ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.352C>T (p.Arg118Trp) (rs28934907)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255874 SCV000229062 pathogenic not provided 2015-03-23 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000012585 SCV000247964 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000255874 SCV000321873 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The R106W missense variant in the MECP2 gene has been reported numerous times in association with Rett syndrome and accounts for approximately 4.4% of mutations in the MECP2 gene (Amir et al., 1999; RettBASE; Vilchis et al., 2014). Additionally, R106W has a strong association with epilepsy, as approximately 78% of patients with the R106W mutation develop epilepsy (Glaze et al., 2010). The R106W mutation is a non-conservative amino acid substitution that alters a highly conserved position in the methyl-binding domain of the MECP2 protein. Additionally, functional studies suggest it significantly impairs the binding of methylated DNA (Ballestar et al., 2000).
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000012585 SCV000537188 likely pathogenic Rett syndrome 2015-07-14 criteria provided, single submitter clinical testing Microcephaly; Developmental delay; Seizures; Frequent hand to face movements
Invitae RCV000552837 SCV000645663 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2017-05-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg106Trp) in the MECP2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals diagnosed with Rett syndrome and is considered one of the most common causes of the disease (PMID: 20098342, 10508514, 23270700, 23421866, 18332345, RettBASE). It is typically associated with earliest onset among pathogenic variants in MECP2 (PMID: 23421866). ClinVar contains an entry for this variant (Variation ID: 11811). Experimental data shows this variant results in impaired chromatin binding, decreased MECP2 accumulation at  chromocentromeres, and reduced transcriptional repression compared to wildtype (PMID: 21831886, 12843318, 11738866).  In addition, expression of this variant in cultured neurons shows reduced dendritic spine density compared to wildtype (PMID: 19442733). For these reasons, this variant has been classified as Pathogenic.
Undiagnosed Diseases Network,NIH RCV000012585 SCV000837693 pathogenic Rett syndrome 2018-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715146 SCV000845974 pathogenic History of neurodevelopmental disorder 2019-03-26 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000012585 SCV000919615 pathogenic Rett syndrome 2018-03-06 criteria provided, single submitter clinical testing Variant summary: MECP2 c.316C>T (p.Arg106Trp) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A functional study, Yusufzai_2000, found the variant to abolish selectivity for methylated DNA binding. The variant was absent in 87536 control chromosomes (ExAC). The variant, c.316C>T, has been reported in the literature in multiple individuals affected with Rett Syndrome (Wan_1999, Cheadle_2000, Buyse_2000, Vacca_2001, and Zahorakova_2007). These data indicate that the variant is very likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000012585 SCV001149830 pathogenic Rett syndrome 2019-10-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000318 SCV001157005 pathogenic not specified 2019-03-25 criteria provided, single submitter clinical testing The MECP2 c.316C>T; p.Arg106Trp variant (rs28934907) has been reported in patients with Rett syndrome (Amir 1999, Psoni 2010). MECP2 protein containing the variant has a reduced binding affinity for methylated DNA (Ballestar 2000, Yusufzai 2000). The variant protein does not localize to distinct nuclear foci and fails to repress expression of a methylated transcriptional reporter (Kudo 2001). Hippocampal pyramidal neurons overexpressing the p.Arg106Trp variant protein have a lower density of mature dendritic spines after 48 hours of culture (Chapleau 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11814). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 106 is highly conserved and lies within the methyl-CpG binding domain. Computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Amir RE et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185-8. Ballestar E et al. Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. Biochemistry. 2000 Jun 20;39(24):7100-6. Chapleau CA et al. Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations. Neurobiol Dis. 2009 Aug;35(2):219-33. Kudo S et al. Functional analyses of MeCP2 mutations associated with Rett syndrome using transient expression systems. Brain Dev. 2001 Dec;23 Suppl 1:S165-73. Psoni S et al. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res. 2010 May;67(5):551-6. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.
OMIM RCV000012585 SCV000032820 pathogenic Rett syndrome 1999-10-01 no assertion criteria provided literature only
RettBASE RCV000012585 SCV000188054 pathogenic Rett syndrome 2013-06-12 no assertion criteria provided curation

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