ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.686C>T (p.Pro229Leu) (rs878853312)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000225456 SCV000282493 likely pathogenic Rett syndrome 2015-07-08 criteria provided, single submitter clinical testing This missense variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a pathogenic outcome. The variant of interest was absent from a large, broad control population (ExAC) and has not been found in affected individuals via publications and/or reputable databases/laboratories. However, an internal sample reports the variant occurring as a de novo event, in which the patient presented with encephalopathy, microcephaly and delayed milestones.
Invitae RCV001056633 SCV001221086 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2019-01-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 217 of the MECP2 protein (p.Pro217Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with autism spectrum disorder (ASD) (PMID: 27824329). This variant is also known as p.Pro229Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 236302). 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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