NM_001110792.2(MECP2):c.1495T>C (p.Ter499Arg) AND Rett syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 23, 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:: RCV003314564.2

Allele description [Variation Report for NM_001110792.2(MECP2):c.1495T>C (p.Ter499Arg)]

NM_001110792.2(MECP2):c.1495T>C (p.Ter499Arg)

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.1495T>C (p.Ter499Arg)

Other names:

*487R; *499R; *394R; NM_001110792.2(MECP2):c.1495T>C; p.Ter499Arg

HGVS:

NC_000023.11:g.154030369A>G
NG_007107.3:g.111735T>C
NM_001110792.2:c.1495T>CMANE SELECT
NM_001316337.2:c.1180T>C
NM_001369391.2:c.1180T>C
NM_001369392.2:c.1180T>C
NM_001369393.2:c.1180T>C
NM_001369394.2:c.1180T>C
NM_001386137.1:c.790T>C
NM_001386138.1:c.790T>C
NM_001386139.1:c.790T>C
NM_004992.4:c.1459T>C
NP_001104262.1:p.Ter499Arg
NP_001303266.1:p.Ter394Arg
NP_001356320.1:p.Ter394Arg
NP_001356321.1:p.Ter394Arg
NP_001356322.1:p.Ter394Arg
NP_001356323.1:p.Ter394Arg
NP_001373066.1:p.Ter264Arg
NP_001373067.1:p.Ter264Arg
NP_001373068.1:p.Ter264Arg
NP_004983.1:p.Ter487Arg
LRG_764t1:c.1495T>C
LRG_764t2:c.1459T>C
AJ132917.1:c.1459T>C
LRG_764:g.111735T>C
LRG_764p1:p.Ter499Arg
LRG_764p2:p.Ter487Arg
NC_000023.10:g.153295820A>G
NG_007107.2:g.111759T>C

Links:

dbSNP: rs267608337

NCBI 1000 Genomes Browser:

rs267608337

Molecular consequence:

NM_001110792.2:c.1495T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001316337.2:c.1180T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001369391.2:c.1180T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001369392.2:c.1180T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001369393.2:c.1180T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001369394.2:c.1180T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001386137.1:c.790T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001386138.1:c.790T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001386139.1:c.790T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_004992.4:c.1459T>C - stop lost - [Sequence Ontology: SO:0001578]

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

Recent activity

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Homo sapiens leucine rich repeat containing 2 (LRRC2), mRNA
Homo sapiens leucine rich repeat containing 2 (LRRC2), mRNA
gi|1519243139|ref|NM_024512.5|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004014722	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (May 2, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005040742	Centre for Population Genomics, CPG	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022))	Likely pathogenic (Apr 23, 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

SCV004014722

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Likely pathogenic
(May 2, 2023)

unknown

clinical testing

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

Citation Link,

SCV005040742

Centre for Population Genomics, CPG

criteria provided, single submitter

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

Likely pathogenic
(Apr 23, 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	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

MECP2 mutation screening in Swedish classical Rett syndrome females.

Erlandson A, Hallberg B, Hagberg B, Wahlström J, Martinsson T.

Eur Child Adolesc Psychiatry. 2001 Jun;10(2):117-21.

PubMed [citation]

PMID:: 11469283

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 Illumina Laboratory Services, Illumina, SCV004014722.1

#	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.1459T>C (p.Ter487ArgextTer27) variant causes a stop-loss that is predicted to result in in-frame elongation of the protein. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been identified in a de novo state in a female with a phenotype consistent with Rett syndrome (PMID: 11469283). The p.Ter487ArgextTer27 variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a de novo state. Based on the available evidence, the c.1459T>C (p.Ter487ArgextTer27) variant is classified as likely 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, SCV005040742.1

#	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 likely pathogenic. At least the following criteria are met: Protein length changes due to stop-loss variant (PM4_Strong). This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 11469283

#	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: May 7, 2024

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