rs61748421
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.538C>T(p.Arg180*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.538C>T | p.Arg180* | stop_gained | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.502C>T | p.Arg168* | 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.538C>T | p.Arg180* | stop_gained | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
| MECP2 | ENST00000303391.11 | c.502C>T | p.Arg168* | 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
Rett syndrome Pathogenic:27Other:1
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PVS1, PS3, PM1, PM2, PP3 -
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Criteria applied: PVS1,PS2_VSTR,PS4,PM2_SUP -
The MECP2 c.502C>T p.(Arg168Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with Rett syndrome, and is one of the most common pathogenic variants associated with the disorder (Kaur et al. 2001; Knight et al. 2013; Cudappah et al. 2014). In the majority of individuals, the variant was identified in a de novo state (Girard et al. 2001; Gu et al. 2000). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Arg168 residue lies in the linker region between the methyl-CpG-binding domain and the transcriptional repressor domain (TRD), and truncation at this residue will abolish the TRD. Functional studies found that when the p.(Arg168Ter) variant MECP2 protein was expressed in Xenopus oocytes, the variant protein failed to repress transcription in contrast to the wild-type protein (Yusufzai and Wolffe 2000). In addition, mice expressing the variant showed several features associated with Rett syndrome, including underweight and motor deficits (Schaevitz et al. 2013). Based on the collective evidence the c.502C>T p.(Arg168Ter) variant is classified as pathogenic for Rett syndrome. -
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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 Rett syndrome (MIM#312750). (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 display X-linked recessive inheritance (PMID: 20301670). (I) 0115 - Variants in this gene are known to have variable expressivity. Both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many individuals with Rett syndrome both in the literature and by clinical laboratories in ClinVar (PMID: 10577905). (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 -
The stop gained variant c.538C>T(p.Arg180Ter) in MECP2 gene is a recurrent variant that has been reported in many individuals affected with Rett syndrome (Wan M et.al.,1999 ) . This variant has been reported to the ClinVar database as Pathogenic . The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The nucleotide change in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -
This variant was previously reported as a recurrent variant and has been reported in many individuals affected with Rett syndrome [PMID: 10577905, 23270700, 24511209]. Experimental studies have shown that this variant impairs the ability of MECP2 to carry out transcriptional repression [PMID: 11058114]. In addition, it was previously shown that in mouse models harboring this variant recapitulated several aspects of the Rett syndrome phenotype [PMID: 24283265, 25541993, 24626160]. -
Variant summary: The MECP2 c.502C>T (p.Arg168X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate the transcriptional repression domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.710delG/p.Gly237fsX11). This variant is reported as one of the most common pathogenic variants in literature and clinical databases. The available clinical data and functional studies are consistent with pathogenic outcome for the variant. This variant is absent in 87628 control chromosomes. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
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 has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome, or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting). -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.154%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.66 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013505 /PMID: 12825077 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
A mosaic hemizygous (somatic mosaicism) nonsense variation in exon 3 of the MECP2 gene that results in premature truncation of the Arginine at codon 180. The observed variant c.538C>T(p.Arg180Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2(HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo (post-zygotic, somatic). In summary, the variant meets our criteria to be classified as a pathogenic variant. -
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not provided Pathogenic:14
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The MECP2 c.502C>T; p.Arg168Ter variant (rs61748421) is one of the most common variants identified in individuals with Rett syndrome (see link, Pidcock 2016, Wan 1999), and is shown to have impaired functional capabilities (Bissonnette 2014, Delepine 2013, Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11828). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to RettBASE database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Bissonnette JM et al. Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X. Neuroscience. 2014 May 16;267:166-76. Delepine C et al. MeCP2 deficiency is associated with impaired microtubule stability. FEBS Lett. 2013 Jan 16;587(2):245-53. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wan M et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec;65(6):1520-9. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9. -
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Recurrent pathogenic variant that accounts for 8-9% of MECP2 pathogenic variants (Percy et al., 2007); Typically associated with classic Rett syndrome but also identified in females with atypical Rett syndrome (Halbach et al., 2012; Neul et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 319 amino acids are lost, and other loss-of-function variants have been reported downstream (Stenson et al., 2014; RettBASE); Published functional studies indicate this variant truncates all of the transcriptional repression domain (TRD) and impairs normal protein function (Yusufzai et al., 2000; Bissonnette et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26175308, 24626160, 10577905, 24283265, 23270700, 24511209, 23238081, 25541993, 18337588, 22190343, 15228575, 28394409, 16077729, 28333917, 18174548, 30564305, 29655203, 31164858, 31209962, 31144778, 31535341, 32393352, 32631363, 11058114, 33144682, 12030010, 31130284, 33258288) -
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The MECP2 c.502C>T (p.Arg168*) variant causes the premature termination of MECP2 protein synthesis. This variant has been reported in the published literature in multiple individuals affected with classic and atypical Rett syndrome, many of which were observed to be de novo (RettBASE (http://mecp2.chw.edu.au/), PMIDs: 10577905 (1999), 10767337 (2000), 11313764 (2001), 16473305 (2006), 24511209 (2014), 32105570 (2020), 32393352 (2020), 32631363 (2020)). Functional studies found that this variant truncates all of the transcriptional repression domain and impairs normal protein function (PMIDs: 11058114 (2000), 24626160 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
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MECP2: PS2:Very Strong, PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting -
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg168*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 319 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: 10577905, 23270700, 24511209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11828). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 24283265, 24626160, 25541993). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.502C>T (p.R168*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, consists of a C to T substitution at nucleotide position 502. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 168. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 65.4% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a common, recurrent pathogenic variant for Rett syndrome and has been associated with earlier onset and more severe symptoms than other Rett syndrome alterations; however, it has also been detected in unaffected females (Wan, 1999; Cuddapah, 2014; Kaur, 2019). Based on the available evidence, this alteration is classified as pathogenic. -
Global developmental delay;C1836830:Developmental regression Pathogenic:1
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Intellectual disability Pathogenic:1
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MECP2-related disorder Pathogenic:1
The MECP2 c.502C>T variant is predicted to result in premature protein termination (p.Arg168*). This nonsense variant has been documented in several individuals with Rett syndrome (see for example Wan et al. 1999. PubMed ID: 10577905; Archer et al. 2006. PubMed ID: 16183801; Philippe et al. 2006. PubMed ID: 16473305; Percy et al. 2007. PubMed ID: 18174548). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at