Submissions for variant NM_001110792.2(MECP2):c.352C>T (p.Arg118Trp)

dbSNP: rs28934907

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255874	SCV000229062	pathogenic	not provided	2015-03-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000012585	SCV000247964	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000255874	SCV000321873	pathogenic	not provided	2022-01-07	criteria provided, single submitter	clinical testing	Reported as a common pathogenic variant in association with Rett syndrome (Amir et al., 1999; Vilchis et al., 2014; RettBASE); Published functional studies suggest it significantly impairs the binding of methylated DNA (Ballestar et al., 2000); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24715477, 20098342, 23270700, 25789914, 19442733, 19217433, 25942534, 25900226, 20231667, 21831886, 11058114, 10852707, 25814391, 26017205, 26379794, 26418480, 26175308, 26278631, 25914188, 25779967, 25659951, 26108439, 26003587, 11738866, 12843318, 27929079, 16077729, 29631775, 30202406, 30564305, 29655203, 10508514, 31095231, 28920956, 32730690, 32369273, 31130284, 33258288, 32105570, 32472557)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000012585	SCV000537188	likely pathogenic	Rett syndrome	2015-07-14	criteria provided, single submitter	clinical testing	Microcephaly; Developmental delay; Seizures; Frequent hand to face movements
Invitae	RCV000552837	SCV000645663	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 106 of the MECP2 protein (p.Arg106Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Rett syndrome (PMID: 10508514, 18332345, 20098342, 23270700, 23421866). ClinVar contains an entry for this variant (Variation ID: 11814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318, 19442733, 21831886). For these reasons, this variant has been classified as Pathogenic.
Undiagnosed Diseases Network, NIH	RCV000012585	SCV000837693	pathogenic	Rett syndrome	2018-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311513	SCV000845974	pathogenic	Inborn genetic diseases	2019-03-26	criteria provided, single submitter	clinical testing	The p.R106W pathogenic mutation (also known as c.316C>T and 390C>T), located in coding exon 2 of the MECP2 gene, results from a C to T substitution at nucleotide position 316. The arginine at codon 106 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was observed in two maternally related half-sisters with Rett syndrome; of note, their mother did not carry the p.R106W mutation indicating the presence of gonadal mosaicism (Amir RE et al. Nat. Genet., 1999 Oct;23:185-8). In another study, this mutation was identified in seven unrelated girls from the Australian Rett Syndrome Database, who had been diagnosed clinically or genetically with Rett syndrome (Knight O et al. Brain Dev., 2013 Nov;35:912-20) This mutation is located in the methyl-cytosine-binding domain (MBD) of the MECP2 protein and impairs its ability to bind and organize pericentric heterochromatin (Agarwal N et al. Hum. Mol. Genet., 2011 Nov;20:4187-95) and selectivity for methylated DNA (Ballestar E et al. Biochemistry, 2000 Jun;39:7100-6; Yusufzai TM et al. Nucleic Acids Res., 2000 Nov;28:4172-9). Two different alterations at the same position, p.R106G and p.R106Q, have been seen in three individuals from the French Cohort of Rett syndrome patients (Bienvenu T et al. Hum. Mol. Genet., 2000 May;9:1377-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012585	SCV000919615	pathogenic	Rett syndrome	2018-03-06	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.316C>T (p.Arg106Trp) results in a non-conservative amino acid change located in the Methyl-CpG DNA binding of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A functional study, Yusufzai_2000, found the variant to abolish selectivity for methylated DNA binding. The variant was absent in 87536 control chromosomes (ExAC). The variant, c.316C>T, has been reported in the literature in multiple individuals affected with Rett Syndrome (Wan_1999, Cheadle_2000, Buyse_2000, Vacca_2001, and Zahorakova_2007). These data indicate that the variant is very likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000012585	SCV001149830	pathogenic	Rett syndrome	2019-10-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000318	SCV001157005	pathogenic	not specified	2019-03-25	criteria provided, single submitter	clinical testing	The MECP2 c.316C>T; p.Arg106Trp variant (rs28934907) has been reported in patients with Rett syndrome (Amir 1999, Psoni 2010). MECP2 protein containing the variant has a reduced binding affinity for methylated DNA (Ballestar 2000, Yusufzai 2000). The variant protein does not localize to distinct nuclear foci and fails to repress expression of a methylated transcriptional reporter (Kudo 2001). Hippocampal pyramidal neurons overexpressing the p.Arg106Trp variant protein have a lower density of mature dendritic spines after 48 hours of culture (Chapleau 2009). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11814). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 106 is highly conserved and lies within the methyl-CpG binding domain. Computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Amir RE et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185-8. Ballestar E et al. Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. Biochemistry. 2000 Jun 20;39(24):7100-6. Chapleau CA et al. Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations. Neurobiol Dis. 2009 Aug;35(2):219-33. Kudo S et al. Functional analyses of MeCP2 mutations associated with Rett syndrome using transient expression systems. Brain Dev. 2001 Dec;23 Suppl 1:S165-73. Psoni S et al. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res. 2010 May;67(5):551-6. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000 Nov 1;28(21):4172-9.
CeGaT Center for Human Genetics Tuebingen	RCV000255874	SCV001246094	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012585	SCV001251404	pathogenic	Rett syndrome	2019-10-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001195924	SCV001366348	pathogenic	Autism, susceptibility to, X-linked 3	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3.
Baylor Genetics	RCV000552837	SCV001523354	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2019-06-20	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 as disease-causing in multiple individuals with Rett syndrome [PMID: 16077729, 11058114, 10508514, 10852707, 20098342]
Illumina Laboratory Services, Illumina	RCV000012585	SCV002034761	pathogenic	Rett syndrome	2021-08-27	criteria provided, single submitter	clinical testing	The MECP2 c.352C>T (p.Arg118Trp) missense variant, also noted as p.Arg106Trp in the literature, is a common pathogenic variant and accounts for 2.79% of cases as per RettBASE (Christodoulou et al. 2003). Across a selection of the available literature, the p.Arg118Trp variant has been reported in a heterozygous state in at least 20 unrelated individuals affected with Rett syndrome, and the variant is typically associated with early onset disorder (Amir et al. 1999; Bebbington et al. 2008; Khalili et al. 2020). The variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggest the variant is rare. The Arg118 residue is located in the critical methyl-CpG binding domain and is shown to result in significantly reduced chromatin binding and decreased MECP2 accumulation at chromocenters compared to wildtype (Agarwal et al. 2011; Sheikh et al. 2016). Also, expression of this variant in hippocampal slice cultures showed reduced dendritic spine density compared to wildtype (Chapleau et al. 2009). This variant was identified in a de novo state. Based on the available evidence, the p.Arg118Trp variant is classified as pathogenic for Rett syndrome.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000012585	SCV002320828	pathogenic	Rett syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV002247329	SCV002517602	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV000012585	SCV002757813	pathogenic	Rett syndrome	2022-10-26	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000012585	SCV003804242	pathogenic	Rett syndrome	2023-01-23	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000012585	SCV003836679	likely pathogenic	Rett syndrome	2020-04-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224092	SCV003920189	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	2021-03-30	criteria provided, single submitter	clinical testing	MECP2 NM_004992.3 exon 3 p.Arg106Trp (c.316C>T): This variant has been reported in the literature in several individuals with Rett syndrome (male and female), with multiple cases reported to be de novo (Amir 1999 PMID:10508514, Glaze 2010 PMID:20231667, Psoni 2010 PMID:20098342, Knight 2013 PMID:23270700, Vilchis 2014 PMID:24715477, Pidcock 2016 PMID:26175308, Shioda 2018 PMID:29631775, RettBASE). Literature suggests that this variant accounts for up to 4.4% of pathogenic variants in MECP2 (Philippe 2006 PMID:16473305, Neul 2008 PMID:18337588, Vilchis 2014 PMID:24715477, RettBASE). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:11814). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies support that this variant impacts the protein through impaired binding affinity to methylated CpGs (Kudo 2001 PMID:11738866, Kudo 2003 PMID:12843318, Agarwal 2011 PMID:21831886). In addition, expression studies of this variant in cultured neurons from postportum brain samples showed significant reduction in dendritic spine dennsity compared to wildtype (Chapleau 2009 PMID:19442733). However, these studies may not accurately represent in vivo biological function. Additionally, this variant is located in the methyl binding domain, where the majority of pathogenic variants in MECP2 have been identified (Philippe 2006 PMID:16473305). In summary, this variant is classified as pathogenic based on the data above.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255874	SCV004220012	pathogenic	not provided	2012-04-16	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with Rett syndrome (PMIDs: 27929079 (2022), 32472557 (2020), 23270700 (2013), 20231667 (2010), 20098342 (2010), 10508514 (1999)). Experimental studies have indicated that the variant is damaging to MECP2 protein function (PMIDs: 27929079 (2016), 21831886 (2011), 19442733 (2009), 12843318 (2003), 11738866 (2001)). Based on the available information, this variant is classified as pathogenic.
Centre for Population Genomics, CPG	RCV000012585	SCV004232325	pathogenic	Rett syndrome	2023-12-11	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: This variant is absent from gnomAD (PM2_Supporting).Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). 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). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4).Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). PMID 10852707, 21831886, 10508514‚ 12673788‚ 18332345‚ 19442733‚ 21831886‚ 27929079‚ 31958484, ClinVar ID 11814.
OMIM	RCV000012585	SCV000032820	pathogenic	Rett syndrome	1999-10-01	no assertion criteria provided	literature only
RettBASE	RCV000012585	SCV000188054	pathogenic	Rett syndrome	2013-06-12	no assertion criteria provided	curation
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255874	SCV001929902	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255874	SCV001951157	pathogenic	not provided		no assertion criteria provided	clinical testing