Submissions for variant NM_001110792.2(MECP2):c.916C>T (p.Arg306Ter)

dbSNP: rs61751362

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000012590	SCV001711975	pathogenic	Rett syndrome	2021-03-26	reviewed by expert panel	curation	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).
GeneDx	RCV000081215	SCV000191049	pathogenic	not provided	2021-02-26	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000081215	SCV000230269	pathogenic	not provided	2013-11-19	criteria provided, single submitter	clinical testing
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000012590	SCV000236516	pathogenic	Rett syndrome	2015-01-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000012590	SCV000248001	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000012590	SCV000268070	likely pathogenic	Rett syndrome	2015-01-01	criteria provided, single submitter	literature only
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000012590	SCV000537183	pathogenic	Rett syndrome	2015-07-12	criteria provided, single submitter	clinical testing
Invitae	RCV000474366	SCV000544614	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-01-31	criteria provided, single submitter	clinical testing	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). 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 (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.
Fulgent Genetics, Fulgent Genetics	RCV000515413	SCV000611280	pathogenic	Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome; Autism, susceptibility to, X-linked 3	2022-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012590	SCV000698546	pathogenic	Rett syndrome	2017-01-31	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000624805	SCV000741622	pathogenic	Inborn genetic diseases	2021-10-05	criteria provided, single submitter	clinical testing	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000012590	SCV000781713	pathogenic	Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012590	SCV000807253	pathogenic	Rett syndrome	2017-09-01	criteria provided, single submitter	clinical testing	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
Athena Diagnostics Inc	RCV000081215	SCV000842739	pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000081215	SCV000885678	pathogenic	not provided	2018-03-16	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012590	SCV001428755	pathogenic	Rett syndrome	2019-12-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000081215	SCV001446766	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000081215	SCV001449947	pathogenic	not provided	2019-02-07	criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420261	SCV001622681	pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate
Suma Genomics	RCV000012590	SCV001837641	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000012590	SCV001870338	pathogenic	Rett syndrome	2020-12-16	criteria provided, single submitter	research	ACMG codes:PVS1,PS3,PS4,PM2,PP5
DASA	RCV000012590	SCV002061284	pathogenic	Rett syndrome	2022-01-05	criteria provided, single submitter	clinical testing	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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000012590	SCV002073116	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	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.
3billion	RCV000012590	SCV002573202	pathogenic	Rett syndrome	2022-09-01	criteria provided, single submitter	clinical testing	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.
MGZ Medical Genetics Center	RCV000012590	SCV002579312	pathogenic	Rett syndrome	2021-07-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000081215	SCV003823546	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515413	SCV003920186	pathogenic	Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome; Autism, susceptibility to, X-linked 3	2021-03-30	criteria provided, single submitter	clinical testing	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335027	SCV004046412	pathogenic	MECP2-Related Disorders		criteria provided, single submitter	clinical testing	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.
Centre for Population Genomics, CPG	RCV000012590	SCV004098855	pathogenic	Rett syndrome	2023-08-14	criteria provided, single submitter	curation	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000081215	SCV004220019	pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003984806	SCV004801241	pathogenic	Syndromic X-linked intellectual disability Lubs type	2024-03-14	criteria provided, single submitter	research
OMIM	RCV000012590	SCV000032825	pathogenic	Rett syndrome	2008-03-11	no assertion criteria provided	literature only
OMIM	RCV000012591	SCV000032826	risk factor	Autism, susceptibility to, X-linked 3	2008-03-11	no assertion criteria provided	literature only
RettBASE	RCV000012591	SCV000188271	pathogenic	Autism, susceptibility to, X-linked 3	2013-12-05	no assertion criteria provided	curation
RettBASE	RCV000012590	SCV000222441	pathogenic	Rett syndrome	2013-12-05	no assertion criteria provided	curation
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000012590	SCV001133059	pathogenic	Rett syndrome	2019-09-26	no assertion criteria provided	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000012590	SCV001427578	pathogenic	Rett syndrome	2019-01-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000081215	SCV001744886	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000081215	SCV001929887	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081215	SCV001951861	pathogenic	not provided		no assertion criteria provided	clinical testing