rs267608327

chrX-154030630-TGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCA-T

Variant summary

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

The NM_001110792.2(MECP2):c.1193_1233del(p.Leu398HisfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L398L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 18)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:2
• 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 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 53 pathogenic variants in the truncated region.
• PP5: Variant X-154030630-TGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCA-T is Pathogenic according to our data. Variant chrX-154030630-TGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030630-TGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCA-T is described in Lovd as [Pathogenic]. Variant chrX-154030630-TGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGGGGCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1193_1233del	p.Leu398HisfsTer5	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1157_1197del	p.Leu386HisfsTer5	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1157_1197del	p.Leu386HisfsTer5	frameshift_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1193_1233del	p.Leu398HisfsTer5	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*529_*569del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*529_*569del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 18

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

GnomAD4 genome Cov.: 18

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2016	Variant summary: The MECP2 c.1157_1197del41 (p.Leu386Hisfs) is a large deletion, resulting in a reading frame shift. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 1380 control chromosomes, but has been identified in numerous classic and atypical Rett Syndrome patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 31, 2017	41 base pair deletion resulting in a frameshift, which is predicted to result in loss of function in the MECP2 gene, where loss of function is a known mechanism of Rett syndrome. This variant has been observed in multiple, unrelated, affected individuals with Rett syndrome (PMID: 12673788) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Molecular Genetics Department, National Research Center	Nov 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 22, 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: 143369 PMID:11269512 , PMID:23810759 , PMID:23696494 , PMID:21878110 , PMID:20031356 ). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -

not provided Pathogenic:4 Other:1

not provided, flagged submission	literature only	RettBASE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 16, 2017	The MECP2 c.1157_1197del, p.Leu386fs variant (rs267608327) is a recurrent deletion found in individuals diagnosed with RETT syndrome (Bienvenu 2002, Chae 2002, Cheadle 2000, Hoffbuhr 2001, Philippe 2006, Ravn 2011, Yaron 2002, Zahorakova 2007), and has associated with both classical disease and a milder form known as the preserved speech variant (Conforti 2002, De Bona 2008, Ravn 2011). It is listed as pathogenic in ClinVar (Variation ID: 143369), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a frameshift, and is predicted to result in a truncated protein. Based on the above information, the variant is classified as pathogenic. References: Bienvenu T et al. Spectrum of MECP2 mutations in Rett syndrome. Genet Test. 2002; 6(1):1-6. Chae J et al. Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome. J Child Neurol. 2002; 17(1):33-6. Cheadle J et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000; 9(7):1119-29. Conforti F et al. Mutation analysis of the MECP2 gene in patients with Rett syndrome. Am J Med Genet A. 2003; 117A(2):184-7. De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000; 8(5):325-30. Hoffbuhr K et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001; 56(11):1486-95. Philippe C et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006; 49(1):9-18. Ravn K et al. Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations. Orphanet J Rare Dis. 2011; 6:58. Yaron Y et al. MECP2 mutations in Israel: implications for molecular analysis, genetic counseling, and prenatal diagnosis in Rett syndrome. Hum Mutat. 2002; 20(4):323-4. Zahorakova D et al. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007; 52(4):342-8. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2022	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26984561, 16473305, 10767337, 11746022, 17142618, 21878110, 23810759, 17387578, 11402105, 21160487, 33168794, 31943886, 34876818, 34782041, 32105570, 32631363) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -

See cases Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 24, 2021	ACMG classification criteria: PVS1, PS4, PM2, PM6 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Nov 11, 2022	ACMG categories: PVS1,PM1,PM2,PP5 -

Autism, susceptibility to, X-linked 3 Pathogenic:1 Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
Pathogenic, flagged submission	curation	RettBASE	Dec 05, 2013	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

This sequence change creates a premature translational stop signal (p.Leu386Hisfs*5) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 10767337, 11746022, 11913567, 12325033, 16473305, 17089071, 17142618, 17387578, 19914908, 21878110). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1157_1197del41 and c.1157del41. ClinVar contains an entry for this variant (Variation ID: 143369). For these reasons, this variant has been classified as Pathogenic. -

Rett syndrome, zappella variant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

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

Pathogenic, flagged submission

curation

RettBASE

Dec 05, 2013

- -

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: rs267608327; hg19: chrX-153296081;