ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.953G>A (p.Arg318His)

dbSNP: rs61751443
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000133290 SCV000248006 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000256087 SCV000322254 pathogenic not provided 2021-03-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate that the p.R306H variant abolishes binding of MECP2 to DNA (Heckman et al., 2014); This variant is associated with the following publications: (PMID: 31780880, 11055898, 12655490, 11214906, 15057977, 16473305, 24970834, 10767337, 23921973)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000133290 SCV000537171 likely pathogenic Rett syndrome 2015-06-30 criteria provided, single submitter clinical testing
NeuroMeGen, Hospital Clinico Santiago de Compostela RCV000133290 SCV000693793 likely pathogenic Rett syndrome 2018-01-01 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV001778753 SCV002016294 pathogenic Neurodevelopmental disorder 2021-08-31 criteria provided, single submitter clinical testing
Invitae RCV001857484 SCV002120295 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2022-12-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg306 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10991688, 14649554, 16473305, 23770565, 24511209, 24970834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 143746). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 23921973). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MECP2 protein (p.Arg306His).
Centre for Population Genomics, CPG RCV000133290 SCV004232314 pathogenic Rett syndrome 2023-12-06 criteria provided, single submitter curation This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong).(PubMed: 11055898‚ 15057977‚ 16473305, 10767337, 23921973 ClinVar database Variation ID: 143746)
RettBASE RCV000133290 SCV000188299 pathogenic Rett syndrome 2011-02-15 no assertion criteria provided curation
Laboratory of Medical Genetics, University of Torino RCV000133290 SCV002583294 pathogenic Rett syndrome 2022-10-09 no assertion criteria provided research

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