rs61750240

chrX-154031020-G-AchrX-154031020-G-C

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.844C>T(p.Arg282Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R282R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:44 O:1
• Conservation: PhyloP100: 2.94

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 149 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031020-G-A is Pathogenic according to our data. Variant chrX-154031020-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031020-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.844C>T	p.Arg282Ter	stop_gained	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.808C>T	p.Arg270Ter	stop_gained	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.844C>T	p.Arg282Ter	stop_gained	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.808C>T	p.Arg270Ter	stop_gained	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:44 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:23 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 31, 2023	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop_gained (c.844C>T) variant is most commonly reported in heterozygous state in patients affected with Rett syndrome (Moog, U. et. al., 2003; Laccone F et. al., 2001) but has also been reported in individuals with atypical Rett syndrome (RettBASE). This variant is clearly defined as a Rett syndrome causative allele that accounts for ~7% of disease-causing variants (Percy A.K. et. al., 2007; Philippe C. et. al., 2006) and has been shown to arise de novo in individuals affected with Rett syndrome (Laccone F et. al., 2001). Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	May 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2018	The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic male with clinical feature s of Rett syndrome (Cheadle et al. 2000, Topcu et al. 2002, Temudo et al. 2007, Knight et al. 2013, Maortua et al. 2013, Cuddapah et al. 2014, Pidcock et al. 20 16) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 270. This alteration occurs within th e last exon and is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yu sufzai and Wollfe 2000, Delepine et al. 2013). In summary, this variant meets cr iteria to be classified as pathogenic for Rett syndrome in an X-linked manner ba sed upon case counts, de novo occurrence, absence from controls, predicted impac t on protein and functional evidence. ACMG/AMP Criteria applied: PS4, PS2, PM6_S , PM2, PVS1_Strong, PS3_Moderate. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Oct 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 30, 2023	- -
Pathogenic, no assertion criteria provided	research	Pediatric Department, Xiangya Hospital, Central South University	-	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome (MIM#312750). (I) 0110 - This gene is known to be predominantly associated with X-linked dominant disease. However, X-linked recessive disease has also been reported. In addition, both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein [(premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Rett syndrome (ClinVar, RettBASE, VCGS). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.808C>T;p.(Arg270*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11058114; 23238081) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11815; PMID: 18174548; PMID: 16473305; PMID: 23270700; PMID: 10854091; PMID: 17089071) - PS4. This variant is not present in population databases (rs61750240- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 11241840) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in one patient with autism [PMID 28831199] and multiple patients in Baylor Genetics with neurodevelopmental phenotypes -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region.. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011815, PMID:10767337). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Sep 25, 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 Specifications 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 assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). (ClinVar Accession: SCV002768332.1 , PMID 10854091, PMID 10854091). 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2016	Variant summary: The MECP2 c.808C>T (p.Arg270X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 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 (e.g. p.Arg294X, p.Ser360X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant lies in the transcription repression domain (TRD) and one of the major functions of MECP2 is repression of transcription mediated by its TRD. Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression. Additionally, this variant is a known common pathogenic variant that has been reported in numerous classic Rett Syndrome patients in the literature and has been classified by multiple clinical labs and databases as pathogenic. This variant was found in 1/86029 control chromosomes at a frequency of 0.0000116. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 11, 2008	- -

not provided Pathogenic:13

Pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	Jan 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Nov 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MECP2: PVS1, PS2, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 08, 2018	The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic 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. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 03, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 30, 2017	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2

Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change creates a premature translational stop signal (p.Arg270*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 217 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: 10854091, 11241840, 16473305, 17089071, 18174548, 23270700; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11815). 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, 23238081). 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

Institute of Human Genetics, University of Leipzig Medical Center

Feb 19, 2021

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2017

The p.R270* pathogenic mutation (also known as c.808C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 808. This changes the amino acid from an arginine to a stop codon within coding exon 3. This common recurrent MECP2 mutation is located in the TRD-NLS (transcription repression domain-nuclear localization signal) region and has been shown to cause a more severe phenotype compared to other MECP2 mutations (Cardoza B et al. Seizure, 2011 Oct;20:646-9; Kifayathullah LA et al. Cytogenet Genome Res. 2010;129(4):290-297). In addition, this mutation has been reported in both males (several with XXY karyotypes) and females with classic Rett syndrome (Reichow B et al. J Autism Dev Disord, 2015 Oct;45:3377-83; De Bona Cet al. Eur J Hum Genet. 2000;8(5):325-330; Cheadle JP et al. Hum Mol Genet. 2000;9(7):1119-1129). Another study found that this mutation is unable to repress transcription, a major function of MeCP2 protein (Yusufzai TM et al. Nucleic Acids Res. 2000;28(21):4172-4179). 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. -

Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 12, 2014

- -

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

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 30, 2020

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

MECP2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 24, 2022

The MECP2 c.844C>T p.(Arg282Ter) nonsense variant, also known as c.808C>T p.(Arg270Ter), occurs in the last exon of the gene, and the resulting transcript may escape nonsense-mediated mRNA decay. However, the premature truncation, which occurs in the transcriptional repression domain, has also been shown to disrupt a conserved AT-hook domain that functions in DNA binding (Baker et al. 2013). This variant has been identified in individuals with a phenotype consistent with Rett syndrome or other MECP2-related disorder, including in some individuals in whom the variant occurred de novo (Laccone et al. 2001; Philippe et al. 2006; Yan et al. 2019; Liu et al. 2020; Martinez-Granero et al. 2021). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013). Transgenic mice expressing the variant in the absence of wildtype MECP2 recapitulated features of the clinical phenotype observed in human patients, including reduced lifespan, brain atrophy, and neurological signs (Baker et al. 2013). Based on the available evidence, the c.844C>T p.(Arg282Ter) variant is classified as pathogenic for MECP2-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.96
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61750240; hg19: chrX-153296471; COSMIC: COSV57657683; COSMIC: COSV57657683;