Submissions for variant NM_001110792.2(MECP2):c.509C>T (p.Thr170Met)

dbSNP: rs28934906

Total submissions: 57

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000133129	SCV000191038	pathogenic	not provided	2021-07-30	criteria provided, single submitter	clinical testing	Recurrent missense substitution that accounts for 9-12% of MECP2 pathogenic variants and has been identified in females with both classic and atypical Rett syndrome (Percy et al., 2007; Neul et al., 2008; Bao et al., 2013; RettBASE); Also identified in males with severe neonatal-onset encephalopathy and in females who did not meet clinical criteria for Rett syndrome but had overlapping clinical features, including pervasive developmental disorder or clinical features suggestive of Angelman syndrome (Suter et al., 2014; Kleefstra et al., 2005; Villard et al., 2000); In vitro functional studies indicate that T158M impairs normal protein function (Yusufzai et al., 2000; Kudo et al., 2003; Agarwal et al., 2011; Lyst et al., 2013; Sheikh et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31031587, 12030010, 12843318, 21831886, 11071498, 28920956, 31535341, 31095231, 30945278, 30868116, 29655203, 30564305, 26175308, 28135719, 17236109, 17881312, 16077729, 25533962, 23921973, 12719401, 26418480, 26647311, 26795593, 23770565, 11058114, 10508514, 18337588, 18174548, 23421866, 14560307, 24511209, 23270700, 19442733, 19217433, 11738866, 11392517, 11738879, 10852707, 27929079)
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000012580	SCV000223837	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000012580	SCV000247971	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000012580	SCV000255791	pathogenic	Rett syndrome	2012-07-25	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000133129	SCV000280901	pathogenic	not provided	2015-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012580	SCV000282491	pathogenic	Rett syndrome	2015-09-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000133129	SCV000331102	pathogenic	not provided	2015-10-02	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000012580	SCV000537196	likely pathogenic	Rett syndrome	2015-07-17	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000012580	SCV000537706	pathogenic	Rett syndrome	2016-06-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000133129	SCV000604152	pathogenic	not provided	2023-10-14	criteria provided, single submitter	clinical testing	The MECP2 c.473C>T; p.Thr158Met variant (rs28934906), is reported in the literature in multiple individuals affected with classical Rett syndrome (see link to RettBASE and references therein). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11811), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 158 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr158Met variant is considered to be pathogenic. References: Link to RettBASE (http://mecp2.chw.edu.au/cgi-bin/mecp2/search/process-search.cgi)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000170110	SCV000645667	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 158 of the MECP2 protein (p.Thr158Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome and is considered one of the most common causes of the condition (PMID: 10508514, 18337588, 23421866, 26647311; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11811). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 10852707, 11058114, 11738866, 12843318, 21831886, 26647311). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000012580	SCV000781705	pathogenic	Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000012580	SCV000845272	pathogenic	Rett syndrome	2018-08-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623451	SCV000845943	pathogenic	Inborn genetic diseases	2020-10-07	criteria provided, single submitter	clinical testing	The c.473C>T (p.T158M) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 473, causing the threonine (T) at amino acid position 158 to be replaced by a methionine (M). Based on data from the Genome Aggregation Database (gnomAD), the MECP2 c.473C>T alteration was not observed, with coverage at this position. The MECP2 c.473C>T (p.T158M) alteration is one of the most common pathogenic variants in MECP2, occurring at a CpG hotspot (Amir, 1999). This alteration has been identified in female patients with both classical Rett syndrome as well as atypical Rett syndrome; more mildly affected individuals have also been described with this alteration (Amir, 1999; Buyse, 2000; Huppke, 2000; Auranen, 2001; Bao, 2013; Suter, 2014). Functional analysis demonstrated that the p.T158M alteration moderately affects MeCP2's ability to bind to methylated DNA and impair selectivity for methylated DNA (Ballestar, 2000; Yusufzai, 2000). The p.T158M alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763199	SCV000893818	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	2018-10-31	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000012580	SCV000999345	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000133129	SCV001246092	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MECP2: PS2, PM1, PM2, PM5, PS3:Moderate, PP3, PS4:Supporting
Blueprint Genetics	RCV000012580	SCV001426150	likely pathogenic	Rett syndrome	2018-03-09	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012580	SCV001428510	pathogenic	Rett syndrome	2018-08-21	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000133129	SCV001447435	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000133129	SCV001450313	pathogenic	not provided	2016-02-22	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000012580	SCV001478268	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012580	SCV001524903	pathogenic	Rett syndrome	2023-10-23	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813975	SCV001755524	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000133129	SCV002017249	pathogenic	not provided	2021-02-12	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000012580	SCV002073016	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	The missense variant p.T158M in MECP2 (NM_004992.3) has been reported in multiple patients with Rett syndrome (Das DK et al; Brown K et al).It is the most common mutation in the Rett database.Functional studies have shown a damaging effect (Agarwal N et al). The variant has been submitted to ClinVar as Pathogenic. The p.T158M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T158M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 158 of MECP2 is conserved in all mammalian species. The nucleotide c.473 in MECP2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000012580	SCV002318550	pathogenic	Rett syndrome	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011811, PMID:10508514). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143590, PMID:11269512). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.945>=0.6, 3CNET: 0.995>=0.75). 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.
Mendelics	RCV002247328	SCV002517600	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273926	SCV002559000	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000012580	SCV003845196	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.473C>T in Exon 4 of the MECP2 gene that results in the amino acid substitution p.Thr158Met was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 11811]. This variant has previously been reported for Rett syndrome by Lee, Stephen Sung Jae, Mimi Wan, and Uta Francke., 2001. Experimental studies have shown that this missense change affects MECP2 protein function by Ballestar, Esteban, Timur M. Yusufzai, and Alan P. Wolffe., 2000. For these reasons this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000763199	SCV003920187	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	MECP2 NM_004992.3 exon 4 p.Thr158Met (c.473C>T): This variant is one of the most common mutations associated with Rett syndrome, identified in several individuals (n>100) including males, with Rett syndrome. This variant has been identified to segregate with disease and has also been reported to occur as de novo (Selected publications: Amir 1999 PMID: 10508514, Villard 2000 PMID:11071498, Neul 2008 PMID:18337588, Bao 2013 PMID:23421866, RettBASE http://mecp2.chw.edu.au/). This variant is not present in large control databases. This variant is present in ClinVar, with multiple labs classifying this variant as pathogenic (Variation ID:11811). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, in vivo functional studies support a deleterious effect of this variant, suggesting impaired binding stability and selectivity for methylated DNA (Yusufzai 2000 PMID:11058114, Bao 2013 PMID:23421866). Furthermore, this variant occurs in exon 4; the vast majority of pathogenic variants 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 16473305). In summary, this variant is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003984805	SCV004801243	pathogenic	Syndromic X-linked intellectual disability Lubs type	2024-03-14	criteria provided, single submitter	research
Centre for Population Genomics, CPG	RCV000012580	SCV004808964	pathogenic	Rett syndrome	2024-02-28	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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). PMID: 16225173 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 16473305 Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
Illumina Laboratory Services, Illumina	RCV004540995	SCV004814138	pathogenic	MECP2-related disorder	2021-12-21	criteria provided, single submitter	clinical testing	The MECP2 c.509C>T p.(Thr170Met) missense variant, also known as c.473C>T p.(Thr158Met), has been identified in individuals with a phenotype consistent with MECP2-related disorders and is reported as one of the most commonly occurring variants in affected individuals (Aron et al. 2019; Xiong et al. 2019; Wen et al. 2020). At least two probands in the literature were confirmed to have de novo inheritance (Xiong et al. 2019). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The c.509C>T variant disrupts hydrogen bonding in a critical region of the C-terminal end of the methyl-DNA binding region (MDB), a well-established functional domain, which leads to compromised binding to methylated DNA and affects stability (Brown et al. 2016). This variant was identified in a de novo state in the proband. The c.509C>T variant is highly conserved through evolution. Based on the available evidence, the c.509C>T p.(Thr170Met) variant is classified as pathogenic for MECP2-related disorders.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000012580	SCV005016492	pathogenic	Rett syndrome	2023-10-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000133129	SCV005046485	pathogenic	not provided	2023-03-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012580	SCV005400182	pathogenic	Rett syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based 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) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability display X-linked recessive inheritance (PMID: 20301670). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated methyl-CpG binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is described in many individuals with atypical and classic Rett syndrome (ClinVar). (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
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000012580	SCV005414358	pathogenic	Rett syndrome	2024-11-06	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000763199	SCV005418096	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		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PS2_Moderate+PP3+PP4+PS3
OMIM	RCV000012580	SCV000032815	pathogenic	Rett syndrome	2007-07-01	no assertion criteria provided	literature only
OMIM	RCV000170110	SCV000032816	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2007-07-01	no assertion criteria provided	literature only
RettBASE	RCV000169935	SCV000188121	pathogenic	Autism, susceptibility to, X-linked 3	2014-02-26	no assertion criteria provided	curation
RettBASE	RCV000170109	SCV000222431	pathogenic	Angelman syndrome	2014-02-26	no assertion criteria provided	curation
RettBASE	RCV000170110	SCV000222432	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2014-02-26	no assertion criteria provided	curation
RettBASE	RCV000012580	SCV000222433	pathogenic	Rett syndrome	2014-02-26	no assertion criteria provided	curation
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000012580	SCV000257511	pathogenic	Rett syndrome	2014-05-21	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000133129	SCV000804259	pathogenic	not provided	2015-04-03	no assertion criteria provided	clinical testing
GeneReviews	RCV000012580	SCV000998923	not provided	Rett syndrome		no assertion provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000763199	SCV001450670	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		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000133129	SCV001929477	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000133129	SCV001952757	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000133129	SCV001973146	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000012580	SCV002583391	pathogenic	Rett syndrome	2022-02-01	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000012580	SCV003927962	pathogenic	Rett syndrome	2023-04-01	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000012580	SCV004101044	pathogenic	Rett syndrome	2023-11-02	no assertion criteria provided	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000133129	SCV004175123	pathogenic	not provided	2022-03-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004540995	SCV005358263	pathogenic	MECP2-related disorder	2024-05-06	no assertion criteria provided	clinical testing	The MECP2 c.473C>T variant is predicted to result in the amino acid substitution p.Thr158Met. This is the most commonly reported pathogenic variant responsible for Rett Syndrome, with over 40 studies cited in the Human Gene Mutation database, and several examples of de novo occurrence (see for example, Amir et al. 1999. PubMed ID: 10508514; Knight. 2013. PubMed ID: 23270700; Guerrini and Parrini. 2012. PubMed ID: 22998673). Functional analysis has indicated that this variant impairs DNA binding affinity (Kucukkal et al. 2015. PubMed ID: 26418480; Yusufzai and Wolffe. 2000. PubMed ID: 11058114). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is absent or extremely rare in general populations. This variant is interpreted as pathogenic.