ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1199_1233del (p.Pro400fs) (rs267608589)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000132928 SCV000845302 likely pathogenic Rett syndrome 2018-08-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286815 SCV001473434 pathogenic none provided 2019-09-13 criteria provided, single submitter clinical testing The MECP2 c.1163_1197del; p.Pro388fs variant (rs267608589), also published as c.1159_1193del, is reported in the literature in multiple individuals affected with classic or atypical Rett syndrome (Fukuda 2005, Hadzsiev 2011, Huppke 2000, Philippe 2006). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 35 nucleotides, so it 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: Fukuda T et al. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005 Apr;27(3):211-7. Hadzsiev K et al. Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations. J Hum Genet. 2011 Mar;56(3):183-7 Huppke P et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. 2000 May 22;9(9):1369-75. Philippe C et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb;49(1):9-18.
Invitae RCV001383623 SCV001582842 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2020-04-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MECP2 gene (p.Pro388Hisfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acids of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Rett Syndrome (PMID: 19914908, 21160487). ClinVar contains an entry for this variant (Variation ID: 143402). This variant disrupts the C-terminus of the MECP2 protein. Other variant(s) that disrupt this region (p.Gln437Alafs*49) have been determined to be pathogenic (PMID: PMID: 11055898, 23696494, 10814718). 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.
GeneDx RCV000132906 SCV001795522 pathogenic not provided 2019-10-16 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15737703, 10814718, 16473305, 21160487)
RettBASE RCV000132906 SCV000187887 not provided not provided no assertion provided not provided
RettBASE RCV000132928 SCV000187909 pathogenic Rett syndrome 2011-11-01 no assertion criteria provided curation

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