rs267608329

chrX-154030627-TGGTGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCAGG-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.1191_1236del(p.Leu398AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 1,077,997 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P397P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., 0 hem., cov: 17)
  • Exomes 𝑓: 0.0000030 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.50

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 55 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154030627-TGGTGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCAGG-T is Pathogenic according to our data. Variant chrX-154030627-TGGTGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCAGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030627-TGGTGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCAGG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1191_1236del	p.Leu398AlafsTer8	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1155_1200del	p.Leu386AlafsTer8	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1155_1200del	p.Leu386AlafsTer8	frameshift_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1191_1236del	p.Leu398AlafsTer8	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*527_*572del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*527_*572del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0000126 AC: 1 AN: 79310 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 18894

Gnomad AFR AF: 0.0000499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000567 AC: 1 AN: 176334 Hom.: 0 AF XY: 0.0000155 AC XY: 1 AN XY: 64326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000300 AC: 3 AN: 998687 Hom.: 0 AF XY: 0.00000310 AC XY: 1 AN XY: 322629

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000302

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000256

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000126 AC: 1 AN: 79310 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 18894

Gnomad4 AFR AF: 0.0000499

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely 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	Jan 21, 2008	- -
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: 143360, PMID: 23696494, 12180070 , 16473305 This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 23696494 This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MECP2: PVS1, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2023	Identified in two unrelated females with Rett syndrome; however, in both published cases the c.1155_1200del46 variant was likely part of a complex allele, as one of the patients also harbored an in-frame insertion/deletion while the other had a second frameshift variant in MECP2 (Lee et al., 2001; Weaving et al., 2003); Also reported as an isolated pathogenic variant in two unrelated females in RettBASE; however, no additional information is available regarding the phenotype or family history (Christodoulou et al., 2003); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12655490, 16473305, 19914908, 12872250, 11738860) -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2023

This sequence change creates a premature translational stop signal (p.Leu386Alafs*8) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the MECP2 protein. This variant is present in population databases (rs267608329, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of Rett syndrome (PMID: 16473305, 19914908). This variant is also known as c.1152_1197del. ClinVar contains an entry for this variant (Variation ID: 143360). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (PMID: 17089071, 17387578, 19914908, 20151026, 21982064). 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. -

Syndromic X-linked intellectual disability Lubs type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2023

- -

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: rs267608329; hg19: chrX-153296078;