rs28934906
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
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
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
GnomAD4 exome Cov.: 34
GnomAD4 genome
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:26Other:1
- -
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). -
- -
- -
- -
- -
- -
- -
- -
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. -
- -
- -
- -
- -
- -
- -
- -
- -
- -
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 -
- -
- -
- -
- -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.87 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV002444187 /PMID: 32901917 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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. -
- -
not provided Pathogenic:14
- -
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) -
- -
- -
- -
- -
- -
- -
MECP2: PS2, PM1, PM2, PM5, PS3:Moderate, PP3, PS4:Supporting -
- -
- -
- -
- -
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) -
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
- -
PM2_Supporting+PS4+PS2_Moderate+PP3+PP4+PS3 -
- -
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. -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:3
- -
- -
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. -
Autism, susceptibility to, X-linked 3 Pathogenic:2
- -
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
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. -
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. -
Neurodevelopmental delay Pathogenic:1
- -
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
- -
Inborn genetic diseases Pathogenic:1
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
- -
Angelman syndrome Pathogenic:1
- -
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at