ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1193_1233del (p.Leu398fs) (rs267608327)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000132895 SCV000230276 pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000168701 SCV000247931 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000168701 SCV000281761 pathogenic Rett syndrome 2016-03-17 criteria provided, single submitter research
GeneDx RCV000132895 SCV000330363 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The c.1157_1197del41 pathogenic variant in the MECP2 gene has been reported previously a a de novo change in multiple patients with Rett syndrome previously tested at GeneDx and in the published literature (Cheadle et al., 2000; Zappella et al., 2001; Philippe et al., 2006; Hadzsiev et al., 2011). This variant is not observed in large population cohorts (Lek et al., 2016). The deletion causes a frameshift starting with codon Leucine 386, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Leu386HisfsX5. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 101 amino acids of the MECP2 protein are lost and replaced by 4 incorrect amino acids. Therefore, the presence of the c.1157_1197del41 pathogenic variant is consistent with the diagnosis of Rett syndrome.
Medical Molecular Genetics Department, National Research Center RCV000168701 SCV000492506 pathogenic Rett syndrome 2016-11-02 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000168701 SCV000537169 pathogenic Rett syndrome 2015-06-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000168701 SCV000698531 pathogenic Rett syndrome 2016-05-26 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.1157_1197del41 (p.Leu386Hisfs) is a large deletion, resulting in a reading frame shift. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 1380 control chromosomes, but has been identified in numerous classic and atypical Rett Syndrome patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Undiagnosed Diseases Network,NIH RCV000168701 SCV000746598 pathogenic Rett syndrome 2017-08-31 criteria provided, single submitter clinical testing 41 base pair deletion resulting in a frameshift, which is predicted to result in loss of function in the MECP2 gene, where loss of function is a known mechanism of Rett syndrome. This variant has been observed in multiple, unrelated, affected individuals with Rett syndrome (PMID: 12673788)
Invitae RCV000645107 SCV000766849 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-09-21 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MECP2 gene (p.Leu386Hisfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acids of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many additional individuals affected with Rett syndrome (PMID: 11913567, 17387578, 10767337, 17089071, 17142618, 19914908, 16473305). A number of these observations were reported to be de novo (PMID: 11746022, 12325033), and it has also been reported to segregate with disease in a two sisters with classic Rett syndrome (PMID: 21878110). This variant is also known as c.1157_1197del41 and c.1157del41. ClinVar contains an entry for this variant (Variation ID: 143369). Many different deletions variants in this region of the MECP2 gene have been reported in affected individuals (PMID: 19914908, 16473305, Invitae) and therefore has been defined as a "deletion prone region" (PMID: 21878110, 14974082). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000132895 SCV000884100 pathogenic not provided 2017-05-16 criteria provided, single submitter clinical testing The MECP2 c.1157_1197del, p.Leu386fs variant (rs267608327) is a recurrent deletion found in individuals diagnosed with RETT syndrome (Bienvenu 2002, Chae 2002, Cheadle 2000, Hoffbuhr 2001, Philippe 2006, Ravn 2011, Yaron 2002, Zahorakova 2007), and has associated with both classical disease and a milder form known as the preserved speech variant (Conforti 2002, De Bona 2008, Ravn 2011). It is listed as pathogenic in ClinVar (Variation ID: 143369), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a frameshift, and is predicted to result in a truncated protein. Based on the above information, the variant is classified as pathogenic. References: Bienvenu T et al. Spectrum of MECP2 mutations in Rett syndrome. Genet Test. 2002; 6(1):1-6. Chae J et al. Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome. J Child Neurol. 2002; 17(1):33-6. Cheadle J et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000; 9(7):1119-29. Conforti F et al. Mutation analysis of the MECP2 gene in patients with Rett syndrome. Am J Med Genet A. 2003; 117A(2):184-7. De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000; 8(5):325-30. Hoffbuhr K et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001; 56(11):1486-95. Philippe C et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006; 49(1):9-18. Ravn K et al. Two new Rett syndrome families and review of the literature: expanding the knowledge of MECP2 frameshift mutations. Orphanet J Rare Dis. 2011; 6:58. Yaron Y et al. MECP2 mutations in Israel: implications for molecular analysis, genetic counseling, and prenatal diagnosis in Rett syndrome. Hum Mutat. 2002; 20(4):323-4. Zahorakova D et al. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007; 52(4):342-8.
Mendelics RCV000168701 SCV001142080 pathogenic Rett syndrome 2019-05-28 criteria provided, single submitter clinical testing
RettBASE RCV000132895 SCV000187875 not provided not provided no assertion provided not provided
RettBASE RCV000169930 SCV000187876 pathogenic Mental retardation, X-linked, syndromic 13 2013-12-05 no assertion criteria provided curation
RettBASE RCV000170099 SCV000222419 pathogenic Autism, susceptibility to, X-linked 3 2013-12-05 no assertion criteria provided curation
RettBASE RCV000168701 SCV000222420 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation

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