rs61751444
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_001110792.2(MECP2):c.961C>T(p.Arg321Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Consequence
MECP2
NM_001110792.2 missense
NM_001110792.2 missense
Scores
4
4
3
Clinical Significance
Conservation
PhyloP100: 2.16
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001110792.2
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-154030902-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 961919.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
?
Variant X-154030903-G-A is Pathogenic according to our data. Variant chrX-154030903-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 143749.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030903-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154030903-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.961C>T | p.Arg321Trp | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.925C>T | p.Arg309Trp | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.961C>T | p.Arg321Trp | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.925C>T | p.Arg309Trp | missense_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Uncertain:3Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:10Uncertain:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Mar 13, 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: 31178897, 26936630) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 26936630, 21178819, 30536762, 21160487, 28089766, 37361459, 31178897 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 | Genetic Services Laboratory, University of Chicago | Jun 22, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | case-control | Biochemistry Laboratory of CDMU, Chengde Medical University | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 12, 2018 | - - |
Uncertain significance, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Pathogenic, no assertion criteria provided | research | Section for Clinical Neurogenetics, University of Tübingen | Aug 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 02, 2023 | PS2_Very Strong, PS4, PM2, PP3 - |
Pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Jul 28, 2022 | The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Aug 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | Jun 02, 2020 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 26, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratoire Génétique Moléculaire, CHRU TOURS | Oct 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28027854, 20479760, 21160487, 17084570, 23810759, 26936630, 28089766, 30536762, 29655203, 29720203, 28837158, 31178897, 32214227) - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:2Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in a 6-year-old male with global delays, stereotypic hand movements, hypotonia, failure to thrive; de novo in a 3-year-old female with global delays and hypotonia; maternally inherited in a 4-year-old male with gloabal delays, dysmorphisms, short stature, macrocehaly, retractile testis, hypothyroidism; de novo in a 2-year-old male with global delay, hypotonia, epilepsy, relative macrocephaly - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein (p.Arg309Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 20479760, 21160487, 23810759, 26936630, 29720203, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143749). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2015 | - - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Apr 05, 2019 | - - |
Autism, susceptibility to, X-linked 3 Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MutationTaster
Benign
D;D
Sift4G
Uncertain
T
Vest4
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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