rs61750239
Variant summary
Our verdict is Uncertain significance. Variant got -2 ACMG points: 2P and 4B. PP3PP4BS2
This summary comes from the ClinGen Evidence Repository: The p.Arg268Trp variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (PMID 12750821, internal database - Invitae) (BS2). The p.Arg268Trp variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 18842453) (PP4). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg268Trp variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.0009792% (no criteria met). In summary, the p.Arg268Trp variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA233007/MONDO:0010726/016
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.838C>T | p.Arg280Trp | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.802C>T | p.Arg268Trp | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.838C>T | p.Arg280Trp | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.802C>T | p.Arg268Trp | missense_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000355 AC: 4AN: 112533Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34697
GnomAD3 exomes AF: 0.00000548 AC: 1AN: 182455Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67367
GnomAD4 exome AF: 0.0000237 AC: 26AN: 1098176Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 3AN XY: 363548
GnomAD4 genome ? AF: 0.0000355 AC: 4AN: 112533Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34697
ClinVar
Submissions by phenotype
not provided Benign:1Other:1
not provided, no classification provided | literature only | RettBASE | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2019 | Reported as pathogenic [in ClinVar/in a well-curated database/through personal communication] but additional evidence is not available [ref]; Reported as pathogenic [in ClinVar/in a well-curated database/through personal communication] but additional evidence is not available [ref]; This variant is associated with the following publications: (PMID: 11469283, 18842453, 12750821) - |
Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the MECP2 protein (p.Arg268Trp). This variant is present in population databases (rs61750239, gnomAD 0.002%). This missense change has been observed in individual(s) with X-linked intellectual disability and/or Rett syndrome (PMID: 11469283, 12750821, 18842453). ClinVar contains an entry for this variant (Variation ID: 143700). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Rett syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Oct 28, 2021 | The p.Arg268Trp variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (PMID 12750821, internal database - Invitae) (BS2). The p.Arg268Trp variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 18842453) (PP4). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg268Trp variant in MECP2 is present in gnomAD v2.1.1 at a frequency of 0.0009792% (no criteria met). In summary, the p.Arg268Trp variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PP3, PP4). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2024 | Unlikely to be causative of Rett syndrome (XLD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at