ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.799C>T (p.Arg267Ter) (rs61749721)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081209 SCV000191046 pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing R255X is a recurrent pathogenic variant that accounts for approximately 8-9% of MECP2 pathogenic variants (Percy et al., 2007). It has been published many times in association with both classic and atypical Rett syndrome (for examples, see Hoffbuhr et al., 2001; Yamada et al., 2001; Neul et al., 2008; Lima et al., 2009). R255X is predicted to cause loss of normal protein function through premature protein truncation, and functional studies indicate this variant impairs microtubule stability and interferes with transcriptional repression (Yusufzai et al., 2000; Delepine et al., 2013). Therefore, the presence of R255X is consistent with a diagnosis of a MECP2-related disorder
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081209 SCV000230266 pathogenic not provided 2016-03-17 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000012602 SCV000247996 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012602 SCV000282496 pathogenic Rett syndrome 2015-10-20 criteria provided, single submitter clinical testing This nonsense variant is predicted to cause a truncated protein, which is commonly known mechanism for disease. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least ten RTT patients. Many clinical labs and databases classify this variant as pathogenic. Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes. Considering all, this variant has been classified as pathogenic.
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000012602 SCV000494538 likely pathogenic Rett syndrome 2016-11-16 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000012602 SCV000537189 pathogenic Rett syndrome 2015-07-15 criteria provided, single submitter clinical testing Developmental arrest; Repeated hand to mouth movements; Microcephaly; Seizures; Normal development to 6 months of age
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999806 SCV000604145 pathogenic not specified 2018-09-28 criteria provided, single submitter clinical testing The MECP2 c.763C>T, p.Arg255Ter variant (rs61749721) induces an early termination codon and is predicted to result in a truncated protein or absent transcript. This variant is one of the most common disease causing variants of Rett syndrome (RTT) (Neul 2008), and has been associated with both classical and atypical RTT (see link to RettBASE and references therein). Functional studies showed p.Arg255Ter to be less stable in vivo and lead to deficient transcriptional repression (Yusufzai 2000). Furthermore, this variant is reported as pathogenic in ClinVar (Variation ID: 11829), and is absent from population databases (Exome Variant Server, Exome Aggregation Consortium). Therefore, this variant is considered to be pathogenic. REFERENCES Link to RettBASE: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Neul JL et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008; 70(16):1313-21. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9.
Fulgent Genetics,Fulgent Genetics RCV000515183 SCV000611281 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
Invitae RCV000553858 SCV000645677 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-12-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MECP2 gene (p.Arg255*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 232 amino acids (~48%) of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Rett syndrome (PMID: 23270700, 1241840, 17089071, 10508514), including several de novo observations. ClinVar contains an entry for this variant (Variation ID: 11829). Experimental studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates Rett syndrome-like phenotypes (PMID: 25634563). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000012602 SCV000680025 pathogenic Rett syndrome 2017-07-28 criteria provided, single submitter clinical testing A heterozygous nonsense variant was identified, NM_004992.3(MECP2):c.763C>T in exon 4 of the MECP2. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 255, NM_004992.3(MECP2):p.(Arg255*). Previous studies have shown that this results in loss of function through protein truncation (Yusufzai TM. et al, 2000). This variant is not present in the gnomAD population database and it has been previously reported multiple times in patients with Rett Syndrome (ClinVar). Additionally, functional studies showed that this variant causes loss of MECP2 transcription repression and DNA binding functions (Yusufzai TM. et al, 2000) and affects microtubule dynamics in astrocytes (Delépine C. et al,2013). Additionally, other truncating variants downstream of c.763C>T in MECP2 have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information, this variant has been classified as PATHOGENIC.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000012602 SCV000803887 pathogenic Rett syndrome 2017-11-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000717933 SCV000848794 pathogenic History of neurodevelopmental disorder 2018-11-10 criteria provided, single submitter clinical testing Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081209 SCV001246087 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
OMIM RCV000012602 SCV000032837 pathogenic Rett syndrome 2008-03-11 no assertion criteria provided literature only
RettBASE RCV000169938 SCV000188235 pathogenic Mental retardation, X-linked, syndromic 13 2013-12-05 no assertion criteria provided curation
RettBASE RCV000012602 SCV000222436 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000012602 SCV000257514 pathogenic Rett syndrome 2014-10-01 no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000012602 SCV000537794 pathogenic Rett syndrome no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000081209 SCV000804257 pathogenic not provided 2015-04-03 no assertion criteria provided clinical testing
GeneReviews RCV000012602 SCV000998925 pathogenic Rett syndrome 2019-09-16 no assertion criteria provided literature only

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