ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.653G>C (p.Gly218Ala) (rs63485860)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457783 SCV000544615 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 206 of the MECP2 protein (p.Gly206Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two male individuals affected with intellectual disability and autism (PMID: 17427193, 26350204). In one family, it was found to segregate with disease in an X-linked recessive inheritance pattern. ClinVar contains an entry for this variant (Variation ID: 143638). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000486134 SCV000568377 uncertain significance not specified 2017-02-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MECP2 gene. The G206A variant has been reported previously in a male individual with autism and intellectual disability; however, the G206A variant was also identified in his unaffected mother and grandmother (Coutinho et al., 2007). The G206A variant was also reported in another male individual with intellectual disability, but additional information was not provided (Grozeva et al., 2015). The G206A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G206A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G206A as a variant of uncertain significance.
RettBASE RCV000133178 SCV000188176 uncertain significance Autism, susceptibility to, X-linked 3 2007-11-01 no assertion criteria provided curation

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