ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.789dup (p.Gly264fs) (rs61749751)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000133229 SCV000917619 pathogenic Rett syndrome 2018-05-23 criteria provided, single submitter clinical testing Variant summary: MECP2 c.753dupC (p.Gly252ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.763C>T (p.Arg255X), c.806delG (p.Gly269fsX20), and c.808C>T (p.Arg570X)). The variant was absent in 21631 control chromosomes (gnomAD). The variant, c.753dupC, has been reported in the literature in individuals affected with Rett Syndrome (Zahorakova_2007, Zeev_2002). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000170112 SCV000996099 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-01-10 criteria provided, single submitter clinical testing This frameshifting variant is predicted to result in the premature truncation of the MECP2 protein. This variant has been described previously in an affected male (nomenclature: c.754insC, PMID: 11913564), and listed as a disease causing variant in the Rett syndrome database (http://mecp2.chw.edu.au/). The male patient previously described with this particular variant had a clinical presentation that included hypotonia, autonomic dysfunction, recurrent urinary tract infections, and apneic spells (PMID: 11913564). This mutation occurs in the transcriptional repression domain (TRD), one of two functionally important domains in MECP2 (PMID: 11913564). This variant is not found in the population allele frequency database, gnomAD, thus it is presumed to be rare. Based on the predicted functional impact of the variant and supporting evidence in the literature, the p.Gly264ArgfsTer7 variant is classified as pathogenic.
Invitae RCV000170112 SCV001394967 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-07-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MECP2 gene (p.Gly252Argfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 235 amino acids of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family with clinical features of Rett syndrome (PMID: 11913564). ClinVar contains an entry for this variant (Variation ID: 143688). This variant disrupts the C-terminus of the MECP2 protein. Other variant(s) that disrupt this region (p.Arg270*) have been determined to be pathogenic (PMID: 18174548, 16473305, 23270700, 10854091). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
RettBASE RCV000133229 SCV000188229 pathogenic Rett syndrome 2007-11-01 no assertion criteria provided curation
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000144424 SCV000189479 not provided not provided no assertion provided not provided
RettBASE RCV000170112 SCV000222435 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2007-11-01 no assertion criteria provided curation

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