rs61749751

chrX-154031074-CG-CchrX-154031074-CG-CGGchrX-154031074-CG-CGGG

Variant summary

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

The NM_001110792.2(MECP2):c.789del(p.Gly264AlafsTer37) 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. P263P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 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 166 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031074-CG-C is Pathogenic according to our data. Variant chrX-154031074-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 143687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031074-CG-C is described in Lovd as [Pathogenic]. Variant chrX-154031074-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.789del	p.Gly264AlafsTer37	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.753del	p.Gly252AlafsTer37	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.789del	p.Gly264AlafsTer37	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.753del	p.Gly252AlafsTer37	frameshift_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	curation	RettBASE	Feb 03, 2006	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 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). PMID: 22139899, 12655490, 21178819, 32954625, 12075485, 15057977, 15862188, 36430969, 31246743, 11913564, ClinVar Variation ID: 143687 This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2023	Reported in the heterozygous state in two female patients with classic Rett syndrome (Huppke et al., 2002; Charman et al., 2005), detailed clinical information was not provided; Reported in the heterozygous state in a female patient with possible Rett syndorme or classic Rett syndrome; detailed clinical information was not provided (Buyse et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12075485, 11055898, 16077736) -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2023

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.Arg255*) have been determined to be pathogenic (Invitae). 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: 143687). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 11055898). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly252Alafs*37) 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. -

MECP2-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

-

This variant is also referred to as c.753del (p.Gly252AlafsTer37) based on an alternate transcript (NM_004992.3). This frameshifting variant in exon 3 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through protein truncation. This variant has been previously reported as a heterozygous change in patients with Rett syndrome (PMID: 12075485, 11055898) (please note in the PMID: 11055898 the variant is called as c.750del). It 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.789del (p.Gly264AlafsTer37) variant is classified as Pathogenic. -

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: rs61749751; hg19: chrX-153296525;