Submissions for variant NM_001110792.2(MECP2):c.842del (p.Gly281fs)

dbSNP: rs61750241

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000168691	SCV001711986	pathogenic	Rett syndrome	2021-03-09	reviewed by expert panel	curation	The p.Gly269Alafs*20 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). This variant has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Rett syndrome (PMID 26984561, 10854091) (PS2_VS). The p.Gly269Alafs*20 variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Gly269Alafs*20 variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PS2_VS, PM2_supporting).
GeneDx	RCV000081211	SCV000190966	pathogenic	not provided	2021-07-26	criteria provided, single submitter	clinical testing	Reported multiple times in association with Rett syndrome in females and neonatal progressive encephalopathy in males (Wan et al., 1999; Moog et al, 2003; Kankirawatana et al., 2006; Le et al., 2018); Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31216405, 30081849, 31095231, 30945278, 30536762, 29655203, 30405208, 10577905, 16832102, 15557528, 22497713, 11058114, 12615169)
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000168691	SCV000223843	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000081211	SCV000230256	pathogenic	not provided	2013-11-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168691	SCV000247997	pathogenic	Rett syndrome	2013-11-15	criteria provided, single submitter	clinical testing
Invitae	RCV000169939	SCV000544619	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly269Alafs*20) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 218 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 and childhood-onset mitochondrial respiratory complex deficiency (PMID: 1057790, 10854091, 12111643, 16473305, 17089071, 26741492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 95202). 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). For these reasons, this variant has been classified as Pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000168691	SCV000680285	pathogenic	Rett syndrome	2017-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624370	SCV000740973	pathogenic	Inborn genetic diseases	2014-06-06	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000168691	SCV000781707	pathogenic	Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000081211	SCV000842737	pathogenic	not provided	2020-08-21	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Ambry Genetics	RCV000624370	SCV000846671	pathogenic	Inborn genetic diseases	2019-03-26	criteria provided, single submitter	clinical testing	The c.806delG pathogenic mutation, located in coding exon 3 of the MECP2 gene, results from a deletion of one nucleotide at nucleotide position 806, causing a translational frameshift with a predicted alternate stop codon (p.G269Afs*20). This mutation has been identified in multiple females with classic Rett syndrome and several males with neonatal progressive encephalopathy (Wan M et al. Am. J. Hum. Genet., 1999 Dec;65:1520-9; Cheadle JP et al. Hum. Mol. Genet., 2000 Apr;9:1119-29; De Bona C et al. Eur. J. Hum. Genet., 2000 May;8:325-30; Leuzzi V et al. Neurology, 2004 Nov;63:1968-70). Of note, this mutation has also been called c.803delG, c.880delG, and p.V288* in the literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000009	SCV000885679	pathogenic	not specified	2019-03-17	criteria provided, single submitter	clinical testing	The MECP2 c.806delG; p.Gly269fs variant (rs61750241) has been reported in multiple individuals affected with Rett syndrome (De Bona 2000, Pan 2002, Philippe 2006). It has also been reported in an individual with childhood-onset mitochondrial respiratory complex deficiency but not in either parent, suggesting a de novo origin in this individual (Kohda 2016). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 95202), and it 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 deletes a single nucleotide, resulting in a frameshift and a premature termination codon in the last exon of the MECP2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated MECP2 protein. Functional analysis of the truncated variant protein indicates an inability to repress transcription through its transcriptional repression domain (Yusufzai 2000). Based on available information, this variant is considered pathogenic. References: De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000 May;8(5):325-30. Kohda M et al. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. Pan H et al. MECP2 gene mutation analysis in Chinese patients with Rett syndrome. Eur J Hum Genet. 2002 Aug;10(8):484-6. Philippe C et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb;49(1):9-18. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168691	SCV000919617	pathogenic	Rett syndrome	2018-03-30	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.806delG (p.Gly269AlafsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.880C>T, p.Arg294X; c.1079C>A, p.Ser360X). The variant was absent in 177658 control chromosomes (gnomAD). c.806delG has been reported in the literature in numerous individuals affected with Rett Syndrome (Li_2007, Miltenberger-Miltenyi_2003), including one family in which the variant segregated with disease (Wan_1999). Additionally, one male mutation carrier was affected with encephalopathy (Leuzzi_2004). At least one publication reports experimental evidence evaluating an impact on protein function which shows this truncation variant disrupts MECP2 protein activity (Yusufzai_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000850572	SCV000992788	pathogenic	Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome	2017-12-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000081211	SCV001500678	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000081211	SCV001760578	pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251971	SCV002523392	pathogenic	See cases	2019-12-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS3, PS4, PM2, PP1
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000168691	SCV002525692	pathogenic	Rett syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This is a recurrent variant, reported in multiple individuals with Rett Syndrome (NBK1497, PMID: 10577905, PMID: 10854091, PMID: 12111643, PMID: 17089071, PMID: 27354166 and others. Note: this variant has historically been described as V288X).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000169939	SCV002559121	pathogenic	Severe neonatal-onset encephalopathy with microcephaly		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000168691	SCV002581580	pathogenic	Rett syndrome	2022-04-13	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227637	SCV003924220	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	2021-12-08	criteria provided, single submitter	clinical testing	MECP2 NM_004992.3 exon 4 p.Gly269Alafs*20 (c.806delG): This variant has been reported in the literature in several individuals (both male and female) with a clinical diagnosis or features of Rett syndrome, segregating with disease in 3 affected family members and identified as likely de novo in at least 3 individuals (Wan 1999 PMID:10577905, De Bona 2000 PMID:10854091, Pan 2002 PMID:12111643, Leuzzi 2004 PMID:15557528, Philippe 2006 PMID:16473305, Falsaperla 2012 PMID:22497713). This variant has also been identified in 1 individual with childhood onset mitochondrial respiratory chain complex deficiency as de novo (Kohda 2016 PMID:26741492). This variant is not present in large control databases. This variant is present in ClinVar with several labs classifying this variant as pathogenic (Variation ID:95202). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Functional studies support a deleterious effect of this variant, specifically the inability to repress transcription (Yusufzai 2000 PMID:11058114). This variant is a deletion of 1 nucleotide at position 806 which results in a premature stop codon 20 amino acids downstream from this location and is predicted to result in a truncated, abnormal protein. This variant occurs in exon 4 which is the last exon of this gene; due to its position it is possible that this protein may escape nonsense mediated decay, but will still result in a truncated protein. Loss of function has been established as a mechanism of disease for this gene; in addition, the vast majority of pathogenic variants in this gene are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic.
Baylor Genetics	RCV003333025	SCV004040645	pathogenic	Syndromic X-linked intellectual disability Lubs type	2023-04-22	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000168691	SCV004042687	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000168691	SCV004047986	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	The frame shift (c.842del) variant has been reported as a de novo occurrence and in at least 2 individuals with Rett syndrome (Zahorakova et. al., 2016; De et. al., 2000). Published functional studies demonstrate that this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai et al., 2000). The p.Gly281AlafsTer20 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing.(Le et. al., 2018). The observed variant is found to be present in last exon. For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG	RCV000168691	SCV004098850	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 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). This variant is absent from gnomAD (PM2_Supporting).
OMIM	RCV000168691	SCV000032817	pathogenic	Rett syndrome	2007-01-01	no assertion criteria provided	literature only
OMIM	RCV000169939	SCV000032818	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2007-01-01	no assertion criteria provided	literature only
RettBASE	RCV000169939	SCV000188244	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2013-06-12	no assertion criteria provided	curation
RettBASE	RCV000170113	SCV000222437	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2013-06-12	no assertion criteria provided	curation
RettBASE	RCV000168691	SCV000222438	pathogenic	Rett syndrome	2013-06-12	no assertion criteria provided	curation
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000168691	SCV000804883	pathogenic	Rett syndrome	2016-05-03	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000081211	SCV001742681	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081211	SCV001956202	pathogenic	not provided		no assertion criteria provided	clinical testing