Submissions for variant NM_001110792.2(MECP2):c.538C>T (p.Arg180Ter)

dbSNP: rs61748421

Total submissions: 43

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000133143	SCV000191039	pathogenic	not provided	2021-03-15	criteria provided, single submitter	clinical testing	Recurrent pathogenic variant that accounts for 8-9% of MECP2 pathogenic variants (Percy et al., 2007); Typically associated with classic Rett syndrome but also identified in females with atypical Rett syndrome (Halbach et al., 2012; Neul et al., 2008); Nonsense variant in the C-terminus predicted to result in protein truncation as the last 319 amino acids are lost, and other loss-of-function variants have been reported downstream (Stenson et al., 2014; RettBASE); Published functional studies indicate this variant truncates all of the transcriptional repression domain (TRD) and impairs normal protein function (Yusufzai et al., 2000; Bissonnette et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26175308, 24626160, 10577905, 24283265, 23270700, 24511209, 23238081, 25541993, 18337588, 22190343, 15228575, 28394409, 16077729, 28333917, 18174548, 30564305, 29655203, 31164858, 31209962, 31144778, 31535341, 32393352, 32631363, 11058114, 33144682, 12030010, 31130284, 33258288)
Genetic Services Laboratory, University of Chicago	RCV000012601	SCV000247974	pathogenic	Rett syndrome	2014-11-10	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000012601	SCV000255792	pathogenic	Rett syndrome	2015-06-15	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000012601	SCV000265599	pathogenic	Rett syndrome	2015-11-12	criteria provided, single submitter	research
Diagnostic Laboratory, Strasbourg University Hospital	RCV000224869	SCV000281749	pathogenic	Intellectual disability	2014-07-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000133143	SCV000330970	pathogenic	not provided	2018-02-08	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000012601	SCV000537177	pathogenic	Rett syndrome	2015-07-09	criteria provided, single submitter	clinical testing
Invitae	RCV000545521	SCV000645668	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg168*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 319 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: 10577905, 23270700, 24511209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11828). 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, 24283265, 24626160, 25541993). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012601	SCV000698540	pathogenic	Rett syndrome	2016-08-22	criteria provided, single submitter	clinical testing	Variant summary: The MECP2 c.502C>T (p.Arg168X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate the transcriptional repression domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.710delG/p.Gly237fsX11). This variant is reported as one of the most common pathogenic variants in literature and clinical databases. The available clinical data and functional studies are consistent with pathogenic outcome for the variant. This variant is absent in 87628 control chromosomes. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000012601	SCV000746420	pathogenic	Rett syndrome	2017-12-03	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626872	SCV000747575	pathogenic	Global developmental delay; Developmental regression	2017-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311514	SCV000845973	pathogenic	Inborn genetic diseases	2018-11-08	criteria provided, single submitter	clinical testing	The p.R168* pathogenic mutation (also known as c.502C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 502. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation is one of eight common Rett syndrome mutations and has been associated with earlier onset and more severe symptoms than other mutations; however, it has also been detected in unaffected females (Wan M et al. Am. J. Hum. Genet., 1999 Dec;65:1520-9; Cuddapah VA et al. J. Med. Genet., 2014 Mar;51:152-8; Knight O et al. Brain Dev., 2013 Nov;35:912-20). In one study, in vitro and in vivo studies showed that this mutation alters expression of downstream genes, induces expansion of lateral neurons, and its mutant protein is able to bind to methylated DNA, suggesting that this mutation may function in a dominant negative manner (Neul JL et al. Neuroscientist, 2004 Apr;10:118-28). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000012601	SCV001149828	pathogenic	Rett syndrome	2020-07-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000133143	SCV001158824	pathogenic	not provided	2020-10-09	criteria provided, single submitter	clinical testing	The MECP2 c.502C>T; p.Arg168Ter variant (rs61748421) is one of the most common variants identified in individuals with Rett syndrome (see link, Pidcock 2016, Wan 1999), and is shown to have impaired functional capabilities (Bissonnette 2014, Delepine 2013, Yusufzai 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11828). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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 Link to RettBASE database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Bissonnette JM et al. Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X. Neuroscience. 2014 May 16;267:166-76. Delepine C et al. MeCP2 deficiency is associated with impaired microtubule stability. FEBS Lett. 2013 Jan 16;587(2):245-53. Pidcock FS et al. Functional outcomes in Rett syndrome. Brain Dev. 2016 Jan;38(1):76-81. Wan M et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec;65(6):1520-9. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.
Genomic Medicine Lab, University of California San Francisco	RCV000012601	SCV001167650	pathogenic	Rett syndrome	2019-02-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000133143	SCV001246089	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000133143	SCV001447189	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000012601	SCV001448879	pathogenic	Rett syndrome	2018-11-08	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000133143	SCV001449659	pathogenic	not provided	2016-12-08	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000012601	SCV001499838	pathogenic	Rett syndrome	2019-06-17	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000012601	SCV001976691	pathogenic	Rett syndrome	2021-10-01	criteria provided, single submitter	clinical testing	PVS1, PS3, PM1, PM2, PP3
3billion	RCV000012601	SCV002012018	pathogenic	Rett syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000011828.27). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000133143	SCV002017254	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012601	SCV002044454	pathogenic	Rett syndrome	2023-12-08	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2_VSTR,PS4,PM2_SUP
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000012601	SCV002072455	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000012601	SCV002581246	pathogenic	Rett syndrome	2023-03-20	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000012601	SCV002762853	pathogenic	Rett syndrome	2021-02-17	criteria provided, single submitter	research	A mosaic hemizygous (somatic mosaicism) nonsense variation in exon 3 of the MECP2 gene that results in premature truncation of the Arginine at codon 180. The observed variant c.538C>T(p.Arg180Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2(HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo (post-zygotic, somatic). In summary, the variant meets our criteria to be classified as a pathogenic variant.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000012601	SCV003836723	pathogenic	Rett syndrome	2022-02-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000012601	SCV004032458	pathogenic	Rett syndrome	2023-01-20	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000012601	SCV004048036	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	The stop gained variant c.538C>T(p.Arg180Ter) in MECP2 gene is a recurrent variant that has been reported in many individuals affected with Rett syndrome (Wan M et.al.,1999 ) . This variant has been reported to the ClinVar database as Pathogenic . The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. 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	RCV000012601	SCV004098730	pathogenic	Rett syndrome	2023-08-14	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: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). 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). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). This variant is absent from gnomAD (PM2_Supporting).
PreventionGenetics, part of Exact Sciences	RCV003390670	SCV004120015	pathogenic	MECP2-related condition	2023-12-08	criteria provided, single submitter	clinical testing	The MECP2 c.502C>T variant is predicted to result in premature protein termination (p.Arg168*). This nonsense variant has been documented in several individuals with Rett syndrome (see for example Wan et al. 1999. PubMed ID: 10577905; Archer et al. 2006. PubMed ID: 16183801; Philippe et al. 2006. PubMed ID: 16473305; Percy et al. 2007. PubMed ID: 18174548). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003984807	SCV004801242	pathogenic	Syndromic X-linked intellectual disability Lubs type	2024-03-14	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000012601	SCV004801465	pathogenic	Rett syndrome	2020-10-01	criteria provided, single submitter	clinical testing	The MECP2 c.502C>T p.(Arg168Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with Rett syndrome, and is one of the most common pathogenic variants associated with the disorder (Kaur et al. 2001; Knight et al. 2013; Cudappah et al. 2014). In the majority of individuals, the variant was identified in a de novo state (Girard et al. 2001; Gu et al. 2000). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Arg168 residue lies in the linker region between the methyl-CpG-binding domain and the transcriptional repressor domain (TRD), and truncation at this residue will abolish the TRD. Functional studies found that when the p.(Arg168Ter) variant MECP2 protein was expressed in Xenopus oocytes, the variant protein failed to repress transcription in contrast to the wild-type protein (Yusufzai and Wolffe 2000). In addition, mice expressing the variant showed several features associated with Rett syndrome, including underweight and motor deficits (Schaevitz et al. 2013). Based on the collective evidence the c.502C>T p.(Arg168Ter) variant is classified as pathogenic for Rett syndrome.
OMIM	RCV000012601	SCV000032836	pathogenic	Rett syndrome	1999-12-01	no assertion criteria provided	literature only
RettBASE	RCV000012601	SCV000188135	pathogenic	Rett syndrome	2013-06-12	no assertion criteria provided	curation
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000012601	SCV000257512	pathogenic	Rett syndrome	2007-06-25	no assertion criteria provided	clinical testing
GeneReviews	RCV000012601	SCV000998924	not provided	Rett syndrome		no assertion provided	literature only
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000012601	SCV001442991	pathogenic	Rett syndrome	2020-06-10	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000133143	SCV001809316	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000133143	SCV001927023	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000133143	SCV001953700	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000133143	SCV001972398	pathogenic	not provided		no assertion criteria provided	clinical testing