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

dbSNP: rs267608327

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2022-03-24	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 (gnomAD); This variant is associated with the following publications: (PMID: 26984561, 16473305, 10767337, 11746022, 17142618, 21878110, 23810759, 17387578, 11402105, 21160487, 33168794, 31943886, 34876818, 34782041, 32105570, 32631363)
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 Children's Health, Delaware	RCV000168701	SCV000537169	pathogenic	Rett syndrome	2015-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645107	SCV000766849	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu386Hisfs*5) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 10767337, 11746022, 11913567, 12325033, 16473305, 17089071, 17142618, 17387578, 19914908, 21878110). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1157_1197del41 and c.1157del41. ClinVar contains an entry for this variant (Variation ID: 143369). 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
CeGaT Center for Human Genetics Tuebingen	RCV000132895	SCV001747675	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251999	SCV002523061	pathogenic	See cases	2021-03-24	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PM6
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000168701	SCV002525929	likely pathogenic	Rett syndrome	2022-04-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002251999	SCV003804920	pathogenic	See cases	2022-11-11	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM1,PM2,PP5
Baylor Genetics	RCV000168701	SCV004041448	pathogenic	Rett syndrome	2023-08-15	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000168701	SCV004808877	pathogenic	Rett syndrome	2024-03-22	criteria provided, single submitter	curation	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (ClinVar Variation ID: 143369 PMID:11269512 , PMID:23810759 , PMID:23696494 , PMID:21878110 , PMID:20031356 ). This variant is absent from gnomAD (PM2_Supporting).
Neuberg Centre For Genomic Medicine, NCGM	RCV000168701	SCV005382398	pathogenic	Rett syndrome	2023-05-20	criteria provided, single submitter	clinical testing	The frameshift variant c.1193_1233del (p.Leu398HisfsTer5) in the MECP2 gene has been reported previously in individuals affected with Rett Syndrome (Chapleau et al., 2013; Ravn et al., 2011). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (multiple submitters). This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000012592	SCV000032827	pathogenic	Rett syndrome, zappella variant	2003-03-01	no assertion criteria provided	literature only
OMIM	RCV000170099	SCV000032828	risk factor	Autism, susceptibility to, X-linked 3	2003-03-01	no assertion criteria provided	literature only
RettBASE	RCV000132895	SCV000187875	not provided	not provided		flagged submission	not provided
RettBASE	RCV000169930	SCV000187876	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2013-12-05	flagged submission	curation
RettBASE	RCV000170099	SCV000222419	pathogenic	Autism, susceptibility to, X-linked 3	2013-12-05	flagged submission	curation
RettBASE	RCV000168701	SCV000222420	pathogenic	Rett syndrome	2013-12-05	no assertion criteria provided	curation