chrX-154031373-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2_SupportingPP4PP3PM1PM5PS4PS3_SupportingPM6
This summary comes from the ClinGen Evidence Repository: The p.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270424/MONDO:0010726/036
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.491C>G | p.Pro164Arg | missense_variant | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.455C>G | p.Pro152Arg | 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.491C>G | p.Pro164Arg | missense_variant | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.455C>G | p.Pro152Arg | 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:9
- -
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 in ≥4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1).At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4).This variant is absent from gnomAD (PM2_Supporting).Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PMID 21831886, PMID22923521) (PS3). -
A heterozygous de novo missense variation in exon 3 of the MECP2 gene that results in the amino acid substitution of Arginine for Proline at codon 164 was detected. The observed variant c.491C>G (p.Pro164Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
- -
- -
The p.Pro152Arg variant in MECP2 (NM_004992.3) has been reported in at least 6 de novo occurrences (biological parentage unconfirmed) in patients with Rett syndrome (PMID 10767337, 10814718, 11241840) and in at least 4 other individuals with clinical features of Rett syndrome (PMID 11055898, 2385859, RettBASE) (PM6_very strong, PP4, PS4). The p.Pro152Arg variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Ala) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18989701, 18989701, 27929079, 26842955, ClinVar) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Immunofluorescence assays have shown that the p.Pro152Arg variant in MECP2 impacts heterochromatin clustering (PMID 21831886, 22923521) (PS3_supporting). The p.Pro152Arg variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Pro152Arg variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PS3_supporting, PM2_supporting, PP3, PP4). -
- -
- -
Variant summary: MECP2 c.455C>G (p.Pro152Arg) results in a non-conservative amino acid change located in the methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 177980 control chromosomes (gnomAD). The variant, c.455C>G, has been reported in the literature in multiple individuals affected with Rett Syndrome, Classic (e.g. Cheadle 2000, Obata 2000, Huppke 2000, Philippe 2006, Buoni 2008). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, demonstrating a disrupted heterochromatin binding for the variant protein (e.g. Adegbola 2009, Sheikh 2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as pathogenic, the other VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:5
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Rett Syndrome (PMID: 30573328 (2019), 29482495 (2018), 24508304 (2014), 24453408 (2013), 23859859 (2013), 23488948 (2013)). This variant has been reported to have a deleterious effect on MECP2 protein function (PMID: 21831886 (2011), 22923521 (2012), 27929079 (2016)). In addition, this variant has been detected in the de novo state in an individual with Rett Syndrome (PMID: 10767337 (2000)).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. -
- -
- -
- -
Several functional studies have shown that P152R has a damaging effect by severely affecting heterochromatin clustering and repressing transcription (PMID: 12843318, 21831886, 22923521); Published functional study using in silico and in vitro approaches demonstrated that P152R had a significant destabilizing effect on the protein (PMID: 26418480); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21831886, 23859859, 22923521, 10767337, 27379843, 31785789, 32472557, 12030010, 31847883, 31440721, 31069529, 12843318, 32477112, 27929079, 26418480) -
not specified Pathogenic:1Uncertain:1
- -
The MECP2 c.455C>G; p.Pro152Arg variant (rs61748404) is reported in the literature in numerous individuals affected with Rett syndrome (Cheadle 2000, Maortua 2013, Sheen 2013, Rettbase) and has been reported to occur de novo (Cheadle 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 143579), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant at this codon (p.Arg152His) has been reported in an individual with Rett syndrome and is considered pathogenic (Sheikh 2016). The proline at codon 152 is highly conserved, and structural modeling suggests that the p.Pro152Arg variant disrupts local hydrogen bonding patterns (Kucukkal 2015). Further, biochemical analyses demonstrate that this variant destabilizes MECP2 protein (Kucukkal 2015), while expression of the p.Pro152Arg variant in cultured cells alters nuclear heterochromatin organization (Agarwal 2011, Casas-Delucchi 2012, Sheikh 2016). Based on available information, this variant is considered to be pathogenic. References: Link to Rettbase: https://www.rettsyndrome.org/ Agarwal N et al. MeCP2 Rett mutations affect large scale chromatin organization. Hum Mol Genet. 2011 Nov 1;20(21):4187-95. Casas-Delucchi CS et al. Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization. Nucleic Acids Res. 2012 Dec;40(22):e176. 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 Apr 12;9(7):1119-29. Kucukkal TG et al. Impact of Rett Syndrome Mutations on MeCP2 MBD Stability. Biochemistry. 2015 Oct 20;54(41):6357-68. Maortua H et al. MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). J Mol Diagn. 2013 Sep;15(5):723-9. Sheen V et al. Atypical features in MECP2 P152R-associated Rett syndrome. Pediatr Neurol. 2013 Aug;49(2):124-6. Sheikh TI et al. From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2. Sci Rep. 2016 Dec 8;6:38590. -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 152 of the MECP2 protein (p.Pro152Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 10814718, 11055898, 11241840, 15173251, 23859859). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143579). 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: 21831886, 22923521, 26418480, 27929079). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
The p.P152R pathogenic mutation (also known as c.455C>G), located in coding exon 3 of the MECP2 gene, results from a C to G substitution at nucleotide position 455. The proline at codon 152 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with Rett syndrome (Cheadle JP et al. Hum. Mol. Genet., 2000 Apr;9:1119-29; Buyse IM et al. Am. J. Hum. Genet., 2000 Dec;67:1428-36; Erlandson A et al. Eur Child Adolesc Psychiatry, 2001 Jun;10:117-21; Chae JH et al. J. Child Neurol., 2004 Jul;19:503-8; Fukuda T et al. Brain Dev., 2005 Apr;27:211-7; Lima FT et al. Arq Neuropsiquiatr, 2009 Sep;67:577-84; Das DK et al. Gene, 2013 Feb;515:78-83; Sheen V et al. Pediatr. Neurol., 2013 Aug;49:124-6). Expression of this mutation in Pmi28 mouse myoblasts demonstrated an increase in protein accumulation at chromocenters (Agarwal N et al. Hum. Mol. Genet., 2011 Nov;20:4187-95). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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:1
MECP2 NM_004992.3 exon 4 p.Pro152Arg (c.455C>G): This variant has been reported in the literature in at least 2 individuals with Rett syndrome, one of whom was reported as de novo (Cheadle 2000 PMID:10767337, Sheen 2013 PMID:23859859). In addition, this variant has been reported in several individuals with Rett syndrome or features of Rett syndrome by the RettBASE database (Christodoulou 2003 PMID:12673788). Furthermore, one publication suggests that this variant is one of the most common variants in reported cases (est. 1.41%) (Sheikh 2016 PMID:27929079). This variant is not present in large control databases and is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:143579). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. Other variants at this same codon (p.Arg152Leu, p.Arg152Ala, p.Arg152His) have been reported in the literature, supporting that this region has significance. Furthermore, this variant occurs in exon 4 of this gene. 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). Functional studies also predict that this variant will impact the protein (Kudo 2003 PMID:12843318, Agarwal 2011 PMID:21831886, Casas-Delucchi 2012 PMID:22923521, Sheikh 2016 PMID:27929079). In summary, this variant is classified as pathogenic. -
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
- -
MECP2-related disorder Pathogenic:1
The variant NM_004992.4:c.455C>G (p.Pro164Arg) results in a proline-to-arginine substitution at codon 164. According to ACMG/AMP guidelines, this variant meets the criteria for PS4, PP4, PS3, PM6, PM2, PM1, PP5, PM5, and PP3, supporting its classification as likely pathogenic -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at