rs61748421

chrX-154031326-G-AchrX-154031326-G-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.538C>T(p.Arg180Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R180R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:43 O:1
• Conservation: PhyloP100: 2.57

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 218 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031326-G-A is Pathogenic according to our data. Variant chrX-154031326-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031326-G-A is described in Lovd as [Pathogenic]. Variant chrX-154031326-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.538C>T	p.Arg180Ter	stop_gained	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.502C>T	p.Arg168Ter	stop_gained	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.538C>T	p.Arg180Ter	stop_gained	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.502C>T	p.Arg168Ter	stop_gained	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:43 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:25 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Jun 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.538C>T(p.Arg180Ter) in MECP2 gene is a recurrent variant that has been reported in many individuals affected with Rett syndrome (Wan M et.al.,1999 ) . This variant has been reported to the ClinVar database as Pathogenic . The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. 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, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, 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). 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). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, criteria provided, single submitter	research	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 17, 2021	A mosaic hemizygous (somatic mosaicism) nonsense variation in exon 3 of the MECP2 gene that results in premature truncation of the Arginine at codon 180. The observed variant c.538C>T(p.Arg180Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2(HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo (post-zygotic, somatic). In summary, the variant meets our criteria to be classified as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 01, 2020	The MECP2 c.502C>T p.(Arg168Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with Rett syndrome, and is one of the most common pathogenic variants associated with the disorder (Kaur et al. 2001; Knight et al. 2013; Cudappah et al. 2014). In the majority of individuals, the variant was identified in a de novo state (Girard et al. 2001; Gu et al. 2000). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Arg168 residue lies in the linker region between the methyl-CpG-binding domain and the transcriptional repressor domain (TRD), and truncation at this residue will abolish the TRD. Functional studies found that when the p.(Arg168Ter) variant MECP2 protein was expressed in Xenopus oocytes, the variant protein failed to repress transcription in contrast to the wild-type protein (Yusufzai and Wolffe 2000). In addition, mice expressing the variant showed several features associated with Rett syndrome, including underweight and motor deficits (Schaevitz et al. 2013). Based on the collective evidence the c.502C>T p.(Arg168Ter) variant is classified as pathogenic for Rett syndrome. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2016	Variant summary: The MECP2 c.502C>T (p.Arg168X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate the transcriptional repression domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.710delG/p.Gly237fsX11). This variant is reported as one of the most common pathogenic variants in literature and clinical databases. The available clinical data and functional studies are consistent with pathogenic outcome for the variant. This variant is absent in 87628 control chromosomes. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. 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	Jul 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jan 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Feb 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PVS1, PS3, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011828.27). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 08, 2023	Criteria applied: PVS1,PS2_VSTR,PS4,PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 25, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 17, 2019	- -

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	May 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	Recurrent pathogenic variant that accounts for 8-9% of MECP2 pathogenic variants (Percy et al., 2007); Typically associated with classic Rett syndrome but also identified in females with atypical Rett syndrome (Halbach et al., 2012; Neul et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 319 amino acids are lost, and other loss-of-function variants have been reported downstream (Stenson et al., 2014; RettBASE); Published functional studies indicate this variant truncates all of the transcriptional repression domain (TRD) and impairs normal protein function (Yusufzai et al., 2000; Bissonnette et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26175308, 24626160, 10577905, 24283265, 23270700, 24511209, 23238081, 25541993, 18337588, 22190343, 15228575, 28394409, 16077729, 28333917, 18174548, 30564305, 29655203, 31164858, 31209962, 31144778, 31535341, 32393352, 32631363, 11058114, 33144682, 12030010, 31130284, 33258288) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2020	The MECP2 c.502C>T; p.Arg168Ter variant (rs61748421) is one of the most common variants identified in individuals with Rett syndrome (see link, Pidcock 2016, Wan 1999), and is shown to have impaired functional capabilities (Bissonnette 2014, Delepine 2013, Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11828). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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 Link to RettBASE database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Bissonnette JM et al. Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X. Neuroscience. 2014 May 16;267:166-76. Delepine C et al. MeCP2 deficiency is associated with impaired microtubule stability. FEBS Lett. 2013 Jan 16;587(2):245-53. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wan M et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec;65(6):1520-9. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2018	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

This sequence change creates a premature translational stop signal (p.Arg168*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 319 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: 10577905, 23270700, 24511209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11828). 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, 24283265, 24626160, 25541993). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Syndromic X-linked intellectual disability Lubs type Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.502C>T (p.R168*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position 502. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 168. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 65.4% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a common, recurrent pathogenic variant for Rett syndrome and has been associated with earlier onset and more severe symptoms than other Rett syndrome alterations; however, it has also been detected in unaffected females (Wan, 1999; Cuddapah, 2014; Kaur, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Global developmental delay;C1836830:Developmental regression Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Jul 25, 2014

- -

MECP2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2023

The MECP2 c.502C>T variant is predicted to result in premature protein termination (p.Arg168*). This nonsense variant has been documented in several individuals with Rett syndrome (see for example Wan et al. 1999. PubMed ID: 10577905; Archer et al. 2006. PubMed ID: 16183801; Philippe et al. 2006. PubMed ID: 16473305; Percy et al. 2007. PubMed ID: 18174548). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.49	T
MetaRNN	Uncertain	0.50	D
MutationTaster	Benign	1.0	A;A;A
Sift4G	Uncertain	0.0080	D
Vest4		0.47
MVP		0.94
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61748421; hg19: chrX-153296777; COSMIC: COSV100318642; COSMIC: COSV100318642;