ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.784C>T (p.Arg262Cys) (rs141382970)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000192395 SCV000247992 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757451 SCV000885676 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing The MECP2 c.748C>T; p.Arg250Cys variant (rs141382970), to our knowledge, has not been reported in the medical literature but is reported as benign by one laboratory in ClinVar (Variation ID: 211466). This variant is observed in the general population at an overall frequency of 0.002% (5/178458 alleles, including 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 250 is highly conserved, and computational algorithms (PolyPhen2, SIFT) predict this variant to be deleterious. However, additional variants at this codon (p.Arg250Arg, p.Arg250His) are considered as polymorphisms that do not cause disease (see link for Rett database). Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to Rett database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic
Invitae RCV001043679 SCV001207437 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2019-02-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 250 of the MECP2 protein (p.Arg250Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs141382970, ExAC 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 211466). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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