rs267608597

chrX-154030665-GG-TA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001110792.2(MECP2):c.1198_1199delinsTA(p.Pro400Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P400P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.20

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 16 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 45 pathogenic variants in the truncated region.
• PP5: Variant X-154030665-GG-TA is Pathogenic according to our data. Variant chrX-154030665-GG-TA is described in ClinVar as [Pathogenic]. Clinvar id is 143395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1198_1199delinsTA	p.Pro400Ter	stop_gained	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1162_1163delinsTA	p.Pro388Ter	stop_gained	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1162_1163delinsTA	p.Pro388Ter	stop_gained	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1198_1199delinsTA	p.Pro400Ter	stop_gained	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*534_*535delinsTA		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*534_*535delinsTA		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 20

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

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change creates a premature translational stop signal (p.Pro388*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the MECP2 protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 17383248). ClinVar contains an entry for this variant (Variation ID: 143395). 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. -

Rett syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 26, 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 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). PMID:17383248 , PMID:31602196 , PMID:20151026 , PMID:17387578 This variant is absent from gnomAD v4 (PM2_Supporting). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2018

The c.1162_1163delCCinsTA pathogenic mutation (p.P388*), located in coding exon 3 of the MECP2 gene, results from an in-frame deletion of CC and insertion of TA at nucleotide positions 1162 to 1163. This changes the amino acid from a proline to a stop codon within coding exon 3. This alteration has been reported in a cohort of subjects with intellectual disability who had previously tested negative for Fragile X syndrome (Lesca G et al. Eur J Med Genet., 2007 Feb;50:200-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2018

The c.1162_1163delCCinsTA variant in the MECP2 gene has been reported previously in a female with borderline intellectual disability without other features of Rett syndrome (Lesca et al., 2007). The c.1162_1163delCCinsTA variant results in the replacement of the normal codon, Proline 388, with a Stop codon, denoted p.Pro388Ter. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1162_1163delCCinsTA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1162_1163delCCinsTA as a pathogenic variant. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 17, 2018

- -

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

Pathogenic, no assertion criteria provided

curation

RettBASE

Nov 01, 2007

- -

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: rs267608597; hg19: chrX-153296116;