Menu
GeneBe

rs61750240

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PM2_SupportingPP5_Very_Strong

The NM_001110792(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 Genomes 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 stop_gained

Scores

2
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:37O:1

Conservation

PhyloP100: 2.94

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 132 pathogenic variants in the truncated region.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 22.
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
MECP2NM_001110792.2 linkuse as main transcriptc.844C>T p.Arg282Ter stop_gained 3/3 ENST00000453960.7
MECP2NM_004992.4 linkuse as main transcriptc.808C>T p.Arg270Ter stop_gained 4/4 ENST00000303391.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.844C>T p.Arg282Ter stop_gained 3/31 NM_001110792.2 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.808C>T p.Arg270Ter stop_gained 4/41 NM_004992.4 P1P51608-1

Frequencies

GnomAD3 genomes
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:37Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rett syndrome Pathogenic:18Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 11, 2008- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversitySep 15, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Children's Mercy Hospital and Clinics-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanyMay 02, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 12, 2018The 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 providedcurationRettBASEDec 05, 2013- -
not provided, no assertion providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testing3billionMar 22, 2022Stop-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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 31, 2023_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP, PP4 -
Pathogenic, criteria provided, single submitterclinical testingDASAMar 05, 2022The 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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn-- -
Pathogenic, no assertion criteria providedresearchPediatric Department, Xiangya Hospital, Central South University-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Klinikum rechts der IsarJan 04, 2018- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 30, 2016Variant 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, no assertion criteria providedclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsOct 03, 2016- -
Pathogenic, no assertion criteria providedclinical testingClinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Apr 01, 2023- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 31, 2018This 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 -
not provided Pathogenic:12
Pathogenic, no assertion criteria providedclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaApr 03, 2015- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022Criteria applied: PVS1, PS2, PM2 -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesNov 21, 2016- -
Pathogenic, criteria provided, single submitterclinical testingPerkinElmer GenomicsOct 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 10, 2013- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Karolinska University Hospital, Karolinska University HospitalJan 30, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 19, 2021Nonsense 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, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 08, 2018The 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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 17, 2015- -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2
Pathogenic, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 01, 2022This 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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 19, 2021- -
Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 12, 2014- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2016- -
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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Autism, susceptibility to, X-linked 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 30, 2020This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
37
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

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: rs61750240; hg19: chrX-153296471; COSMIC: COSV57657683; COSMIC: COSV57657683;