rs267608455
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001110792.2(MECP2):c.400G>A(p.Val134Met) 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V134A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.400G>A | p.Val134Met | missense_variant | 2/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.364G>A | p.Val122Met | missense_variant | 3/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.400G>A | p.Val134Met | missense_variant | 2/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.364G>A | p.Val122Met | missense_variant | 3/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jan 15, 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 an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 17089071, PMID 28837158 Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate).ClinVar Variation ID: 143546 Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 17089071 - |
Pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Oct 26, 2021 | The p.Val122Met variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID: 17089071) (PP4). The p.Val122Met variant in MECP2 occurs in the de novo state (biological parentage unconfirmed) in this individual. It is also reported in the mosaic state in a male patient with clinical features of Rett syndrome (PMID 28837158, internal database - GeneDx) and therefore confirmed to be de novo (PS2, PS4_supporting). The p.Val122Met variant occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val122Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Val122Met variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2, PM1, PS4_supporting, PM2_supporting, PP3, PP4). - |
Uncertain significance, no assertion criteria provided | curation | RettBASE | Feb 18, 2008 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2016 | The V122M missense variant in the MECP2 gene has been reported previously as a de novo variant in a female patient with Rett syndrome (Li et al., 2007). The V122M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V122M variant is a conservative amino acid substitution. This substitution alters a conserved position predicted to be part of the hydrophobic core within the mCpG-binding domain (MBD) of the MECP2 protein (Wakefield et al., 1999). A different missense variant in the same codon (V122A) as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with MECP2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at