rs267608571

Positions:

• chrX-154030685-TGGCACGGG-T

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.1171_1178del​(p.Pro391ThrfsTer11) variant causes a frameshift change. 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. P391P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.37

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 63 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154030685-TGGCACGGG-T is Pathogenic according to our data. Variant chrX-154030685-TGGCACGGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 143342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030685-TGGCACGGG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1171_1178del	p.Pro391ThrfsTer11	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1135_1142del	p.Pro379ThrfsTer11	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1135_1142del	p.Pro379ThrfsTer11	frameshift_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1171_1178del	p.Pro391ThrfsTer11	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*507_*514del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*507_*514del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 31, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP,PS2_MOD -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 12, 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: 143342, PMID 15558314 This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	The c.1135_1142delCCCGTGCC pathogenic variant in the MECP2 gene has been reported previously in an individual with an MECP2-related disorder (Oexle et al., 2005). The deletion causes a frameshift starting with codon Proline 379 changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Pro379ThrfsX11. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 108 amino acids are replaced with 10 incorrect amino acids. The c.1135_1142delCCCGTGCC is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

This sequence change creates a premature translational stop signal (p.Pro379Thrfs*11) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 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 MECP2-related conditions (PMID: 15558314). ClinVar contains an entry for this variant (Variation ID: 143342). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Gln437Alafs*49) have been determined to be pathogenic (PMID: 11055898; 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. For these reasons, this variant has been classified as Pathogenic. -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Nov 18, 2005

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Aug 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608571; hg19: chrX-153296136;