rs61750241

chrX-154031021-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS2 PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Gly269Alafs*20 variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199475/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:32
• Conservation: PhyloP100: 7.37

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 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.842del	p.Gly281AlafsTer20	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.806del	p.Gly269AlafsTer20	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.842del	p.Gly281AlafsTer20	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.806del	p.Gly269AlafsTer20	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:32

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 03, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0 , this variant is classified as Pathogenic . At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND in at least 2 individuals with unconfirmed parental relationships (PS2_Very strong). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 09, 2021	The p.Gly269Alafs*20 variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, PM2_supporting). -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Aug 25, 2020	This is a recurrent variant, reported in multiple individuals with Rett Syndrome (NBK1497, PMID: 10577905, PMID: 10854091, PMID: 12111643, PMID: 17089071, PMID: 27354166 and others. Note: this variant has historically been described as V288X). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2018	Variant summary: MECP2 c.806delG (p.Gly269AlafsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.880C>T, p.Arg294X; c.1079C>A, p.Ser360X). The variant was absent in 177658 control chromosomes (gnomAD). c.806delG has been reported in the literature in numerous individuals affected with Rett Syndrome (Li_2007, Miltenberger-Miltenyi_2003), including one family in which the variant segregated with disease (Wan_1999). Additionally, one male mutation carrier was affected with encephalopathy (Leuzzi_2004). At least one publication reports experimental evidence evaluating an impact on protein function which shows this truncation variant disrupts MECP2 protein activity (Yusufzai_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frame shift (c.842del) variant has been reported as a de novo occurrence and in at least 2 individuals with Rett syndrome (Zahorakova et. al., 2016; De et. al., 2000). Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000). The p.Gly281AlafsTer20 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing.(Le et. al., 2018). The observed variant is found to be present in last exon. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 15, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 09, 2017	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 21, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2021	Reported multiple times in association with Rett syndrome in females and neonatal progressive encephalopathy in males (Wan et al., 1999; Moog et al, 2003; Kankirawatana et al., 2006; Le et al., 2018); Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 31216405, 30081849, 31095231, 30945278, 30536762, 29655203, 30405208, 10577905, 16832102, 15557528, 22497713, 11058114, 12615169) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	May 04, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change creates a premature translational stop signal (p.Gly269Alafs*20) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 218 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 individuals with Rett syndrome and childhood-onset mitochondrial respiratory complex deficiency (PMID: 1057790, 10854091, 12111643, 16473305, 17089071, 26741492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 95202). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 17, 2019

The MECP2 c.806delG; p.Gly269fs variant (rs61750241) has been reported in multiple individuals affected with Rett syndrome (De Bona 2000, Pan 2002, Philippe 2006). It has also been reported in an individual with childhood-onset mitochondrial respiratory complex deficiency but not in either parent, suggesting a de novo origin in this individual (Kohda 2016). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 95202), and it is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single nucleotide, resulting in a frameshift and a premature termination codon in the last exon of the MECP2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated MECP2 protein. Functional analysis of the truncated variant protein indicates an inability to repress transcription through its transcriptional repression domain (Yusufzai 2000). Based on available information, this variant is considered pathogenic. References: De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000 May;8(5):325-30. Kohda M et al. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. Pan H et al. MECP2 gene mutation analysis in Chinese patients with Rett syndrome. Eur J Hum Genet. 2002 Aug;10(8):484-6. Philippe C et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb;49(1):9-18. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -

Syndromic X-linked intellectual disability Lubs type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 22, 2023

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2020

The c.806delG (p.G269Afs*20) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a deletion of one nucleotide at position 806, causing a translational frameshift with a predicted alternate stop codon after 20 amino acids. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts ~40% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). The c.806delG (p.G269Afs*20) alteration has been identified previously in a woman with motor coordination difficulties, mild learning disability, and skewed X chromosome inactivation, as well as her sister and daughter who were affected with classic Rett syndrome, and her son who died from congenital encephalopathy (Wan, 1999). De novo c.806delG (p.G269Afs*20) alterations have also been identified in two male patients with progressive encephalopathy characterized by neonatal onset severe hypotonia, apneic episodes, respiratory failure, and microcephaly; one boy additionally had a movement disorder characterized by irregular brief jerks (Leuzzi, 2004; Kankirawatana, 2006). One patient died at 36 months of age (Leuzzi, 2004), and the other patient died at 27 months of age (Kankirawatana, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 19, 2019

ACMG classification criteria: PVS1, PS3, PS4, PM2, PP1 -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Dec 08, 2021

MECP2 NM_004992.3 exon 4 p.Gly269Alafs*20 (c.806delG): This variant has been reported in the literature in several individuals (both male and female) with a clinical diagnosis or features of Rett syndrome, segregating with disease in 3 affected family members and identified as likely de novo in at least 3 individuals (Wan 1999 PMID:10577905, De Bona 2000 PMID:10854091, Pan 2002 PMID:12111643, Leuzzi 2004 PMID:15557528, Philippe 2006 PMID:16473305, Falsaperla 2012 PMID:22497713). This variant has also been identified in 1 individual with childhood onset mitochondrial respiratory chain complex deficiency as de novo (Kohda 2016 PMID:26741492). This variant is not present in large control databases. This variant is present in ClinVar with several labs classifying this variant as pathogenic (Variation ID:95202). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Functional studies support a deleterious effect of this variant, specifically the inability to repress transcription (Yusufzai 2000 PMID:11058114). This variant is a deletion of 1 nucleotide at position 806 which results in a premature stop codon 20 amino acids downstream from this location and is predicted to result in a truncated, abnormal protein. This variant occurs in exon 4 which is the last exon of this gene; due to its position it is possible that this protein may escape nonsense mediated decay, but will still result in a truncated protein. Loss of function has been established as a mechanism of disease for this gene; in addition, the vast majority of pathogenic variants in this gene are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic. -

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

Pathogenic, no assertion criteria provided

curation

RettBASE

Jun 12, 2013

- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61750241; hg19: chrX-153296472;