X-154031405-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.459C>G(p.Tyr153*) variant causes a stop gained change. 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 (★★).
Frequency
Consequence
NM_001110792.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MECP2 | NM_001110792.2 | c.459C>G | p.Tyr153* | stop_gained | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.423C>G | p.Tyr141* | stop_gained | Exon 4 of 4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MECP2 | ENST00000453960.7 | c.459C>G | p.Tyr153* | stop_gained | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.423C>G | p.Tyr141* | stop_gained | Exon 4 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 34
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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The MECP2 c.423C>G; p.Tyr141Ter variant (rs61748396) has been reported in several individuals with Rett syndrome (see Buyse 2000, De Bona 2000, Giunti 2001, Nielsen 2001, Vacca 2001, Yamada 2001, Zahorakova 2007). It is reported as pathogenic in ClinVar (Variation ID:11833), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database, 1000 Genomes Project). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Buyse IM et al. Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. Am J Hum Genet. 2000 Dec;67(6):1428-36. De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000 May;8(5):325-30. Giunti L et al. Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation. Brain Dev. 2001 Dec;23 Suppl 1:S242-5. Nielsen JB et al. MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern. Eur J Hum Genet. 2001 Mar;9(3):178-84. Vacca M et al. Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females. J Mol Med (Berl). 2001;78(11):648-55. Yamada Y et al. Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation. Hum Mutat. 2001 Sep;18(3):253. Zahorakova D et al. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007;52(4):342-8. Epub 2007 Feb 15. -
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PM2, PS1, PS4, PVS1_strong -
Rett syndrome Pathogenic:5
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011833.8, PS4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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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 2.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease(PMID: 11313756, PMID: 11738883,PMID: 17387578, PMID: 15737703, PMID: 17089071) (PS4). It is reported as pathogenic in ClinVar (Variation ID:11833). -
Variant summary: The MECP2 c.423C>G (p.Tyr141X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.502C>T, p.Arg168X; c.710delG, p.Gly237fsX11; c.730C>T, p.Gln244X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 177332 control chromosomes (gnomAD and Zahorakova_2007) and has been reported in numerous RTT patients in the literature from a broad range of ethnicities (Bienvenu_2002, Fukuda_2005, Li_2007, Nielsen_2001, Zahorakova_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
This sequence change creates a premature translational stop signal (p.Tyr141*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 346 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 10854091). ClinVar contains an entry for this variant (Variation ID: 11833). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (PMID: 17387578, 19914908). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.423C>G (p.Y141*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to G substitution at nucleotide position 423. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 141. This alteration occurs in the last exon of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 71% of the protein. Premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in multiple individuals with classic Rett syndrome (Nielsen, 2001; Giunti, 2001; Fukuda, 2005; Zahorakova, 2007; De Bona, 2000). In addition, c.423C>A (p.Y141*) was observed in a female with a phenotype suggestive of Angelman syndrome and some features of Rett syndrome (Watson, 2001). The p.Y141 amino acid is located in the methyl-CpG binding domain (MBD) of the MeCP2 protein. The MBD is one of two major functional domains of MeCP2 and is necessary for DNA binding in vitro (Free, 2001; Du, 2015). Based on the available evidence, this alteration is classified as pathogenic. -
Angelman syndrome Pathogenic:1
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Atypical Rett syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at