rs61751362
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS3_SupportingPVS1PS2PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA121700/MONDO:0010726/016
Frequency
Consequence
NM_001110792.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MECP2 | NM_001110792.2 | c.916C>T | p.Arg306* | stop_gained | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.880C>T | p.Arg294* | stop_gained | Exon 4 of 4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MECP2 | ENST00000453960.7 | c.916C>T | p.Arg306* | stop_gained | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.880C>T | p.Arg294* | stop_gained | Exon 4 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:22
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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 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). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). -
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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. -
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Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene, where both protein instability and increased cell death have been demonstrated (OMIM, PMID: 27442528). (N) 0104 - Mechanism of disease for this gene is dominant negative. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 4 of 4). (P) 0301 - Variant is absent from gnomAD. (P) 0601 - Variant affects at the well established (essential) functional C-terminal region (PMID: 27442528). (P) 0701 - Comparable variants also predicted to result in a truncated protein, have very strong previous evidence for pathogenicity in patients with Rett syndrome (Decipher, ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in multiple de novo individuals with Rett syndrome (Decipher, ClinVar). (P) 0905 - No published segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function, where both animal models and transfected cell lines demonstrated increased cell death (PMID: 27442528). (P) 1204 - De Novo Variant (Parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
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ClinGen VCEP: PVS1, PS2_very strong, PS4, PS3_supporting, PM2_supporting -
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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. -
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 -
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. -
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ACMG codes:PVS1,PS3,PS4,PM2,PP5 -
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000620373 /PMID: 32746448). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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). -
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not provided Pathogenic:12
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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. -
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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) -
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This variant causes the premature termination of MECP2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with Rett syndrome (PMID: 11241840 (2001), 23270700 (2013), 31535341 (2020)). In addition, a functional study reported this variant resulted in a damaging effect on protein function (PMID: 11058114 (2000)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
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PM2, PS2_very_strong, PS4, PVS1 -
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MECP2-related disorder Pathogenic:3
The MECP2 c.880C>T variant is predicted to result in premature protein termination (p.Arg294*). This variant has been reported in individuals with Rett syndrome (Milunsky et al. 2001. PubMed ID: 11960578; Fukuda et al. 2005. PubMed ID: 15737703; LIMA et al. 2009. PubMed ID: 19722030; Psoni et al. 2012. PubMed ID: 21982064). Of note, this variant has also been reported in individuals with atypical Rett syndrome and has been associated with a slightly milder form of disease (Fukuda et al. 2005. PubMed ID: 15737703; Psoni et al. 2012. PubMed ID: 21982064). A transcription assay performed in Xenopus oocytes showed that this variant altered protein function (Yusufzai et al. 2000. PubMed ID: 11058114). 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. -
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. -
The variant NM_004992.4:c.880C>T (p.Arg306)* introduces a premature stop codon at codon 306, likely resulting in a truncated protein or nonsense-mediated decay (NMD). Based on ACMG/AMP guidelines, this variant meets the criteria for PS4, PS3, PS2, PVS1, PM2, and PP5, supporting its classification as pathogenic. These criteria reflect the loss-of-function effect of the variant, as well as additional evidence from functional studies and computational predictions suggesting a damaging effect on the protein. -
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
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. -
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Autism, susceptibility to, X-linked 3 Pathogenic:1Other:1
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Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
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 gene product 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (internal data). 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. -
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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
PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at