NM_001110792.2(MECP2):c.799C>T (p.Arg267Ter) AND MECP2-related disorder

Germline classification:: Pathogenic (2 submissions)
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:: RCV004545727.2

Allele description [Variation Report for NM_001110792.2(MECP2):c.799C>T (p.Arg267Ter)]

NM_001110792.2(MECP2):c.799C>T (p.Arg267Ter)

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.799C>T (p.Arg267Ter)

Other names:

p.R255*:CGA>TGA; NM_001110792.2(MECP2):c.799C>T; p.Arg267Ter; p.Arg255Ter

HGVS:

NC_000023.11:g.154031065G>A
NG_007107.3:g.111039C>T
NM_001110792.2:c.799C>TMANE SELECT
NM_001316337.2:c.484C>T
NM_001369391.2:c.484C>T
NM_001369392.2:c.484C>T
NM_001369393.2:c.484C>T
NM_001369394.2:c.484C>T
NM_001386137.1:c.94C>T
NM_001386138.1:c.94C>T
NM_001386139.1:c.94C>T
NM_004992.4:c.763C>T
NP_001104262.1:p.Arg267Ter
NP_001303266.1:p.Arg162Ter
NP_001356320.1:p.Arg162Ter
NP_001356321.1:p.Arg162Ter
NP_001356322.1:p.Arg162Ter
NP_001356323.1:p.Arg162Ter
NP_001373066.1:p.Arg32Ter
NP_001373067.1:p.Arg32Ter
NP_001373068.1:p.Arg32Ter
NP_004983.1:p.Arg255Ter
NP_004983.1:p.Arg255Ter
LRG_764t1:c.799C>T
LRG_764t2:c.763C>T
AJ132917.1:c.763C>T
LRG_764:g.111039C>T
LRG_764p1:p.Arg267Ter
LRG_764p2:p.Arg255Ter
NC_000023.10:g.153296516G>A
NG_007107.2:g.111063C>T
NM_001110792.1:c.799C>T
NM_004992.3:c.763C>T
NM_004992.4:c.763C>T
NP_004983.1:p.Arg255*
p.(Arg255*)
p.Arg255X

Protein change:

R162*; ARG255TER

Links:

OMIM: 300005.0021; dbSNP: rs61749721

NCBI 1000 Genomes Browser:

rs61749721

Molecular consequence:

NM_001110792.2:c.799C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001316337.2:c.484C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369391.2:c.484C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369392.2:c.484C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369393.2:c.484C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001369394.2:c.484C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386137.1:c.94C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386138.1:c.94C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001386139.1:c.94C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004992.4:c.763C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: MECP2-related disorder
Synonyms:: MECP2-Related Disorders; MECP2-related condition
Identifiers:: MedGen: C5880921

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004046073	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005345128	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (May 8, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004046073

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

SCV005345128

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(May 8, 2024)

germline

clinical testing

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	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

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046073.1

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

Description

This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Loss-of-function variation in MECP2 is an established mechanism of disease (PMID: 22781840, 26942018, 31527487). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). The c.799C>T (p.Arg267Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic.

#	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 PreventionGenetics, part of Exact Sciences, SCV005345128.1

#	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.763C>T variant is predicted to result in premature protein termination (p.Arg255*). This variant has previously been reported to be causative for Rett Syndrome (Amir et al. 1999. PubMed ID: 10508514; Yusufzai et al. 2000. PubMed ID: 11058114; Pitcher et al. 2015. PubMed ID: 25634563) and it occurred de novo (Wang et al. 2019. PubMed ID: 31512412). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic.

#	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 13, 2024

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