ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.916C>T (p.Arg306Ter) (rs61751362)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081215 SCV000191049 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The R294X variant in the MECP2 gene is a recurrent pathogenic variant that has been published many times in association with Rett syndrome (RettBASE; Knight et al., 2013; Boban et al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation, with the loss of the last 193 amino acids of the protein. Functional studies demonstrate that R294X leads to a decrease in protein stability (Yusufzai et al., 2000; Nikitina et al., 2007). The R294X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R294X as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081215 SCV000230269 pathogenic not provided 2013-11-19 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000012590 SCV000236516 pathogenic Rett syndrome 2015-01-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000012590 SCV000248001 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000012590 SCV000268070 likely pathogenic Rett syndrome 2015-01-01 criteria provided, single submitter literature only
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000012590 SCV000537183 pathogenic Rett syndrome 2015-07-12 criteria provided, single submitter clinical testing
Invitae RCV000474366 SCV000544614 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-11-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the MECP2 mRNA at codon 294 (p.Arg294*). While this is not anticipated to result in nonsense-mediated decay, it is expected to delete the last 192 amino acids of the MECP2 protein. This variant has been reported as one of the most common nonsense variants in individuals with Rett syndrome (PMID: 23270700, 16473305, 18332345, 11241840, 15737703, 19722030), including one affected male (PMID: 17236109). ClinVar contains an entry for this variant (Variation ID: 11819). Experimental studies have shown that this nonsense change slightly destabilizes the MECP2 protein and disrupts its ability to repress transcription (PMID: 11058114), and that expression of this truncated protein results in increased levels of apoptosis in cell culture and model organisms (PMID: 27442528, 28785396) and in altered microtubule dynamics in cells from an affected individual (PMID: 26604147). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515413 SCV000611280 pathogenic Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; Mental retardation, X-linked, syndromic 13; Rett syndrome; Autism, susceptibility to, X-linked 3 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012590 SCV000698546 pathogenic Rett syndrome 2017-01-31 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.880C>T (p.Arg294X) 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.1079C>A/p.Ser360X)). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 87847 control chromosomes. It has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional study proved mutant protein R294X with loss of function (Yusufzai_ 2000). Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624805 SCV000741622 pathogenic Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000012590 SCV000781713 pathogenic Rett syndrome 2016-11-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000012590 SCV000807253 pathogenic Rett syndrome 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with global delays and hypotonia
Athena Diagnostics Inc RCV000081215 SCV000842739 pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000081215 SCV000885678 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing The MECP2 c.880C>T; p.Arg294Ter variant (rs61751362) is reported in the medical literature in individuals with classical Rett syndrome and atypical Rett syndrome (see link to RettBASE below and references therein, Cheadle 2000, Pidcock 2016, Wen 2017, Wang 2016). Additionally, the variant protein is reported to have lowered expression, to have slightly reduced stability, and to be unable to repress transcription (Wen 2017, Yusufzai 2000). The variant is reported in the ClinVar database (Variation ID: 11819). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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. Considering available information, this variant is classified as pathogenic. References: Link to RettBase variants: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle JP et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000 Apr 12;9(7):1119-29. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wen Z et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism. 2017 Aug 3;8:43. Wang T et al. De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun. 2016 Nov 8;7:13316. Yusufzai TM and Wolffe AP. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.
OMIM RCV000012590 SCV000032825 pathogenic Rett syndrome 2008-03-11 no assertion criteria provided literature only
OMIM RCV000012591 SCV000032826 risk factor Autism, susceptibility to, X-linked 3 2008-03-11 no assertion criteria provided literature only
RettBASE RCV000012591 SCV000188271 pathogenic Autism, susceptibility to, X-linked 3 2013-12-05 no assertion criteria provided curation
RettBASE RCV000012590 SCV000222441 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000012590 SCV001133059 pathogenic Rett syndrome 2019-09-26 no assertion criteria provided clinical testing

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