chrX-154030912-G-A

Position:

• chrX-154030912-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP1 PM2_Supporting PS4 PM1 PS3_Supporting PS2

This summary comes from the ClinGen Evidence Repository: The p.Arg306Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 individuals with Rett Syndrome (PMID 10577905, 11309679, 19189931; internal database, GeneDx) (PS2_very strong). This variant has been observed in at least 4 other individuals with Rett syndrome (PMID 24511209, 23238081, RettBase) (PS4). The p.Arg306Cys variant occurs in the well-characterized transcriptional repression domain (TRD) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). This variant is absent in gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, p.Arg306Cys variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM1, PM2_supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA212529/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:47 O:1
• Conservation: PhyloP100: 7.09

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 13 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.952C>T	p.Arg318Cys	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.916C>T	p.Arg306Cys	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.952C>T	p.Arg318Cys	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.916C>T	p.Arg306Cys	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:47 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:24 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Dec 13, 2022	This variant has been observed in individuals with Rett syndrome (RTT) and accounts for approximately 5% of all classical RTT cases [PMID: 10991688, 11214906, 14649554, 16473305, 24511209]. The variant occurs in the well-characterized transcriptional repression domain (TRD) the functional domain of MECP2 and experimental studies have shown that this variant affects MECP2 function [PMID: 23770565, 23770587, 24970834, 26647311]. This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 26, 2019	This variant is also referred to in the literature as c.916C>T (p.Arg306Cys) due to use of a different reference transcript (NM_004992.3). This variant is a recurrent alteration that has been reported in multiple individuals with Rett syndrome (PMID: 10577905, 26175308, 29655203, 30792901, 11738864, 19309283, 28394482). RettBASE, a MECP2 variation database, reports the p.Arg318Cys change accounts for approximately 5% of Rett syndrome diagnoses (http://mecp2.chw.edu.au/) (PMID: 28544139). This variant has also been reported as Pathogenic by multiple clinical diagnostic laboratories in the ClinVar database (Variation ID: 11824). Functional studies have shown this missense variant disrupts the ability of the MeCP2 protein to associate with co-repressors (PMID: 23770587, 23770565, 24970834), impairs DNA-binding in vivo and in vitro (PMID: 26647311, 11058114), and results in decreased microtubule stability (PMID: 23238081). The c.952C>T (p.Arg318Cys) variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.952C>T (p.Arg318Cys) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 09, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 26, 2014	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Feb 26, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Jun 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2017	Variant summary: The MECP2 c.916C>T (p.Arg306Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant decreased microtubule (MT) stability and down-regulated GRID1, a gene in the neurotransmitter pathway which is known to be down-regulated in the absence of functional MECP2 (Delepine_FEBSL_2013, Livide_EJHG_2014). In addition, a study using the Mecp2R306C mouse knock-out model recapitulated RTT-like features, such as compromised mobility and motor coordination and reduction in brain weight (Lyst_Natneurosci_2013). This variant is absent in 87936 control chromosomes including broad and large populations from ExAC. This variant was reported in numerous patients with RTT syndrome (Buyse_AJHG_2000, Obata_JMG_2000, Xiang_JMG_2000), including instances of de novo occurrence and it is considered the second most common RTT-causing missense mutation. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Dec 18, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 09, 2018	PS4, PM1, PM2, PM5, PP3, PP4, PP5 -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Arg306Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 individuals with Rett Syndrome (PMID 10577905, 11309679, 19189931; internal database, GeneDx) (PS2_very strong). This variant has been observed in at least 4 other individuals with Rett syndrome (PMID 24511209, 23238081, RettBase) (PS4). The p.Arg306Cys variant occurs in the well-characterized transcriptional repression domain (TRD) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). This variant is absent in gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, p.Arg306Cys variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PS4, PM1, PM2_supporting, PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R306C in MECP2 (NM_004992.4) has been previously reported in at least 4 individuals affected with Rett syndrome (Cortelazzo et al, 2014). Experimental studies have shown that this missense change abolishes the interaction between MECP2 and its co-repressor and impairs DNA-binding both in vitro and in vivo (Lyst et al, 2013; Heckman et al. 2014). The p.R306C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R306C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 306 of MECP2 is conserved in all mammalian species. The nucleotide c.916 in MECP2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 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 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). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 10, 2017	The MECP2 c.916C>T p.(Arg306Cys) missense variant has been reported in at least six studies in which it was found in a total of 39 individuals with Rett syndrome (Wan et al. 1999; Bourdon et al. 2001; Schanen et al. 2004; Li et al. 2007; Cortelazzo et al. 2014; Pidcock et al. 2016). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies in patient fibroblasts and cultured cortical neurons, demonstrated that the p.(Arg306Cys) variant protein resulted in almost total depolymerization of microtubules under the effect of cold-induced stress and also rendered the variant protein incapable of interacting with the nuclear receptor co-repressor complex as compared with wildtype protein (Delépine et al. 2013; Ebert et al. 2013). In addition, transgenic mice expressing the p.(Arg306Cys) variant protein recapitulated many of the phenotypes seen in affected individuals (Heckman et al. 2014; Brown et al. 2015). Based on the collective evidence, the c.916C>T p.(Arg306Cys) variant is classified as pathogenic for Rett syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 34837432). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.82). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011824). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 10577905, 11309679, 19189931). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 2323808, 24511209). Different missense changes at the same codon (p.Arg318His, p.Arg318Leu, p.Arg318Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143746, VCV000143747, VCV000521860). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MECP2: PS2, PS4, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2020	Published functional studies demonstrate that the R306C variant results in a damaging effect (Heckman et al., 2014; Kruusvee et al., 2017); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23770565, 11058114, 27428650, 26647311, 28212680, 32393352, 24511209, 10577905, 23770587, 23238081, 24970834, 24916645, 28348241, 19309283, 16077729, 26175308, 17276711, 11738864, 28394482, 29655203, 30792901, 31139143, 31095231, 25762136, 30577886, 12030010, 31130284, 33278787) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2023	In the published literature, this variant has been reported in multiple individuals affected with Rett syndrome (PMIDs: 10767337 (2000), 10814719 (2000), 23238081 (2013), and 24511209 (2014)), and has been reported in multiple symptomatic individuals as a de novo occurrence (PMIDs: 10577905 (1999), 11309679 (2001), 19189931 (2009), and 32393352 (2020)). In addition, functional studies report this variant is damaging to MECP2 protein function (PMIDs: 23770565 (2013), 23770587 (2013), 24970834 (2014), and 26647311 (2016)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 24, 2020	The MECP2 c.916C>T; p.Arg306Cys variant (rs28935468) is a recurrent alteration in individuals diagnosed with Rett syndrome, and often found as a de novo change (Cheadle 2000, Wan 1999, RettBase). Transgenic mice expressing the variant protein show developmental and behavioral phenotypes reminiscent of the clinical symptoms found in human patients (Brown 2016, Heckman 2014). Functional characterization of the MECP2 variant protein indicates disruption in its association with co-repressors, such as HDAC3 and the NCoR complex (Ebert 2013, Heckman 2014, Lyst 2013), and reduction in in-vivo DNA occupancy (Heckman 2014). This results in a failure of the MECP2 protein in mediating transcriptional repression at its targets (Ebert 2013, Lyst 2013). Another missense variant at this residue, p.Arg306His, has also been implicated in Rett syndrome (Cheadle 2000, RettBase). The p.Arg306Cys variant is listed as pathogenic in ClinVar (Variation ID: 11824), and is not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, the p.Arg306Cys variant is classified as pathogenic. References: RettBase: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Brown K et al. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum Mol Genet. 2016; 25(3):558-70. 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. Ebert D et al. Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature. 2013; 499(7458):341-5. Heckman L et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014 Jun 26; 3. Lyst M et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci. 2013; 16(7):898-902. Wan M et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999; 65(6):1520-9. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 12, 2023	This variant has been identified in multiple unrelated individuals with Rett syndrome and occurs de novo in multiple individuals. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In some published literature, this variant is referred to as c.990C>T and c.991C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23770565, 24970834, 23770587, 26647311) The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	May 15, 2018	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 306 of the MECP2 protein (p.Arg306Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (RTT) and accounts for approximately 5% of all classical RTT cases (PMID: 10991688, 11214906, 14649554, 16473305, 24511209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11824). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. Experimental studies have shown that this missense change affects MECP2 function (PMID: 23770565, 23770587, 24970834, 26647311). This variant disrupts the p.Arg306 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767337, 14649554, 16473305). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2018

The p.R306C pathogenic mutation (also known as c.916C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 916. The arginine at codon 306 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been observed in multiple individuals with Rett syndrome, both inherited and de novo occurrences (Wan M et al. Am. J. Hum. Genet., 1999 Dec;65:1520-9; Buyse IM et al. Am. J. Hum. Genet., 2000 Dec;67:1428-36; Yamashita Y et al. Brain Dev., 2001 Dec;23 Suppl 1:S157-60; Heilstedt HA et al. Am. J. Med. Genet., 2002 Aug;111:238-42; Schanen C et al. Am. J. Med. Genet. A, 2004 Apr;126A:129-40; Zhang Q et al. Am. J. Med. Genet. B Neuropsychiatr. Genet., 2017 Jun;174:451-457). Functional studies demonstrated that this alteration had decreased microtubule stability, abolished the interaction of MeCP2 with the NCoR/SMRT co-repressor, and down regulated GRID1 expression (Delépine C et al. FEBS Lett., 2013 Jan;587:245-53; Lyst MJ et al. Nat. Neurosci., 2013 Jul;16:898-902; Livide G et al. Eur. J. Hum. Genet., 2015 Feb;23:195-201). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 23, 2019

ACMG categories: PS2,PM2,PM5,PP3,PP4,PP5 -

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 exon4 p.Arg306Cys (c.916C>T): This variant is one of the most common pathogenic variants in MECP2 and has been reported in the literature in several individuals with Rett syndrome incliuding at least two de novo occurrences (Wan 1999 PMID: 10577905; Yamashita 2001 PMID: 11738864, Jian 2005 PMID: 16077729; Voutoufianakis 2007 PMID: 17276711; Fendri-Kriaa 2009; PMID: 19309283; Delepine 2013 PMID: 23238081; Cortelazzo 2014 PMID: 24511209; Livide 2015 PMID: 24970834; Pidcock 2016 PMID: 26175308; Zhang 2017 PMID: 28394482; Lindy 2018 29655203; Long 2019 31139143; Scocchia 2019 30792901). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 11824). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, both in vitro and in vivo functional studies have shown a deleterious effect for this variant (Delepine 2013 PMID: 23238081; Ebert 2013 PMID: 23770587; Lyst 2013 PMID: 23770656; Heckman 2014 PMID: 24970834; Livide 2015 PMID: 24970834; Brown 2016 PMID: 26647311). However, these studies may not accurately represent in vivo human biological function. In summary, this variant is classified as pathogenic based on the data above. -

Angelman syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Feb 20, 2006

- -

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

Pathogenic, criteria provided, single submitter

research

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Nov 01, 2021

A heterozygous missense variation in exon 3 of the MECP2 gene that results in the amino acid substitution of Cysteine for Arginine at codon 318 was detected. The observed variant c.952C>T (p.Arg318Cys) has not been reported in the 1000 genomes and gnomAD databases. The in-silico predictions of the variant are damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. This variant has previously been reported in patients affected with Rett syndrome. Segregation analysis showed the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as a pathogenic variant. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Jul 25, 2014

- -

MECP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

The MECP2 c.916C>T variant is predicted to result in the amino acid substitution p.Arg306Cys. This variant has been reported to be causative for Rett Syndrome (Wan et al. 1999. PubMed ID: 10577905; Aldosary et al. 2020. PubMed ID: 32105570; OMIM: #312750). The pathogenicity of this recurrent variant is supported by functional studies, as well as its presence in numerous affected individuals (Brown et al. 2016. PubMed ID: 26647311). Some studies indicate a favorable outcome with increased mobility and delayed regression resulting from this change, in comparison to other pathogenic MECP2 variants (Schanen et al. 2004. PubMed ID: 15057977; Pidcock et al. 2016. PubMed ID: 26175308). While more than 99% of pathogenic MECP2 variants occur de novo in the affected patient, at least one case of maternal transmission is reported for the p.Arg306Cys missense change (Wan et al. 1999. PubMed ID: 10577905). Variably skewed X-chromosome inactivation is predicted to underlie the range of phenotypic severity observed in individuals with this change (Wan et al. 1999. PubMed ID: 10577905). Of note, other missense variants affecting the same amino acid (p.Arg306His, p.Arg306Pro, p.Arg306Leu) have also been reported to be pathogenic for Rett syndrome (HGMD database; Cheadle et al. 2000. PubMed ID: 10767337). Taken together, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.55	D
MutationTaster	Benign	1.0	A;A
Sift4G	Benign	0.17	T
Vest4		0.44
MVP		0.98
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs28935468; hg19: chrX-153296363; COSMIC: COSV100318414; COSMIC: COSV100318414;