rs28934906
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001110792.2(MECP2):c.509C>T(p.Thr170Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
MECP2
NM_001110792.2 missense
NM_001110792.2 missense
Scores
11
4
2
Clinical Significance
Conservation
PhyloP100: 9.45
Genes affected
MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant X-154031355-G-A is Pathogenic according to our data. Variant chrX-154031355-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031355-G-A is described in Lovd as [Pathogenic]. Variant chrX-154031355-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154031355-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MECP2 | NM_001110792.2 | c.509C>T | p.Thr170Met | missense_variant | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.473C>T | p.Thr158Met | missense_variant | 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.509C>T | p.Thr170Met | missense_variant | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.473C>T | p.Thr158Met | missense_variant | Exon 4 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
GnomAD4 genome
Cov.:
23
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:57Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:26Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 21, 2018 | - - |
| Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Feb 28, 2024 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 25, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 04, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Mar 22, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jul 17, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Jun 08, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 02, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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 - |
| Pathogenic, no assertion criteria provided | curation | RettBASE | Feb 26, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 23, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 09, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics | - | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Feb 01, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | May 21, 2014 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2007 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Nov 06, 2024 | - - |
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 14, 2023 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2021 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Feb 22, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 17, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | MECP2: PS2, PM1, PM2, PM5, PS3:Moderate, PP3, PS4:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 12, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Apr 03, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 22, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Mar 18, 2022 | - - |
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:4
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS4+PS2_Moderate+PP3+PP4+PS3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2025 | 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. - |
| Pathogenic, no assertion criteria provided | curation | RettBASE | Feb 26, 2014 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2007 | - - |
Autism, susceptibility to, X-linked 3 Pathogenic:2
| Pathogenic, no assertion criteria provided | curation | RettBASE | Feb 26, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 22, 2023 | The missense c.509C>T (p.Thr170Met) variant in MECP2 gene has been reported in individuals affected with MECP2 related disorders (Brown K et al. 2016; Guo H, et. al., 2018). Experimental studies have shown that this missense change affects MECP2 function (Yusufzai TM et al. 2000). The p.Val67Glu variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/Pathogenic (multiple submitters). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid at this position in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 170 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
MECP2-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 06, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 21, 2021 | 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. - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 14, 2024 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2024 | 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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; Halfmeyer, 2022). This amino acid position is highly conserved in available vertebrate species. 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). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Abnormality of the nervous system Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Angelman syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | curation | RettBASE | Feb 26, 2014 | - - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;T;T
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.
Sift4G
Uncertain
D;D;.;D;D
Polyphen
D;D;.;.;.
Vest4
MutPred
Loss of phosphorylation at T158 (P = 0.0197);.;Loss of phosphorylation at T158 (P = 0.0197);.;.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at