ClinVar Miner

Submissions for variant NM_004992.3(MECP2):c.397C>T (p.Arg133Cys) (rs28934904)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000081202 SCV000604146 pathogenic not provided 2017-09-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624907 SCV000740730 pathogenic Inborn genetic diseases 2014-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Ambry Genetics RCV000715531 SCV000846360 pathogenic History of neurodevelopmental disorder 2017-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Athena Diagnostics Inc RCV000081202 SCV000842734 pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000030666 SCV000257510 pathogenic Rett syndrome 2010-04-30 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000081202 SCV000804251 pathogenic not provided 2015-04-03 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081202 SCV000230257 pathogenic not provided 2016-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000081202 SCV000191035 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing R133C is a recurrent pathogenic variant that accounts for 4-7% of MECP2 pathogenic variants (Percy et al., 2007). This variant is often observed in females with the preserved speech variant of Rett syndrome, but has also been identified in females with classic and atypical Rett syndrome and in a male with hypotonia, developmental delay, and a movement disorder (RettBASE; Leonard et al., 2003; Neul et al., 2008; Bebbington et al., 2008; Masuyama et al., 2005). The R133C variant 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. This substitution alters a highly conserved position in the methyl-binding domain of the protein, and functional studies indicate that it impairs binding to methylated DNA (Yusufzai et al., 2000; Galvao et al., 2005).
GeneReviews RCV000030666 SCV000041140 pathologic Rett syndrome 2012-06-28 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000030666 SCV000193634 pathogenic Rett syndrome 2013-07-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030666 SCV000698538 pathogenic Rett syndrome 2016-09-29 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.397C>T (p.Arg133Cys) variant involves the alteration of a non-conserved nucleotide. Arg133 is located in the Methyl-CpG DNA binding domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This prediction was confirmed by one functional study showing MECP2 R133C resulted in the complete disruption of its ability to bind to methylated DNA (Yusufzai_2000). This variant has been reported as a de novo variant in numerous RTT patients, some of whom are reported to have a mild phenotype, and is one of the most common pathogenic variant in MECP2. This variant is absent in 87882 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000460141 SCV000544618 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 133 of the MECP2 protein (p.Arg133Cys). 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 (rs28934904, ExAC no frequency). This variant has been reported in 4-7% of individuals diagnosed with Rett syndrome (PMID: 23421866, 11738879, 26418480, 16473305, 22368975). It is typically associated with a later age of onset (>6 y/o) than other pathogenic variants in MECP2 (PMID: 23421866). ClinVar contains an entry for this variant (Variation ID: 11809). Experimental studies have shown that this missense variant reduces the affinity of MECP2 for methylated DNA, although the effect is less than for other MECP2 variants (PMID: 21831886, 10852707, 11058114, 12843318, 11738866). When expressed in mice, this variant is associated with intermediate survival between those expressing the wild-type protein and those with complete loss of the protein (PMID: 26647311). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000445570 SCV000537194 uncertain significance not specified 2015-07-16 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000030666 SCV000574734 pathogenic Rett syndrome 2016-10-03 no assertion criteria provided clinical testing
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000030666 SCV000223850 pathogenic Rett syndrome criteria provided, single submitter clinical testing
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000030666 SCV000494539 pathogenic Rett syndrome 2016-11-16 criteria provided, single submitter clinical testing
OMIM RCV000012578 SCV000032812 pathogenic Rett syndrome, zappella variant 2009-03-01 no assertion criteria provided literature only
OMIM RCV000030666 SCV000032813 pathogenic Rett syndrome 2009-03-01 no assertion criteria provided literature only
RettBASE RCV000169934 SCV000188081 pathogenic Angelman syndrome 2013-12-05 no assertion criteria provided curation
RettBASE RCV000170107 SCV000222428 pathogenic Mental retardation, X-linked, syndromic 13 2013-12-05 no assertion criteria provided curation
RettBASE RCV000030666 SCV000222429 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation

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