ClinVar Miner

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

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Total submissions: 20
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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: 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
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
Division of Genomic Diagnostics,The 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

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