Submissions for variant NM_001110792.2(MECP2):c.952C>T (p.Arg318Cys) (rs28935468)

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081218	SCV000190987	pathogenic	not provided	2019-01-08	criteria provided, single submitter	clinical testing	The R306C variant in the MECP2 gene has been reported multiple times previously in association with Rett syndrome (Wan et al., 1999; RettBASE). Published functional studies demonstrate that the R306C variant results in a damaging effect (Heckman et al., 2014; Kruusvee et al., 2017). The R306C variant is not observed in large population cohorts (Lek et al., 2016). It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The presence of R306C is consistent with the diagnosis of Rett syndrome in this individual.
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics	RCV000012597	SCV000223842	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000081218	SCV000230267	pathogenic	not provided	2015-02-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory,University of Chicago	RCV000012597	SCV000248005	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV000224156	SCV000281744	pathogenic	Intellectual disability	2014-07-25	criteria provided, single submitter	clinical testing
Invitae	RCV000466020	SCV000544613	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2019-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 306 of the MECP2 protein (p.Arg306Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs28935468, ExAC no frequency). This variant is clearly defined as a Rett Syndrome (RTT) causative allele, accounting for over 200 RTT cases, or approximately 5% of all classical RTT cases (PMID: 14649554, 16473305, 24511209, 10991688, 11214906). ClinVar contains an entry for this variant (Variation ID: 11824). A different missense substitution at this codon (p.Arg306His) has also been observed in many RTT cases and has been determined to be pathogenic (PMID: 14649554, 16473305, 10767337). This suggests that the arginine residue is critical for MECP2 protein function and that other missense substitutions at this position may also be pathogenic. 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 (PMID: 23770565, 24970834, 23770587, 26647311). For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000081218	SCV000610040	pathogenic	not provided	2017-08-24	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000012597	SCV000698547	pathogenic	Rett syndrome	2017-05-11	criteria provided, single submitter	clinical testing	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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc	RCV000012597	SCV000781714	pathogenic	Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000081218	SCV000884099	pathogenic	not provided	2017-08-15	criteria provided, single submitter	clinical testing	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 not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, the 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.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000081218	SCV000920485	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000012597	SCV000928372	pathogenic	Rett syndrome	2018-07-09	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP3, PP4, PP5
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000012597	SCV000994545	pathogenic	Rett syndrome	2016-06-29	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000012597	SCV000999382	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000012597	SCV001426148	pathogenic	Rett syndrome	2018-06-27	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000012597	SCV001426580	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012597	SCV001440007	pathogenic	Rett syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000012597	SCV001445896	pathogenic	Rett syndrome	2019-07-26	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000012597	SCV000032832	pathogenic	Rett syndrome	2004-04-15	no assertion criteria provided	literature only
RettBASE	RCV000012597	SCV000188298	pathogenic	Rett syndrome	2014-02-26	no assertion criteria provided	curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000012597	SCV000257515	pathogenic	Rett syndrome	2014-06-26	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000202468	SCV000257516	pathogenic	Angelman syndrome	2006-02-20	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000081218	SCV000804261	pathogenic	not provided	2015-04-03	no assertion criteria provided	clinical testing
GeneReviews	RCV000012597	SCV000998927	pathogenic	Rett syndrome	2019-09-16	no assertion criteria provided	literature only