NM_001110792.2:c.789dupC

Variant names:

• chrX-154031074-C-CG
• rs61749751
• NM_001110792.2:c.789dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.789dupC​(p.Gly264ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P263P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: -3.38
• Publications: 5 publications found

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 437 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031074-C-CG is Pathogenic according to our data. Variant chrX-154031074-C-CG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 143688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.789dupC	p.Gly264ArgfsTer7	frameshift	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.753dupC	p.Gly252ArgfsTer7	frameshift	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.474dupC	p.Gly159ArgfsTer7	frameshift	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.789dupC	p.Gly264ArgfsTer7	frameshift	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.753dupC	p.Gly252ArgfsTer7	frameshift	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.753dupC	p.Gly252ArgfsTer7	frameshift	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:4

Jan 10, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (ClinVar Variation ID:143688 PMID: 22139899, 12655490, 21178819, 32954625, 12075485, 15057977, 15862188, 36430969, 31246743, 11913564). This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome without confirmation of paternity and maternity (PM6). (PMID: 32954625, 31246743). Co-segregation with disease in multiple affected family members in at least 2 informative meiosis (PP1). PMID: 11913564 This variant is absent from gnomAD (PM2_Supporting).

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 23, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MECP2 c.753dupC (p.Gly252ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.763C>T (p.Arg255X), c.806delG (p.Gly269fsX20), and c.808C>T (p.Arg570X)). The variant was absent in 21631 control chromosomes (gnomAD). The variant, c.753dupC, has been reported in the literature in individuals affected with Rett Syndrome (Zahorakova_2007, Zeev_2002). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Nov 01, 2007

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:3

Nov 01, 2007

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Jan 10, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant is predicted to result in the premature truncation of the MECP2 protein. This variant has been described previously in an affected male (nomenclature: c.754insC, PMID: 11913564), and listed as a disease causing variant in the Rett syndrome database (http://mecp2.chw.edu.au/). The male patient previously described with this particular variant had a clinical presentation that included hypotonia, autonomic dysfunction, recurrent urinary tract infections, and apneic spells (PMID: 11913564). This mutation occurs in the transcriptional repression domain (TRD), one of two functionally important domains in MECP2 (PMID: 11913564). This variant is not found in the population allele frequency database, gnomAD, thus it is presumed to be rare. Based on the predicted functional impact of the variant and supporting evidence in the literature, the p.Gly264ArgfsTer7 variant is classified as pathogenic.

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly252Argfs*7) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 235 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Rett syndrome (PMID: 11913564). This variant is also known as E258X. ClinVar contains an entry for this variant (Variation ID: 143688). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg270*) have been determined to be pathogenic (PMID: 10854091, 16473305, 18174548, 23270700). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1 Other:1

May 11, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.4
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61749751; hg19: chrX-153296525;