rs61751362
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PM2_SupportingPP5_Very_Strong
The NM_001110792(MECP2):c.916C>T(p.Arg306Ter) 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. R306R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
MECP2
NM_001110792 stop_gained
NM_001110792 stop_gained
Scores
3
3
3
Clinical Significance
Conservation
PhyloP100: 3.16
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 119 pathogenic variants in the truncated region.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 23.
PP5
?
Variant X:154030948-G>A is Pathogenic according to our data. Variant chrX-154030948-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11819. Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030948-G-A is described in Lovd as [Pathogenic]. Variant chrX-154030948-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.916C>T | p.Arg306Ter | stop_gained | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.880C>T | p.Arg294Ter | stop_gained | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.916C>T | p.Arg306Ter | stop_gained | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.880C>T | p.Arg294Ter | stop_gained | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomesCov.: 23
GnomAD3 genomes
Cov.:
23
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:36Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:19
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 | DASA | Jan 05, 2022 | The c.880C>T;p.(Arg294*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 11819; PMID: 31535341; 28465761; 26800272; 23270700; 16473305; 18332345; 11241840; 15737703; 19722030; 29046627) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history(PMID: 23810759) - PS2. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11058114; 26604147) - PS3_moderate. This variant is not present in population databases (rs61751362, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Mar 26, 2021 | The p.Arg294* 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). The p.Arg294* variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (internal database, GeneDx) (PS2_very strong). The p.Arg294* variant in MECP2 has been observed in at least 5 other individuals with Rett syndrome (PMID: 15737703, 11960578, 19722030, 21982064, RettBASE) (PS4). A transcription assay performed in Xenopus oocytes has shown that this variant impacts protein function (PMID 11058114) (PS3_supporting). The p.Arg294* variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg294* variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting). - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 16, 2020 | ACMG codes:PVS1,PS3,PS4,PM2,PP5 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 11, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jul 12, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is 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 observed in multiple (>3) similarly affected unrelated individuals (PMID: 11960578, 15737703, 19722030, 21982064). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 11241840). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011819/ PMID: 10767337/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 31, 2017 | Variant summary: The MECP2 c.880C>T (p.Arg294X) 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.c.1079C>A/p.Ser360X)). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87847 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional study proved mutant protein R294X with loss of function (Yusufzai_ 2000). Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 03, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 28, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Center for Human Genetics, University of Leuven | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine | - | The stop gained p.R294* in MECP2 (NM_004992.3) has been reported multiple times in females affected with Rett syndrome and is also present in the Rett database (Boban et al; Wen Z et al). It has shown to promote apoptosis of identified neurons in vivo (Williams A et al). It has been submitted to the ClinVar database as Pathogenic. The p.R294* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with global delays and hypotonia - |
Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Jan 19, 2015 | - - |
Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
not provided Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Karolinska University Hospital, Karolinska University Hospital | Feb 07, 2019 | - - |
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 | PerkinElmer Genomics | Aug 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 16, 2018 | The MECP2 c.880C>T; p.Arg294Ter variant (rs61751362) is reported in the medical literature in individuals with classical Rett syndrome and atypical Rett syndrome (see link to RettBASE below and references therein, Cheadle 2000, Pidcock 2016, Wen 2017, Wang 2016). Additionally, the variant protein is reported to have lowered expression, to have slightly reduced stability, and to be unable to repress transcription (Wen 2017, Yusufzai 2000). The variant is reported in the ClinVar database (Variation ID: 11819). This variant 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 induces an early termination codon and is predicted to result in a truncated protein. Considering available information, this variant is classified as pathogenic. References: Link to RettBase variants: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle JP 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 Apr 12;9(7):1119-29. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wen Z et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism. 2017 Aug 3;8:43. Wang T et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun. 2016 Nov 8;7:13316. Yusufzai TM and Wolffe AP. 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 | GeneDx | Feb 26, 2021 | Common recurrent variant that accounts for approximately 7% of MECP2 pathogenic variants (Percy et al., 2007); Observed in females with both classic and atypical Rett syndrome, often associated with a milder clinical presentation, and has been identified in a male with progressive microcephaly, developmental regression, and a movement disorder (RettBASE; Neul et al., 2008; Lundvall et al., 2006); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 193 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); Functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it is defective in promoting nucleosome-nucleosome bridging (Yusufzai et al., 2000; Nikitina et al., 2007); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11058114, 26604147, 10991688, 17660293, 23270700, 27159028, 27824329, 10767337, 27255190, 29321033, 28785396, 29421650, 29595472, 29056246, 16077729, 26175308, 17420824, 11738864, 18337588, 17236109, 18174548, 30693677, 30564305, 30536762, 31209962, 31535341, 32105570, 32472557, 32005694, 33994118, 12030010, 31130284, 31031587) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 19, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics Inc | Mar 28, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
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:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | This variant has been reported in the literature in numerous individuals with Rett syndrome, including males, and as de novo in at least 1 individual with autism spectrum disorder (ASD) (Selected publications: Cheadler 2000 PMID:10767337, Yamashita 2001 PMID:11738864, Jian 2005 PMID:16077729, Lundvall 2006 PMID:17236109, Stachon 2007 PMID:17420824, Wen 2017 PMID:28785396). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:11819). Functional studies support that this variant will impact the protein, suggesting repression of transcription and instability (Yusufzai 2000 PMID:11058114). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or abnormal protein. Of note, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. However, the vast majority of pathogenic variants in this gene (including this variant) are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. Loss of function has been established for this gene, but missense variants have been described as pathogenic as well (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 21, 2022 | - - |
Autism, susceptibility to, X-linked 3 Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
risk factor, no assertion criteria provided | literature only | OMIM | Mar 11, 2008 | - - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change creates a premature translational stop signal (p.Arg294*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 193 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 (PMID: 11241840, 15737703, 16473305, 17236109, 18332345, 19722030, 23270700). ClinVar contains an entry for this variant (Variation ID: 11819). 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, 26604147, 27442528, 28785396). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
MECP2-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is also known as c.880C>T (p.Arg294Ter) due to use of an alternate transcript. This nonsense variant found in exon 4 of 4 is predicted to result in truncation of the MeCP2 protein. This variant has been previously reported in individuals with MECP2-related disorders (PMID:16473305, 11241840, 15737703, 19722030, 11960578, 21982064). Functional studies have shown that the c.916C>T (p.Arg306Ter) variant destabilizes the MeCP2 protein and expression of the truncated protein in-vitro results in increased apoptosis levels (PMID: 11058114, 27442528, 28785396). The c.916C>T (p.Arg306Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.916C>T (p.Arg306Ter) variant is classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2021 | The c.880C>T (p.R294*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position 880. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 294. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 38% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in many females with classic Rett syndrome. In addition, several studies show that this pathogenic variant is associated with a milder phenotype including, but not limited to: a later age at diagnosis (5-6 years of age), delayed onset of regression, later onset of stereotypical behaviors, more retention of words and hand function, and ambulatory ability (Cheadle, 2000; Fieremans, 2016; Pidcock, 2016; Wen, 2017; Colvin, 2004; Fehr, 2010). The p.R294* amino acid is located within the transcription repression domain, which normally binds methylated DNA in the context of chromatin, leading to long-term transcriptional repression (Hite, 2009). Functional analysis demonstrated that the p.R294* alteration retains DNA binding capabilities at levels comparable to those of the wild-type protein, but failed to repress DNA transcription (Yusufzai, 2000). Based on the available evidence, this alteration is classified as pathogenic. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Apr 26, 2021 | PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Uncertain
D
MutationTaster
Benign
A;A
Sift4G
Pathogenic
D
Vest4
MVP
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Find out SpliceAI and Pangolin per-transcript scores at