ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.838C>T (p.Arg280Trp) (rs61750239)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000133241 SCV000329416 uncertain significance not provided 2015-12-22 criteria provided, single submitter clinical testing The R268W variant has been reported previously as a de novo variant in a female with Rett syndrome; however, this individual also had a de novo nonsense variant in MECP2 ( Erlandson et al., 2001). Subsequently, the R268W variant has been identified in other females with Rett syndrome (Renieri et al., 2003; Buoni et al., 2008). Additionally, the R268W variant has been reported in a male with X-linked intellectual disability who inherited the variant from his unaffected mother (Renieri et al., 2003). The R268W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R268W 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 occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000707260 SCV000836350 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 268 of the MECP2 protein (p.Arg268Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs61750239, ExAC 0.002%). This variant has been observed in a family affected with X-linked mental retardation and individuals affected with Rett syndrome; however, one of these individuals also possessed a pathogenic p.Arg270* variant in MECP2 (PMID: 12750821, 11469283, 18842453). ClinVar contains an entry for this variant (Variation ID: 143700). 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.
Fulgent Genetics,Fulgent Genetics RCV000766083 SCV000897558 uncertain significance Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; Mental retardation, X-linked, syndromic 13; Rett syndrome; Autism, susceptibility to, X-linked 3 2018-10-31 criteria provided, single submitter clinical testing
RettBASE RCV000133241 SCV000188243 not provided not provided no assertion provided not provided

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