ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.538C>T (p.Arg180Ter) (rs61748421)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000133143 SCV000191039 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing The R168X nonsense variant in the MECP2 gene is a well-published variant that accounts for 8-9% of MECP2 variants associated with Rett syndrome (Percy et al., 2007). This variant is typically associated with classic Rett syndrome but has also been identified in females with atypical Rett syndrome (Neul et al., 2008; Halbach et al., 2012). The R168X variant is not observed in large population cohorts (Lek et al., 2016). R168X is predicted to cause loss of normal protein function through protein truncation as the last 319 amino acids, encoding the transcription repression (TR) domain, are removed. Therefore, the presence of R168X is consistent with a diagnosis of an MECP2-related disorder
Genetic Services Laboratory,University of Chicago RCV000012601 SCV000247974 pathogenic Rett syndrome 2014-11-10 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000012601 SCV000255792 pathogenic Rett syndrome 2015-06-15 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000012601 SCV000265599 pathogenic Rett syndrome 2015-11-12 criteria provided, single submitter research
Diagnostic Laboratory, Strasbourg University Hospital RCV000224869 SCV000281749 pathogenic Intellectual disability 2014-07-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000133143 SCV000330970 pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000012601 SCV000537177 pathogenic Rett syndrome 2015-07-09 criteria provided, single submitter clinical testing
Invitae RCV000545521 SCV000645668 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2020-01-08 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 168 (p.Arg168*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 331 amino acids of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This is a recurrent variant that has been reported in many individuals affected with Rett syndrome (PMID: 10577905, 23270700, 24511209). In several of these individuals, the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11828). Experimental studies have shown that this nonsense change impairs the ability of MECP2 to carry out transcriptional repression (PMID: 11058114). In addition, a mouse model carrying this variant recapitulates several aspects of the Rett syndrome phenotype (PMID: 24283265, 25541993, 24626160). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012601 SCV000698540 pathogenic Rett syndrome 2016-08-22 criteria provided, single submitter clinical testing 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000012601 SCV000746420 pathogenic Rett syndrome 2017-12-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626872 SCV000747575 pathogenic Global developmental delay; Developmental regression 2017-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715145 SCV000845973 pathogenic History of neurodevelopmental disorder 2018-11-08 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Institute of Human Genetics,Klinikum rechts der Isar RCV000012601 SCV001149828 pathogenic Rett syndrome 2020-07-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001514 SCV001158824 pathogenic not specified 2019-03-13 criteria provided, single submitter clinical testing 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: 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.
Genomic Medicine Lab, University of California San Francisco RCV000012601 SCV001167650 pathogenic Rett syndrome 2019-02-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000133143 SCV001246089 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
OMIM RCV000012601 SCV000032836 pathogenic Rett syndrome 1999-12-01 no assertion criteria provided literature only
RettBASE RCV000012601 SCV000188135 pathogenic Rett syndrome 2013-06-12 no assertion criteria provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000012601 SCV000257512 pathogenic Rett syndrome 2007-06-25 no assertion criteria provided clinical testing
GeneReviews RCV000012601 SCV000998924 pathogenic Rett syndrome 2019-09-16 no assertion criteria provided literature only

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