rs61748420
Variant summary
Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PS2PM2_SupportingPP1_Strong
This summary comes from the ClinGen Evidence Repository: The p.Arg167Trp variant (NM_004992.3) in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with MECP2-related disorders through testing completed at GeneDx (PS2_very strong). The variant has been reported to segregate in at least five informative meioses in published literature (Couvert et al., 2001) (PP1_strong). The p.Arg167Trp variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg167Trp variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PP1_strong, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170308/MONDO:0010726/016
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.535C>T | p.Arg179Trp | missense_variant | 3/3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.499C>T | p.Arg167Trp | missense_variant | 4/4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.535C>T | p.Arg179Trp | missense_variant | 3/3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
MECP2 | ENST00000303391.11 | c.499C>T | p.Arg167Trp | missense_variant | 4/4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 0.00000273 AC: 3AN: 1098208Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 363562
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
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 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 15, 2022 | This variant has been reported in multiple male individuals with an X-linked intellectual developmental disorder. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function shows this variant causes a chromatin binding defect, increasing the number of chromocenters and decreasing their size (PMID: 27929079). Further research is needed to determine disease consequence. This variant segregates with disease in multiple families. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2024 | Heterozygous carrier females with resting tremors have been reported (PMID: 14598336); Functional studies show the R167W mutant protein is defective, as when expressed in mouse myoblast cells, chromocenter clustering reduced in size and increased in number (PMID: 27929079); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30083362, 26490184, 11309367, 26350204, 27323888, 27929079, 30536762, 35032046, 34271245, 31440721, 14598336) - |
Rett syndrome Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Dec 13, 2021 | The p.Arg167Trp variant (NM_004992.3) in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with MECP2-related disorders through testing completed at GeneDx (PS2_very strong). The variant has been reported to segregate in at least five informative meioses in published literature (Couvert et al., 2001) (PP1_strong). The p.Arg167Trp variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg167Trp variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PP1_strong, PM2_supporting). - |
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: Co-segregation with disease in multiple affected family members (> 5 informative meiosis) (PP1_Strong). PMID: 11309367 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).(PMID: 11309367, 30536762, ClinVar Variation ID: 143603) This variant is absent from gnomAD (PM2_Supporting). - |
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 MECP2-related disease (OMIM). (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 demonstrate X-linked recessive inheritance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and typically affects hemizygous males where the variant was inherited from an asymptomatic mother (PMID: 26490184, ClinVar). However, rare reports of affected females have been described, who presented with nonprogressive resting tremour, epilepsy or a neuropsychiatric phenotype [DECIPHER, PMID: 11309367, Gonzaga-Jauregui C, et al. (2021)]. (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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Nov 27, 2017 | - - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Feb 15, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Nov 23, 2022 | - - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 09, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the MECP2 protein (p.Arg167Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MECP2-related conditions (PMID: 11309367, 14598336, 26350204, 26490184, 27929079, 30083362). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143603). 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) performed at Invitae 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: 27929079). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2019 | The p.R167W pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 499. The arginine at codon 167 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation segregated with disease in four affected males over two generations within a large family and was absent in a healthy maternally related male (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6). Affected males in this family were noted to have moderate intellectual disability, microcephaly, seizures, hypoactivity, poor coordination, brisk tendon reflexes, difficulties with written language, verbal stereotypies, and resting tremors, which were also observed in two obligate carrier females (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6; Gomot M et al. Am. J. Med. Genet. A, 2003 Dec;123A:129-39). In another family, this mutation was detected in 3 affected brothers and their mother, who demonstrated skewed X-inactivation (Bianciardi L et al. J. Hum. Genet., 2016 Feb;61:95-101). C2C12 cells expressing this mutation demonstrated an increased number of chromocenters with decreased size (Sheikh TI et al. Sci Rep, 2016 12;6:38590). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Sep 16, 2019 | ACMG classification criteria: PS3, PS4, PM2, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at