rs28934904
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS2PP3PM2_SupportingPM1PS4
This summary comes from the ClinGen Evidence Repository: The p.Arg133Cys (NM_004992) variant in MECP2 has been reported as an assumed de novo occurrence in at least 4 individuals with Rett Syndrome (PMID:10814718, PMID:10991688, PMID:12707946) (PS2_very-strong). The p.Arg133Cys variant has been observed in at least 4 other individuals with Rett Syndrome (PMID:10814718, PMID:10991688, PMID:12707946, PMID:17387578, PMID:16473305) (PS4). The p.Arg133Cys variant occurs in the well-characterized (Methyl-DNA binding [MDB]: aa 90-162) functional domain of the MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg133Cys variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary the p.Arg133Cys variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS2_very-strong, PS4, PM1, PP3, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211250/MONDO:0010726/016
Frequency
Consequence
NM_001386137.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MECP2 | NM_001110792.2 | c.433C>T | p.Arg145Cys | missense_variant | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.397C>T | p.Arg133Cys | 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.433C>T | p.Arg145Cys | missense_variant | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.397C>T | p.Arg133Cys | 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:23Other:1
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The p.Arg133Cys (NM_004992) variant in MECP2 has been reported as an assumed de novo occurrence in at least 4 individuals with Rett Syndrome (PMID: 10814718, PMID: 10991688, PMID: 12707946) (PS2_very-strong). The p.Arg133Cys variant has been observed in at least 4 other individuals with Rett Syndrome (PMID: 10814718, PMID: 10991688, PMID: 12707946, PMID: 17387578, PMID: 16473305) (PS4). The p.Arg133Cys variant occurs in the well-characterized (Methyl-DNA binding [MDB]: aa 90-162) functional domain of the MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg133Cys variant in MECP2 is absent from gnomAD (PM2_Supporting). In summary the p.Arg133Cys variant in MECP2 is classified as Pathogenic for Rett Syndrome based on the ACMG/AMP criteria (PS2_very-strong, PS4, PM1, PP3, PM2_supporting). -
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Variant summary: The MECP2 c.397C>T (p.Arg133Cys) variant involves the alteration of a non-conserved nucleotide. Arg133 is located in the Methyl-CpG DNA binding domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This prediction was confirmed by one functional study showing MECP2 R133C resulted in the complete disruption of its ability to bind to methylated DNA (Yusufzai_2000). This variant has been reported as a de novo variant in numerous RTT patients, some of whom are reported to have a mild phenotype, and is one of the most common pathogenic variant in MECP2. This variant is absent in 87882 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
ACMG classification criteria: PS3 supporting, PS4 strong, PM2, PM5 moderated, PM6 moderated, PP1 supporting, PP3 supporting -
PS3, PS4, PM2, PM5, PP3 -
A heterozygous de novo missense variation in exon 3 of the MECP2 gene that results in the amino acid substitution of Cysteine for Arginine at codon 145 was detected. The observed variant c.433C>T (p.Arg145Cys) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
The missense variant p.R133C in MECP2 (NM_004992.4) has been previously reported in individuals affected with Rett Syndrome (Sheikh et al, 2016). Experimental studies reveal damaging effect on protein structure and function (Sheikh et al, 2016; Brown et al, 2016). The variant has been submitted to ClinVar as Pathogenic.The p.R133C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R133C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 133 of MECP2 is conserved in all mammalian species. The nucleotide c.397 in MECP2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
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 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). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). -
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This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP5;PP3;PM2;PS4;PS2 -
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The c.397C>T;p.(Arg133Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11809; OMIM: 300005.0001; PMID: 20301670; 12746406; 27929079; 28394482; 26175308; 23810759) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 27929079; 26647311; 23260135; 26418480) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (MBD) - PM1. This variant is not present in population databases (rs28934904, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID:547103) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 10508514; 23810759) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 28394482) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
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not provided Pathogenic:15
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The MECP2 c.397C>T (p.Arg133Cys) variant has been reported in the published literature in individuals with classic Rett Syndrome (PMID: 10767337 (2000), 11241840 (2001), 11269512 (2001), 11376998 (2001), 12567420 (2003), 18332345 (2008), 26647311 (2016)). Although this variant has been reported in individuals with classical Rett syndrome, it appears to be associated with milder clinical phenotype when compared to other disease associated variants in this gene (PMID: 18332345 (2008), 26175308 (2016), 15057977 (2004)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease ((PMID: 17101771 (2007), 34324427 (2021), 26647311 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
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This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with Rett syndrome and neonatal encephalopathy. It also appears to occur de novo in multiple individuals. Although this variant has been reported in individuals with classical Rett syndrome, it appears to be associated with milder clinical phenotype when compared to other disease associated variants in this gene (PMID: 18332345, 26175308,15057977). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused impaired binding to DNA (PMID: 17101771, 34324427, 26647311). The variant is located in a region that is considered important for protein function and/or structure. -
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The MECP2 c.397C>T; p.Arg133Cys variant has been described in multiple individuals affected with typical or atypical Rett syndrome, including several de novo occurrences (Amir 1999, Cheadle 2000, Nielsen 2001, Neul 2019, Wen 2020, Zappella 2003). The p.Arg133Cys variant has been associated with a milder phenotype compared to other variants of MECP2 (Leonard 2003). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.986), and functional studies demonstrate reduced activity of the variant protein compared to wildtype (Brown 2016). Based on available information, this variant is considered to be pathogenic. References: Amir RE et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 23(2):185-8. PMID: 10508514. Brown K et al. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum Mol Genet. 2016 Feb 1;25(3):558-70. PMID: 26647311. 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. 9(7):1119-29. PMID: 10767337. Leonard et al. Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations?. J Med Genet. 2003 May; 40(5): e52. PMID: 12746406. Neul et al. The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. Am J Med Genet B Neuropsychiatr Genet. 2019 Jan;180(1):55-67. PMID: 30536762. Nielsen JB et al. A 77-year-old woman and a preserved speech variant among the Danish Rett patients with mutations in MECP2. Brain Dev. Suppl 2001 1:S230-2. PMID: 11738879. Wen et al. MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort. Clin Genet. 2020 Sep;98(3):240-250. PMID: 32472557. Zappella M et al. Study of MECP2 gene in Rett syndrome variants and autistic girls. Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119B(1):102-7. PMID: 12707946. -
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MECP2: PS4, PM1, PM2, PM5, PS2:Moderate, PP3 -
Recurrent pathogenic variant that accounts for 4-7% of MECP2 pathogenic variants (PMID: 18174548); Published functional studies demonstrate that mutant R133C MeCP2 protein accumulates at chromocenters (in vivo) at a different, statistically significant, extent than the wild type protein (PMID: 21831886); Often observed in females with the preserved speech variant of Rett syndrome, but has also been identified in females with classic and atypical Rett syndrome, and in a male with hypotonia, developmental delay, and a movement disorder (PMID: 18332345, 12746406, 18337588, 16122633; RettBASE); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22368975, 10508514, 11738866, 26064184, 23421866, 31139143, 10852707, 23270700, 11738879, 12843318, 11058114, 26418480, 26647311, 26795593, 27255190, 12746406, 18337588, 16122633, 16314321, 27929079, 25533962, 16077729, 28135719, 26175308, 11738864, 28394482, 29655203, 30536762, 29915382, 31535341, 31647993, 31623504, 32631363, 32472557, 33860439, 32005694, 12030010, 31130284, 33098801, 35872528, 35599849, 34271245, 31440721, 31069529, 35074918, 18332345, 18174548, 21831886) -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 133 of the MECP2 protein (p.Arg133Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 11738879, 16473305, 22368975, 23421866, 26418480). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11809). 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. -
Neurodevelopmental delay Pathogenic:1
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Syndromic X-linked intellectual disability Lubs type Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.397C>T (p.R133C) 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 397, causing the arginine (R) at amino acid position 133 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation (also referred to as c.471C>T) was originally identified as a de novo alteration in a sporadic case with Rett syndrome (Amir, 1999). Subsequently, this mutation has been described in numerous individuals with Rett syndrome (Philippe, 2006; Bao, 2013; Zhang, 2017). p.R133C is one of the most common missense mutations in MECP2 and currently represents 4.7% of all MECP2 variants reported in the IRSA MECP2 Variation Database (RettBASE) (Christodoulou, 2003). This mutation is located in the highly conserved methyl-CpG binding domain of the MECP2 protein and impairs binding to methylated DNA in vitro (Yusufzai, 2000; Free, 2001). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Rett syndrome, zappella variant Pathogenic:1
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Angelman syndrome Pathogenic:1
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X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
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Intellectual disability Pathogenic:1
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MECP2-related disorder Pathogenic:1
The MECP2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Cys. This variant has been reported in over 25 publications to be causative for Rett syndrome; in some individuals, the variant was reported to occur de novo (see, for example, Amir et al. 1999. PubMed ID: 10508514; Bebbington et al. 2008. PubMed ID: 18332345; reported as c.421C>T, Stojanovic et al. 2019. PubMed ID: 31623504). Patients with this variant may present with a milder phenotype, which is consistent with in vitro functional studies and occurrence in male subjects (Leonard et al. 2003. PubMed ID: 12746406; Sheikh et al. 2016. PubMed ID: 27929079). An alternative nucleotide change affecting the same amino acid (p.Arg133Gly) has also been reported in an individual with Rett syndrome (Bienvenu et al. 2002. PubMed ID: 12180070). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. -
not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at