rs61749743

Positions:

• chrX-154031117-AC-A
• chrX-154031117-AC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000453960.7(MECP2):​c.746del​(p.Gly249ValfsTer11) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G249G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.52

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 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 365 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031117-AC-A is Pathogenic according to our data. Variant chrX-154031117-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 11846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031117-AC-A is described in Lovd as [Pathogenic]. Variant chrX-154031117-AC-A is described in Lovd as [Pathogenic]. Variant chrX-154031117-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.746del	p.Gly249ValfsTer11	frameshift_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.710del	p.Gly237ValfsTer11	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.746del	p.Gly249ValfsTer11	frameshift_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.710del	p.Gly237ValfsTer11	frameshift_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 2.0, 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, RettBase internal database, PMID: 21160487, PMID: 11241840). 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	Jan 18, 2016	This frameshift variant alters amino acid position 237 leading to premature termination codon 10 amino acids downstream. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least seven RTT patients. Functional studies have shown the variant to alter the expression levels of several proteins, however the clinical relevance of these altered expressions are uncertain. Reputable databases list variant as “Pathogenic”. Considering all evidence, the variant was classified as Deleterious Variant. -
Pathogenic, no assertion criteria provided	curation	RettBASE	Nov 01, 2011	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 21, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with MECP2-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability demonstrate X-linked recessive inheritance (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant does not affect an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other downstream truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar, and has been observed in individuals with Rett syndrome in the literature (PMID: 21160487). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Gly255*) have been determined to be pathogenic (PMID: 1241840, 10508514, 17089071, 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 11846). This variant is also known as 706delG. This premature translational stop signal has been observed in individual(s) with Rett Syndrome (PMID: 10805343, 18842453, 19724012). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly237Valfs*11) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 250 amino acid(s) of the MECP2 protein. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 24, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2017

The c.710delG pathogenic mutation, located in coding exon 3 of the MECP2 gene, results from a deletion of one nucleotide at nucleotide position 710, causing a translational frameshift with a predicted alternate stop codon (p.G237Vfs*11). This mutation has been detected in several individuals with diagnoses of Rett syndrome (Laccone F et al. Hum. Mutat., 2001 Mar;17:183-90; Buoni S et al. Clin Neurophysiol, 2008 Nov;119:2455-8; Freilinger M et al. Dev Med Child Neurol, 2010 Oct;52:962-5; Zhang J et al. Clin. Genet., 2012 Dec;82:526-33; Hadzsiev K et al. J. Hum. Genet., 2011 Mar;56:183-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61749743; hg19: chrX-153296568;