X-154031074-CG-CGG

Position:

• chrX-154031074-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.789dupC​(p.Gly264fs) 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 (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.473 CDS is truncated, and there are 0 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 [Likely_pathogenic]. Clinvar id is 143688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.789dupC	p.Gly264fs	frameshift_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.753dupC	p.Gly252fs	frameshift_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.789dupC	p.Gly264fs	frameshift_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.753dupC	p.Gly252fs	frameshift_variant	4/4	1	NM_004992.4	ENSP00000301948.6

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

Pathogenic, no assertion criteria provided	curation	RettBASE	Nov 01, 2007	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 10, 2024	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2018	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. -
Likely pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:3

Pathogenic, no assertion criteria provided	curation	RettBASE	Nov 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 19, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 143688). This variant is also known as E258X. This premature translational stop signal has been observed in individual(s) with clinical features of Rett syndrome (PMID: 11913564). This variant is not present in population databases (gnomAD no frequency). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jan 10, 2018	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. -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 11, 2021	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749751; hg19: chrX-153296525;