM_001110792.1:c.844C>T
NM_001110792.2:c.844C>T
NM_001316337.2:c.529C>T
NM_004992.3:c.808C>T
p.(Arg270*)
p.Arg270X

Protein change:

R177*; ARG270TER

Links:

OMIM: 300005.0005; dbSNP: rs61750240

NCBI 1000 Genomes Browser:

rs61750240

Molecular consequence:

NM_001110792.2:c.844C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001316337.2:c.529C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369391.2:c.529C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369392.2:c.529C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369393.2:c.529C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369394.2:c.529C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386137.1:c.139C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386138.1:c.139C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386139.1:c.139C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004992.4:c.808C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000191047	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 19, 2021)	germline	clinical testing	Citation Link,
SCV000230264	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (May 10, 2013)	germline	clinical testing	Citation Link,
SCV000537198	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2015)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10944854, 11245712, 15287421, 12180070, 10814719, 11055898, 25741868
SCV000778230	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	no assertion criteria provided	Pathogenic (Nov 21, 2016)	germline	clinical testing
SCV000804250	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia See additional submitters Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Pathogenic (Apr 3, 2015)	germline	clinical testing
SCV000885680	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jun 8, 2018)	germline	clinical testing	Citation Link,
SCV001150513	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2022)	germline	clinical testing	Citation Link,
SCV001449677	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001929888	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001965916	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001979370	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002017246	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175154	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	no assertion criteria provided	Pathogenic (Jan 29, 2020)	unknown	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	7	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing
South East Asian	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.

Amano K, Nomura Y, Segawa M, Yamakawa K.

J Hum Genet. 2000;45(4):231-6.

PubMed [citation]

PMID:: 10944854

MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features.

Auranen M, Vanhala R, Vosman M, Levander M, Varilo T, Hietala M, Riikonen R, Peltonen L, Järvelä I.

Neurology. 2001 Mar 13;56(5):611-7.

PubMed [citation]

PMID:: 11245712

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000191047.12

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

Description

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587)

#	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 Eurofins Ntd Llc (ga), SCV000230264.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	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	unknown	not provided	not provided	not provided		7	not provided	not provided	not provided

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV000537198.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

#	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		1	not provided	not provided	not provided

From Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes, SCV000778230.1

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

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000804250.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885680.1

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

Description

The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle J et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000; 9(7):1119-29. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001150513.27

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

MECP2: PVS1, PS2, PM2

#	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		6	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449677.1

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001929888.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001965916.1

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001979370.1

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

From Revvity Omics, Revvity, SCV002017246.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare, SCV004175154.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South East Asian	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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