ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter) (rs61750240)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081212 SCV000191047 pathogenic not provided 2017-10-18 criteria provided, single submitter clinical testing R270X is a common recurrent variant that accounts for approximately 7% of MECP2 pathogenic variants (Percy et al., 2007). This variant is often observed in females with classic Rett syndrome but has also been identified in patients with atypical Rett syndrome (RettBASE; Neul et al., 2008; Bebbington et al., 2008). R270X is predicted to cause loss of normal protein function through protein truncation. Functional studies indicate that R270X impairs the stability of the MECP2 protein and affects its ability to repress transcription (Yusufzai & Wolffe, 2000). Therefore, the presence of R270X is consistent with a diagnosis of Rett syndrome
Genetic Services Laboratory,University of Chicago RCV000146359 SCV000193642 pathogenic Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome 2014-02-12 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000012586 SCV000223840 pathogenic Rett syndrome criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081212 SCV000230264 pathogenic not provided 2013-05-10 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000081212 SCV000537198 pathogenic not provided 2015-07-17 criteria provided, single submitter clinical testing
Invitae RCV000169940 SCV000544624 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-09-03 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 270 (p.Arg270*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 217 amino acids of the MECP2 protein. This variant is not present in population databases (rs61750240, ExAC no frequency). This variant is clearly defined as a Rett syndrome causative allele that accounts for ~7% of disease-causing variants (PMID: 18174548, 16473305, 23270700, 10854091, 17089071) and has been shown to arise de novo in individuals affected with Rett syndrome (PMID: 11241840). It is most commonly reported in individuals affected with classic Rett syndrome but has also been reported in individuals with atypical Rett syndrome (RettBASE). ClinVar contains an entry for this variant (Variation ID: 11815). Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (PMID: 11058114, 23238081). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515283 SCV000611282 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 RCV000012586 SCV000698544 pathogenic Rett syndrome 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.808C>T (p.Arg270X) 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. p.Arg294X, p.Ser360X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant lies in the transcription repression domain (TRD) and one of the major functions of MECP2 is repression of transcription mediated by its TRD. Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression. Additionally, this variant is a known common pathogenic variant that has been reported in numerous classic Rett Syndrome patients in the literature and has been classified by multiple clinical labs and databases as pathogenic. This variant was found in 1/86029 control chromosomes at a frequency of 0.0000116. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624100 SCV000741795 pathogenic Inborn genetic diseases 2016-10-12 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 RCV000012586 SCV000781709 pathogenic Rett syndrome 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000081212 SCV000885680 pathogenic not provided 2018-06-08 criteria provided, single submitter clinical testing The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). 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 RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Cheadle J 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; 9(7):1119-29. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000012586 SCV000967749 pathogenic Rett syndrome 2018-09-12 criteria provided, single submitter clinical testing The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic male with clinical feature s of Rett syndrome (Cheadle et al. 2000, Topcu et al. 2002, Temudo et al. 2007, Knight et al. 2013, Maortua et al. 2013, Cuddapah et al. 2014, Pidcock et al. 20 16) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 270. This alteration occurs within th e last exon and is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yu sufzai and Wollfe 2000, Delepine et al. 2013). In summary, this variant meets cr iteria to be classified as pathogenic for Rett syndrome in an X-linked manner ba sed upon case counts, de novo occurrence, absence from controls, predicted impac t on protein and functional evidence. ACMG/AMP Criteria applied: PS4, PS2, PM6_S , PM2, PVS1_Strong, PS3_Moderate.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000012586 SCV000999372 pathogenic Rett syndrome criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000012586 SCV001149827 pathogenic Rett syndrome 2018-01-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081212 SCV001150513 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196907 SCV001367541 pathogenic Global developmental delay; Abnormal facial shape; Microcephaly 2020-01-30 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM4. This variant was detected in heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000012586 SCV001428769 pathogenic Rett syndrome 2019-09-24 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
OMIM RCV000012586 SCV000032821 pathogenic Rett syndrome 2008-03-11 no assertion criteria provided literature only
RettBASE RCV000169940 SCV000188246 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2013-12-05 no assertion criteria provided curation
RettBASE RCV000012586 SCV000222439 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000012586 SCV000574735 pathogenic Rett syndrome 2016-10-03 no assertion criteria provided clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000081212 SCV000778230 pathogenic not provided 2016-11-21 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000081212 SCV000804250 pathogenic not provided 2015-04-03 no assertion criteria provided clinical testing
GeneReviews RCV000012586 SCV000998926 pathogenic Rett syndrome 2019-09-16 no assertion criteria provided literature only

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