rs61755763
Variant summary
Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_StrongPM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001110792.2(MECP2):c.408G>T(p.Leu136Phe) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L136V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 24 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.408G>T | p.Leu136Phe | missense_variant | 2/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.372G>T | p.Leu124Phe | missense_variant | 3/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.408G>T | p.Leu136Phe | missense_variant | 2/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.372G>T | p.Leu124Phe | 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, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Oct 11, 2022 | The c.372G>T (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the mosaic state in a male patient with a neurodevelopmental phenotype consistent with the MECP2 gene (internal database - Invitae) and therefore confirmed to be de novo (PS2). The c.372G>T (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>T (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). The c.372G>C variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (PMID 10991688, 12843318) (PS1). In summary, the c.372G>T (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PS2, PM1, PM2_supporting). - |
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: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (PS1).(PMID 10991688, 12843318) Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). 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 At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). 17089071 This variant is absent from gnomAD (PM2_Supporting). - |
Uncertain significance, no assertion criteria provided | curation | RettBASE | Feb 18, 2008 | - - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2021 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318). 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. ClinVar contains an entry for this variant (Variation ID: 143550). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10991688). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 124 of the MECP2 protein (p.Leu124Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at