rs28934907

chrX-154032268-G-AchrX-154032268-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):c.352C>T(p.Arg118Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 4.35

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154032268-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-154032268-G-A is Pathogenic according to our data. Variant chrX-154032268-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032268-G-A is described in Lovd as [Pathogenic]. Variant chrX-154032268-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.352C>T	p.Arg118Trp	missense_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4	c.316C>T	p.Arg106Trp	missense_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.352C>T	p.Arg118Trp	missense_variant	2/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.316C>T	p.Arg106Trp	missense_variant	3/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 14, 2015	Microcephaly; Developmental delay; Seizures; Frequent hand to face movements -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Oct 26, 2022	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Dec 11, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Apr 24, 2020	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 27, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 01, 2018	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 16, 2012	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 20, 2019	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] -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 25, 2019

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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.316C>T (p.R106W) alteration is located in exon 3 (coding exon 2) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 316, causing the arginine (R) at amino acid position 106 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, 1999). 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, 2013). 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, 2000). 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, 2011) and selectivity for methylated DNA (Ballestar, 2000; Yusufzai, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

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. -

Autism, susceptibility to, X-linked 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3. -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;.;D;D;D;D;D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D;D;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.94		Loss of disorder (P = 0.0132);.;Loss of disorder (P = 0.0132);.;Loss of disorder (P = 0.0132);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28934907; hg19: chrX-153297719; COSMIC: COSV57654085; COSMIC: COSV57654085;