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rs61748421

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 Genomes 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

Scores

2
4
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:42O:1

Conservation

PhyloP100: 2.57
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 201 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
MECP2NM_001110792.2 linkuse as main transcriptc.538C>T p.Arg180Ter stop_gained 3/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.502C>T p.Arg168Ter stop_gained 4/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.538C>T p.Arg180Ter stop_gained 3/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.502C>T p.Arg168Ter stop_gained 4/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:42Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:25Other:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 01, 2020The 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, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesDec 03, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 09, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLaboratoire de Génétique Moléculaire, CHU BordeauxFeb 02, 2022- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Medicine Lab, University of California San FranciscoFeb 14, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterDec 08, 2023Criteria applied: PVS1,PS2_VSTR,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMar 20, 2023- -
Pathogenic, criteria provided, single submittercurationCentre for Population Genomics, CPGAug 14, 2023This 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 submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyNov 12, 2015- -
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg 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, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenJul 15, 2020- -
Pathogenic, criteria provided, single submitterresearchFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsFeb 17, 2021A 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 22, 2016Variant 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 submitterclinical testingUndiagnosed Diseases Network, NIHJun 17, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital BonnJan 20, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 10, 2014- -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncJun 15, 2015- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 1999- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityNov 08, 2018- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized MedicineJun 10, 2020- -
Pathogenic, no assertion criteria providedcurationRettBASEJun 12, 2013- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensOct 01, 2021PVS1, PS3, PM1, PM2, PP3 -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalJun 25, 2007- -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021Stop-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. -
not provided Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 15, 2021Recurrent 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 providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 09, 2020The 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, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 08, 2018- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalDec 08, 2016- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 07, 2022- -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 03, 2024This 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 submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 14, 2024- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 08, 2018The p.R168* pathogenic mutation (also known as c.502C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 502. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation is one of eight common Rett syndrome mutations and has been associated with earlier onset and more severe symptoms than other mutations; however, it has also been detected in unaffected females (Wan M et al. Am. J. Hum. Genet., 1999 Dec;65:1520-9; Cuddapah VA et al. J. Med. Genet., 2014 Mar;51:152-8; Knight O et al. Brain Dev., 2013 Nov;35:912-20). In one study, in vitro and in vivo studies showed that this mutation alters expression of downstream genes, induces expansion of lateral neurons, and its mutant protein is able to bind to methylated DNA, suggesting that this mutation may function in a dominant negative manner (Neul JL et al. Neuroscientist, 2004 Apr;10:118-28). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Global developmental delay;C1836830:Developmental regression Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
MECP2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 08, 2023The 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. -
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingDiagnostic Laboratory, Strasbourg University HospitalJul 25, 2014- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61748421; hg19: chrX-153296777; COSMIC: COSV100318642; COSMIC: COSV100318642; API