Submissions for variant NM_001110792.2(MECP2):c.1193_1236del (p.Leu398fs)

dbSNP: rs63749748

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000170100	SCV000223852	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000170100	SCV000247932	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000170100	SCV000255790	pathogenic	Rett syndrome	2015-07-09	criteria provided, single submitter	clinical testing
Invitae	RCV000473761	SCV000544617	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-08-02	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 10814718, 17387578, 19371229, 19914908, 22525432). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu386Glnfs*4) 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. ClinVar contains an entry for this variant (Variation ID: 143372). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Tyr450Leufs*37) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756326	SCV000884101	pathogenic	not provided	2017-07-27	criteria provided, single submitter	clinical testing	The MECP2 c.1157_1200del; p.Leu386fs variant (rs63749748) has been reported in the literature in several individuals affected with Rett syndrome (Huppke 2000, Khajuria 2009, Vacca 2001, see RettBASE and references therein). It is reported in the ClinVar database as pathogenic (Variation ID: 143372), and is absent from general population databases (1000 Genome Project, Exome Variant Server, Genome Aggregation Database). This variant creates a frameshift and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.1157_1200del: https://www.ncbi.nlm.nih.gov/clinvar/variation/143372/ Link to RettBASE variation database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic 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. Khajuria R et al. Rapid detection of deletions in hotspot C-terminal segment region of MECP2 by routine PCR method: report of two classical Rett syndrome patients of Indian origin. Genet Test Mol Biomarkers. 2009 Apr;13(2):277-80. Vacca M et al. Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females. J Mol Med (Berl). 2001;78(11):648-55.
Mendelics	RCV000170100	SCV001142079	pathogenic	Rett syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000756326	SCV001246082	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000170100	SCV001426956	pathogenic	Rett syndrome	2020-07-02	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1157_1200del44 (p.Leu386GlnfsX4) 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. The variant was absent in 176334 control chromosomes (gnomAD). c.1157_1200del44 has been reported in the literature in multiple individuals affected with Rett Syndrome (e.g. Huppke_2000, Khajuria_2009, Vacca_2001, Weaving_2003). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000756326	SCV001447319	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000756326	SCV001450373	pathogenic	not provided	2018-01-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000756326	SCV002017243	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing
DASA	RCV000170100	SCV002061237	pathogenic	Rett syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The c.1157_1200del;p.(Leu386Glnfs*4) is a null frameshift variant (NMD) in the MECP2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 143372; PMID: 16473305; 22561697; 22525432; 19914908; 19371229; 17387578) - PS4. This variant is not present in population databases (rs63749748, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 12655490) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion	RCV000170100	SCV002572667	pathogenic	Rett syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000143372). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV000756326	SCV002770297	pathogenic	not provided	2022-11-09	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26984561, 22561697, 16077736, 23696494, 27090848, 19914908, 19371229, 10814718)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000756326	SCV002774384	pathogenic	not provided	2021-08-14	criteria provided, single submitter	clinical testing	The frameshift variant causes the premature termination of MECP2 protein synthesis. In addition, it has been reported in individuals with Rett syndrome in the published literature (PMID: 17387578 (2007), 12655490 (2003), 12567420 (2003), 11313756 (2001), 10814718 (2000)). Therefore, the variant is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000170100	SCV003806838	pathogenic	Rett syndrome	2022-03-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated
PreventionGenetics, part of Exact Sciences	RCV003390827	SCV004121531	pathogenic	MECP2-related condition	2022-09-23	criteria provided, single submitter	clinical testing	The MECP2 c.1157_1200del44 variant is predicted to result in a frameshift and premature protein termination (p.Leu386Glnfs*4). This is a recurrent de novo variant reported in female individuals with Rett syndrome (Table 1, Huppke et al. 2000. PubMed ID: 10814718; Table 2, referred to as 1158del44bp, Giunti et al. 2001. PubMed ID: 11738883; Table 1, referred to as 1156-1199del, Nielsen et al. 2001. PubMed ID: 11313756; Table 1, referred to as 1156-1199del, Nielsen et al. 2001. PubMed ID: 11738879; Table 1, Vacca et al. 2001. PubMed ID: 11269512; Table 2, referred to as 1230del44, Watson et al. 2001. PubMed ID: 11283202; Table 1, Zahorakova et al. 2007. PubMed ID: 17387578; Fendri-Kriaa et al. 2012. PubMed ID: 22561697; Table S1, Wen et al. 2020. PubMed ID: 32472557). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/143372/). Frameshift variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Centre for Population Genomics, CPG	RCV000170100	SCV004232303	pathogenic	Rett syndrome	2023-11-22	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). (PMIDs: 11738883‚ 15737703‚ 10814718‚ 11269512‚ 11283202‚ 11313756‚ 12567420‚ 16473305‚ 17387578‚ 19371229‚ 22525432, ClinVar database(Variation ID: 143372) This variant is absent from gnomAD (PM2_Supporting).
RettBASE	RCV000132897	SCV000187878	pathogenic	Angelman syndrome	2012-09-27	no assertion criteria provided	curation
RettBASE	RCV000170100	SCV000222421	pathogenic	Rett syndrome	2012-09-27	no assertion criteria provided	curation