ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1187C>T (p.Pro396Leu) (rs193922676)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588422 SCV000698530 uncertain significance not specified 2016-04-01 criteria provided, single submitter clinical testing Variant Summary: The c.1151C>T (p.Pro384Leu) variant involves the alteration of a non-conserved nucleotide resulting in the substitution of a conserved Proline 384 residue by Leucine in the C-Terminal domain of MECP2. Although this amino acid change is considered to be a non-conserved substitution by BLOSUM50 and BLOSUM62, 3/5 in silico tools predict a neutral outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.001% (1/80,748 chromosomes). It has been reported in the literature in 2 patients with nonspecific mental retardation without strong evidence for causality (Zvereff et al, 2012). It was reportedly observed as an inherited variant (unaffected carrier mother) in one case and as a de-novo event in the other. In the absence of an unequivocal confirmation of maternity and paternity, this contradictory evidence cannot be weighted into its classification. The variant has been reported by the RettBase mutation database as a variant of unknown significance citing the report by Zvereff et al, 2012. Therefore, taken together, this variant has been re-classified as a VUS until additional evidence becomes available.
Invitae RCV000822137 SCV000962926 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 384 of the MECP2 protein (p.Pro384Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs193922676, ExAC 0.01%). This variant has been reported in the literature in individuals affected with mental retardation of unknown etiology, and at least one of them has been shown to be de novo (PMID: 22277191). ClinVar contains an entry for this variant (Variation ID: 36490). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
RettBASE RCV000170251 SCV000222583 uncertain significance Mental retardation, X-linked, syndromic 13 2012-09-27 no assertion criteria provided curation

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