ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1200_1243del (p.Pro400_Pro401insTer) (rs61752992)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000132932 SCV000190976 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing The c.1164_1207del44 pathogenic variant in the MECP2 gene has been reported previously in females and males with classic Rett syndrome or a Rett-like phenotype (Huppke et al., 2006; Dayer et al., 2007; RettBASE). The deletion causes a frameshift starting with codon Proline 389 and changes this amino acid to a premature Stop codon, denoted p.Pro389Ter (P389X). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 98 amino acids of the MECP2 protein are lost. The c.1164_1207del44 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1164_1207del44 as a pathogenic variant.
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000170103 SCV000223848 pathogenic Rett syndrome criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000132932 SCV000230247 pathogenic not provided 2014-11-22 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000170103 SCV000247935 pathogenic Rett syndrome 2015-06-24 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000491803 SCV000299216 pathogenic Smith-Magenis Syndrome-like 2016-08-15 criteria provided, single submitter research mother presented with highly skewed x inactivation; daughter was random.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415090 SCV000493008 pathogenic Delayed speech and language development; Delayed gross motor development; Loss of ability to walk 2014-03-07 criteria provided, single submitter clinical testing
Invitae RCV000169932 SCV000544621 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-12-11 criteria provided, single submitter clinical testing This sequence change deletes 44 nucleotides from exon 4 of the MECP2 mRNA (c.1164_1207del44), causing a frameshift at codon 389. This creates a premature translational stop signal in the last exon of the MECP2 mRNA (p.Pro389*). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MECP2 protein. This variant is not present in population databases (rs63749749, ExAC no frequency). This variant is considered a recurrent variant and has been reported in many individuals and families affected with Rett syndrome or intellectual disability (PMID: 17089071, 17387578, 19914908, 21982064, 20151026). This variant is also known as c.1164_1207del44 in the literature. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624849 SCV000740856 pathogenic Inborn genetic diseases 2015-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768267 SCV000898819 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 2018-04-23 criteria provided, single submitter clinical testing MECP2 NM_004992.3 exon 4 p.Pro389* (c.1164_1207del): This variant has been reported in the literature in several individuals with Rett syndrome (Dayer 2007 PMID:16844334, Zaharakova 2007 PMID:17387578, Bebbington 2010 PMID:19914908, RettBASE (http://mecp2.chw.edu.au/mecp2/index.php)). Of note, the reported clinical phenotype of these individuals was variable and features were present in both male and female probands. This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:143406). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a deletion of 44 nucleotides and creates a premature stop at codon 389 which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic.
Mendelics RCV000170103 SCV001142078 pathogenic Rett syndrome 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000170103 SCV001150165 pathogenic Rett syndrome 2019-09-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002125 SCV001159976 pathogenic not specified 2018-09-13 criteria provided, single submitter clinical testing The MECP2 c.1164_1207del44; p.Pro389Ter variant (rs63749749), is reported in the literature in multiple individuals and families affected with Rett syndrome or intellectual disability (Bebbington 2010, Li 2007, see link to RettBASE and references therein). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 143406), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MECP2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Additionally, other truncating variants downstream have been identified in patients with Rett syndrome and are considered pathogenic (RettBASE and references therein). Based on available information, the p.Pro389Ter variant is considered to be pathogenic. References: Link to RettBASE: http://mecp2.chw.edu.au/mecp2/index.php Bebbington A et al. Updating the profile of C-terminal MECP2 deletions in Rett syndrome. J Med Genet. 2010 Apr;47(4):242-8. Li MR et al. MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. J Hum Genet. 2007;52(1):38-47.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000132932 SCV001334428 pathogenic not provided 2019-12-12 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196663 SCV001367286 pathogenic Seizures; Delayed speech and language development; Microcephaly; Delayed gross motor development; Loss of ability to walk; Delayed fine motor development 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. This variant was detected in heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000170103 SCV001428674 pathogenic Rett syndrome 2020-02-05 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
RettBASE RCV000169931 SCV000187884 pathogenic Autism, susceptibility to, X-linked 3 2012-08-10 no assertion criteria provided curation
RettBASE RCV000169932 SCV000187913 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2012-08-10 no assertion criteria provided curation
RettBASE RCV000170102 SCV000222423 pathogenic Mental retardation, X-linked, syndromic 13 2012-08-10 no assertion criteria provided curation
RettBASE RCV000170103 SCV000222424 pathogenic Rett syndrome 2012-08-10 no assertion criteria provided curation
Clinical Genomics Program,Stanford Medicine RCV000170103 SCV001427211 pathogenic Rett syndrome 2019-12-17 no assertion criteria provided clinical testing The p.Pro389* variant in the MECP2 gene has been previously reported in >20 unrelated individuals with classic or variant Rett syndrome (Buyse et al., 2000; Li et al., 2007; Zahorakova et al., 2007; Augenstein et al., 2009; Bebbington et al., 2010; Psoni et al., 2012; Halbach et al., 2016; Krishnaraj et al., 2017). The p.Pro389* variant was identified de novo in this individual and previously reported de novo in at least two additional individuals with classic or variant Rett syndrome (Zahorakova et al., 2007; Psoni et al., 2012). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/); however, the ability to detect this type of variation is limited. The p.Pro389* (c.1164_1207del44) variant results in 44 base pair deletion, which causes a premature termination codon 1 amino acid downstream. This premature termination codon is in exon 4 of 4 coding exons, and is therefore not predicted to undergo nonsense-mediated decay, increasing the likelihood of an expressed protein. This variant is located in the C-terminal region of MECP2. Frameshift and other truncating variants have been well described in this region and are predicted to disrupt the function of MECP2 (Kaur et al., 2019). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.1164_1207del44 variant as pathogenic for X-linked MECP2-associated disorders, based on the information above. [ACMG evidence codes used: PVS1, PS2; PS4, PM2_supporting]

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