Submissions for variant NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter)

dbSNP: rs61750240

Total submissions: 43

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081212	SCV000191047	pathogenic	not provided	2021-04-19	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 217 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and in RETTbase (HGMD; RETTbase); Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587)
Genetic Services Laboratory, University of Chicago	RCV000146359	SCV000193642	pathogenic	Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome	2014-02-12	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000012586	SCV000223840	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000081212	SCV000230264	pathogenic	not provided	2013-05-10	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000081212	SCV000537198	pathogenic	not provided	2015-07-17	criteria provided, single submitter	clinical testing
Invitae	RCV000169940	SCV000544624	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg270*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 217 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: 10854091, 11241840, 16473305, 17089071, 18174548, 23270700; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11815). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515283	SCV000611282	pathogenic	Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome; Autism, susceptibility to, X-linked 3	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012586	SCV000698544	pathogenic	Rett syndrome	2016-09-30	criteria provided, single submitter	clinical testing	Variant summary: The MECP2 c.808C>T (p.Arg270X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 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 (e.g. p.Arg294X, p.Ser360X, etc.). One in silico tool predicts a damaging outcome for this variant. This variant lies in the transcription repression domain (TRD) and one of the major functions of MECP2 is repression of transcription mediated by its TRD. Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression. Additionally, this variant is a known common pathogenic variant that has been reported in numerous classic Rett Syndrome patients in the literature and has been classified by multiple clinical labs and databases as pathogenic. This variant was found in 1/86029 control chromosomes at a frequency of 0.0000116. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000624100	SCV000741795	pathogenic	Inborn genetic diseases	2016-10-12	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000012586	SCV000781709	pathogenic	Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000081212	SCV000885680	pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing	The MECP2 c.808C>T; p.Arg270Ter variant (rs61750240) is a recurrent alteration in patients diagnosed with Rett syndrome (Cheadle 2000, Dragich 2000, RettBase). Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11815), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic 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. Dragich J et al Rett syndrome: a surprising result of mutation in MECP2. Hum Mol Genet. 2000; 9(16):2365-75. Yusufzai T et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000012586	SCV000967749	pathogenic	Rett syndrome	2018-09-12	criteria provided, single submitter	clinical testing	The p.Arg270X variant in MECP2 has been reported in at least 80 heterozygous fem ales, including at least 6 de novo cases and 1 mosaic male with clinical feature s of Rett syndrome (Cheadle et al. 2000, Topcu et al. 2002, Temudo et al. 2007, Knight et al. 2013, Maortua et al. 2013, Cuddapah et al. 2014, Pidcock et al. 20 16) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 270. This alteration occurs within th e last exon and is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yu sufzai and Wollfe 2000, Delepine et al. 2013). In summary, this variant meets cr iteria to be classified as pathogenic for Rett syndrome in an X-linked manner ba sed upon case counts, de novo occurrence, absence from controls, predicted impac t on protein and functional evidence. ACMG/AMP Criteria applied: PS4, PS2, PM6_S , PM2, PVS1_Strong, PS3_Moderate.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000012586	SCV000999372	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000012586	SCV001149827	pathogenic	Rett syndrome	2018-01-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000081212	SCV001150513	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	MECP2: PVS1, PS2, PM2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196907	SCV001367541	pathogenic	Autism, susceptibility to, X-linked 3	2020-01-30	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012586	SCV001428769	pathogenic	Rett syndrome	2023-03-31	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP, PP4
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000012586	SCV001448873	pathogenic	Rett syndrome	2017-09-15	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000081212	SCV001449677	pathogenic	not provided	2017-01-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012586	SCV001527167	pathogenic	Rett syndrome	2018-12-31	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to occur de novo in one patient with autism [PMID 28831199] and multiple patients in Baylor Genetics with neurodevelopmental phenotypes
Institute of Human Genetics, University of Leipzig Medical Center	RCV001705588	SCV001934452	pathogenic	Syndromic X-linked intellectual disability Lubs type	2021-02-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000081212	SCV002017246	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing
DASA	RCV000012586	SCV002107116	pathogenic	Rett syndrome	2022-03-05	criteria provided, single submitter	clinical testing	The c.808C>T;p.(Arg270*) variant creates a premature translational stop signal in the MECP2 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11058114; 23238081) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 11815; PMID: 18174548; PMID: 16473305; PMID: 23270700; PMID: 10854091; PMID: 17089071) - PS4. This variant is not present in population databases (rs61750240- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 11241840) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion	RCV000012586	SCV002318910	pathogenic	Rett syndrome	2022-03-22	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): 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/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011815, PMID:10767337). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000012586	SCV002598531	pathogenic	Rett syndrome	2022-05-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012586	SCV002768332	pathogenic	Rett syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rett syndrome (MIM#312750). (I) 0110 - This gene is known to be predominantly associated with X-linked dominant disease. However, X-linked recessive disease has also been reported. In addition, both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (I) 0204 - Variant is predicted to result in a truncated protein [(premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Rett syndrome (ClinVar, RettBASE, VCGS). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000012586	SCV004046997	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	The stop_gained (c.844C>T) variant is most commonly reported in heterozygous state in patients affected with Rett syndrome (Moog, U. et. al., 2003; Laccone F et. al., 2001) but has also been reported in individuals with atypical Rett syndrome (RettBASE). This variant is clearly defined as a Rett syndrome causative allele that accounts for ~7% of disease-causing variants (Percy A.K. et. al., 2007; Philippe C. et. al., 2006) and has been shown to arise de novo in individuals affected with Rett syndrome (Laccone F et. al., 2001). Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in MECP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG	RCV000012586	SCV004101577	pathogenic	Rett syndrome	2023-09-25	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 2.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence with confirmed parental relationships in at least 2 individuals with Rett syndrome , or in at least 1 individual with confirmed parental relationships AND assumed the novo in at least 2 individuals with unconfirmed parental relationships (PS2_Very_Strong). (ClinVar Accession: SCV002768332.1 , PMID 10854091, PMID 10854091). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting).
Daryl Scott Lab, Baylor College of Medicine	RCV000012586	SCV004102713	pathogenic	Rett syndrome	2023-11-10	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000012586	SCV004123070	pathogenic	Rett syndrome	2023-07-01	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000012586	SCV004171246	pathogenic	Rett syndrome	2023-11-30	criteria provided, single submitter	clinical testing
OMIM	RCV000012586	SCV000032821	pathogenic	Rett syndrome	2008-03-11	no assertion criteria provided	literature only
RettBASE	RCV000169940	SCV000188246	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2013-12-05	no assertion criteria provided	curation
RettBASE	RCV000012586	SCV000222439	pathogenic	Rett syndrome	2013-12-05	no assertion criteria provided	curation
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000012586	SCV000574735	pathogenic	Rett syndrome	2016-10-03	no assertion criteria provided	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000081212	SCV000778230	pathogenic	not provided	2016-11-21	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000081212	SCV000804250	pathogenic	not provided	2015-04-03	no assertion criteria provided	clinical testing
GeneReviews	RCV000012586	SCV000998926	not provided	Rett syndrome		no assertion provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000081212	SCV001929888	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000081212	SCV001965916	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081212	SCV001979370	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000012586	SCV003927896	pathogenic	Rett syndrome	2023-04-01	no assertion criteria provided	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000012586	SCV004032207	pathogenic	Rett syndrome		no assertion criteria provided	research