ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.842del (p.Gly281fs) (rs61750241)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081211 SCV000190966 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The c.806delG pathogenic variant in the MECP2 gene has been reported multiple times in association with Rett syndrome in females and neonatal progressive encephalopathy in males (Wan et al., 1999; Kankirawatana et al., 2006). The deletion causes a frameshift starting with codon Glycine 269, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Gly269AlafsX20. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation and is consistent with the diagnosis of a MECP2-related disorder. The variant is found in INFANT-EPI panel(s).
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000168691 SCV000223843 pathogenic Rett syndrome criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081211 SCV000230256 pathogenic not provided 2013-11-12 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000168691 SCV000247997 pathogenic Rett syndrome 2013-11-15 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000168691 SCV000255794 pathogenic Rett syndrome 2014-10-03 criteria provided, single submitter clinical testing
Invitae RCV000169939 SCV000544619 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-12-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MECP2 gene (p.Gly269Alafs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 218 amino acids of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Rett syndrome (PMID: 10854091, 12111643, 16473305, 17089071) and found to segregate with disease in one family (PMID: 1057790). It was also reported in an individual with childhood-onset mitochondrial respiratory complex deficiency (PMID: 26741492). In the literature, this variant is also known as V288X. ClinVar contains an entry for this variant (Variation ID: 95202). This variant has been reported to affect MECP2 protein function (PMID: 11058114). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000168691 SCV000680285 pathogenic Rett syndrome 2017-12-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624370 SCV000740973 pathogenic Inborn genetic diseases 2014-06-06 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 RCV000168691 SCV000781707 pathogenic Rett syndrome 2016-11-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000081211 SCV000842737 pathogenic not provided 2014-10-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000715840 SCV000846671 pathogenic History of neurodevelopmental disorder 2019-03-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000009 SCV000885679 pathogenic not specified 2019-03-17 criteria provided, single submitter clinical testing The MECP2 c.806delG; p.Gly269fs variant (rs61750241) has been reported in multiple individuals affected with Rett syndrome (De Bona 2000, Pan 2002, Philippe 2006). It has also been reported in an individual with childhood-onset mitochondrial respiratory complex deficiency but not in either parent, suggesting a de novo origin in this individual (Kohda 2016). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 95202), and it 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 deletes a single nucleotide, resulting in a frameshift and 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 MECP2 protein. Functional analysis of the truncated variant protein indicates an inability to repress transcription through its transcriptional repression domain (Yusufzai 2000). Based on available information, this variant is considered pathogenic. References: De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000 May;8(5):325-30. Kohda M et al. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. Pan H et al. MECP2 gene mutation analysis in Chinese patients with Rett syndrome. Eur J Hum Genet. 2002 Aug;10(8):484-6. 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. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.
Integrated Genetics/Laboratory Corporation of America RCV000168691 SCV000919617 pathogenic Rett syndrome 2018-03-30 criteria provided, single submitter clinical testing Variant summary: MECP2 c.806delG (p.Gly269AlafsX20) 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.880C>T, p.Arg294X; c.1079C>A, p.Ser360X). The variant was absent in 177658 control chromosomes (gnomAD). c.806delG has been reported in the literature in numerous individuals affected with Rett Syndrome (Li_2007, Miltenberger-Miltenyi_2003), including one family in which the variant segregated with disease (Wan_1999). Additionally, one male mutation carrier was affected with encephalopathy (Leuzzi_2004). At least one publication reports experimental evidence evaluating an impact on protein function which shows this truncation variant disrupts MECP2 protein activity (Yusufzai_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000850572 SCV000992788 pathogenic Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; Mental retardation, X-linked, syndromic 13; Rett syndrome 2017-12-31 criteria provided, single submitter clinical testing
RettBASE RCV000169939 SCV000188244 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2013-06-12 no assertion criteria provided curation
RettBASE RCV000170113 SCV000222437 pathogenic Mental retardation, X-linked, syndromic 13 2013-06-12 no assertion criteria provided curation
RettBASE RCV000168691 SCV000222438 pathogenic Rett syndrome 2013-06-12 no assertion criteria provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000168691 SCV000804883 pathogenic Rett syndrome 2016-05-03 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.